SEVERE ASTHMA F O R U M 1 Severe Asthma - Basic and Clinical Views severe asthma forum E-ISSN 2738-4128 The Severe Asthma Forum book series intends to publish scientific monographs based on papers at the annual scientific conference Severe Asthma Forum - SAF, South-eastern meeting (Slovenia, Croatia, Serbia). The monographs will be published during the annual SAF conference, and they will bring the latest research and reviews in the field of diagnosis and treatment of asthma. Editor-in-Chief Assist. Prof. Sabina Škrgat MD, PhD University Medical Centre Ljubljana; Faculty of Medicine, University of Ljubljana; Ljubljana, Slovenia Editorial Board Prof. Mitja Košnik MD, PhD. University Clinic for Pulmonary and Al ergic Diseases Golnik; Faculty of Medicine, University of Ljubljana; Golnik, Ljubljana, Slovenia Prof. Sanja Popović-Grle MD, PhD University Hospital Centre Zagreb; Clinical Center for Pulmonary Diseases Jordanovac; University of Zagreb, School of Medicine; Zagreb, Croatia 1.0severeasthmaforum SEVERE ASTHMA F O R U M 1 Severe Asthma - Basic and Clinical Views Edited by Sabina Škrgat 2 0 2 2 moji mami to my mother Contents Sabina Škrgat 11 Prvi monografiji o hudi astmi na pot: predgovor Sabina Škrgat 13 Preface 1.0 Basic Principles in Severe Asthma Matija Rijavec and Peter Korošec 17 Endotypes and Immune Cel s in Severe Asthma 2.0 Long Journey of Corticosteroids Stylianos Vittorakis, Chrysa Kontogianni, Anastasia Levounets, Eleftherios Zervas and Mina Gaga 27 The Story of Corticosteroids in Asthma Sabina Škrgat, Peter Kopač, Natalija Edelbaher and Tomaž Kocjan 37 Chal enges of Systemic Glucocorticoids Taper in the Treatment of Severe Asthma 3.0 Multidisciplinary Approach in Severe Asthma Ramesh J Kurukulaaratchy and Chellan Eames 45 The Multi-Disciplinary Team Approach to Specialist Adult Difficult Asthma Care Irena Hočevar Boltežar 67 The Characteristics of Upper Respiratory Tract in the Patients with Asthma and the Patients with Episodic Laryngeal Obstruction 4.0 Diagnostic and Therapeutic Chalenges in Severe Asthma Matjaž Fležar 77 Lung Function Tests to be Used in Severe Asthma: Spirometry and Bronchodilator Test, Diffusion Capacity for CO, Induced Sputum, Body Plethysmography, Electronic PEF Measurements Marina Lampalo 83 Biomarkers in Severe Asthma 5.0 Asthma Phenotypes and Therapeutic Possibilities Peter Kopač and Mihaela Zidarn 93 Asthma and Aspirin Exacerbated Respiratory Disease Žarko Vrbica 105 T2-low Asthma Ljiljana Bulat Kardum 115 Eosinophilic and Al ergic Asthma Phenotype and Therapeutic Possibilities 6.0 A View Toward Controversies and Dilemmas Sanja Popović-Grle 127 Controversies and Dilemmas in Severe Asthma 141 Contributors 147 Index Prvi monografiji o hudi astmi na pot Predgovor Sabina Škrgat1,2 Astma je bolezen dihalnih poti, ki v svojih huotorinolaringologi. Taki bolniki nedvomno 1 University Medical Centre dih oblikah za bolnika predstavlja težko brepotrebujejo psihološko podporo, ustrezno res­ Ljubljana, Ljubljana, Slovenia me – zaradi potrebe po stalnem zdravljenju, piratorno fizioterapijo, nadzor nad prejeman2 Faculty of Medicine, University of Ljubljana, zavoljo stranskih učinkov zdravil in pridružejem zdravil, kliničnega farmacevta in dieteti­ Ljubljana, Slovenia nih bolezni ter poslabšanj. In zaradi ves čas ka ter izurjeno medicinsko sestro. Ko bolniki prisotne bojazni pred ponovnim »izbruhom«. tak pristop začutijo in se odzovejo z ureditvijo Bolniki zato nimajo polnega življenja, kot bi astme, nemalokrat rečejo, da so redkokje dega želeli, in so tako v resnici prikrajšani za ležni tako celovite obravnave. Moj odgovor marsikatero lepo doživetje. njim v oči je enostaven: Skozi vrata ambulan­ In zaradi astme se da še vedno umreti. te niso vstopila pljuča, temveč vi kot človek. Moji učitelji so zavoljo astme še videli umira­ Navadno sledi trenutek prijetne tišine, droben ti mlade ljudi na intenzivnih oddelkih. Imenasmešek in trenutek ganjenosti. Pri bolniku la sem to izjemno srečo, da sem kot zdravnica in meni kot terapevtu. Ker je obema uspelo – pričela delati v obdobju, ko je bilo zdravljenje bolniku in moji ekipi. z inhalacijskimi glukokortikoidi že vpeljano, Menim, da je za dober izzid stroke, po­ čeprav vedenje o skrivnostih vdihovalnikov in leg odlično organiziranega »mikrookolja«, v inhalacijskih zdravil še daleč ni bilo tako pokaterem bolnike obravnavamo, potreben še jasnjeno, kot je danes. To je bila prava revostrokovni konsenz na nacionalni ravni, kar lucija pri zdravljenju te bolezni. Sedaj, v dobi pa smo na številnih področjih pravzaprav dobioloških zdravil, kot terapevti pravzaprav žisegli. Jagoda na smetani je zagotovo sodelovimo zgodbo naslednje, morda druge revoluvanje na mednarodni ravni, tako v širši regiji cije v zdravljenju astme. In vendar vidimo, da kot na ravni Evropskega respiratornega zdruvsemu znanju navkljub še vedno ni mogoče ženja. Zato se je leta 2018 rodil »Severe asthpreprečiti občasnega ali rednega zdravljenja s ma forum – a joint Southeast European Mesistemskimi glukokortikoidi, vsaj pri nekaterih eting on Severe Asthma«. Ideja o ustanovitvi bolnikih ne. Ti nosijo posebno breme stranforuma je nastala v sodelovanju s profesorjem skih učinkov in zapletov zdravljenja. So ran­ Petrom Korošcem, izjemnim poznavalcem ljivi in imajo dokazano povečano umrljivost, bazičnih principov in zakonitosti astme. Soin prav na te bolnike sem posebej pozorna. delovanje z njim je bil privilegij in priložnost Tovrstne bolnike je namreč treba obravnavaza odlične »brainstorminge«. Mednarodti multidisciplinarno: zanje ni dovolj le zdravna sodelovanja ponujajo možnost preverjanik pulmolog, pač pa morajo sodelovati tudi nja lastnega znanja, stroke in organiziranosti. gastroenterologi, endokrinologi, diabetologi, So ogledalo kvalitete lastnega dela. Odličen https://doi.org/10.26493/978-961-293-157-5.11-12 primer tovrstnega dela je sodelovanje v inici-ativi SHARP (Severe Heterogeneous Asth- ma Research col aborration, Patient-cente- red) pri Evropskem respiratornem združenju. Zahvaljujem se profesorju Ratku Djukano- viću za povabilo v to strokovno skupino. In neznansko se veselim še nečesa – vedo- željnosti mladih, ki jih imam čast učiti, ki mi z lahkoto sledijo, ki opazijo kaj, česar jaz ne, in mi to spoštljivo povedo, ki imajo pogum za 12 nove in težke začetke. In imajo občutek za te bolnike, ki so vendarle malo posebni. Pričujoča monografija je nastajala dol- go in premišljeno. Ideja je bila pravzaprav iz- rečena v družbi mojih prijateljev, profesorjev Zvonke Zupanič Slavec in Jonatana Vinkler- sw ja. V tem varnem »duhu« je plula naprej. Uži- ie v vala sem na poti njenega nastajanja zaradi la odzivanja in truda avtorjev. In zaradi njiho- icin vega občutka odgovornosti, ki ga je bilo čutiti l c ves čas več kot enoletnega dela. Monografijo, dn a ki je pred bralcem, tvori šest temeljnih pogla- sic vij. Osnovnim bazičnim principom patoge- a - b neze astme sledi poglavje o dolgi poti gluko- am kortikoidov pri zdravljenju astme, ki povzema h tako zgodovinski vidik in razvoj zdravljenja, st ae kot tudi osvetljuje problem stranskih učinkov re in breme oralnih glukokortikoidov. Zgodbo v v monografiji nato razvijamo z multidiscipli- 1: se narnim pristopom k zdravljenju, z diagnostič- mur nimi in terapevtskimi izzivi in fenotipi astme fo ter zaključimo s protislovji in dilemami, ki še amh obstajajo. Na tem mestu se posebej zahvalju- st jem profesorjema Sanji Popović-Grle in Mit- aer ji Košniku za odlično opravljeno vlogo. Žele- ev li smo zapisati strokovne tekste in jih pustiti v se branje kolegom zdravnikom in njihovim ti- mom, ki so v umetnosti astme že izurjeni, in tistim, ki bodo to šele postali. Če jim bo pri- čujoča monografija pri tem pomagala, je na- men dosežen. Ker obravnava bolnika s hudo astmo ni zgolj zdravljenje, je kanček umetnosti. Srečno. Preface Sabina Škrgat1,2 Asthma is an airway disease which, in its se- otorhinolaryngologist. Undoubtedly impor- 1 University Medical Centre vere forms, represents a serious burden for pa- tant and valuable partners in the team are Ljubljana, Ljubljana, Slovenia tients – due to continuous treatment and its also an experienced severe asthma nurse, psy-2 Faculty of Medicine, University of Ljubljana, side effects, comorbidities and asthma exacer- chologist, nutritionist, good respiratory phys- Ljubljana, Slovenia bations. Many of them have a continuous fear iotherapist and clinical pharmacist to provide of new exacerbations that might happen in fu-support. When patients experience this ap- ture and a lower quality of life as they are de- proach which enables them to control their prived of many a fine experience. asthma, they often say that they are not of- It is still possible to die because of asth- ten treated so comprehensively. My answer to ma. My teachers still saw young people die in them is simple and clear: “You are not mere-intensive care units due to severe asthma ex- ly the lungs that come through the door of our acerbations. I was exceptional y fortunate to outpatient clinic, but you are a whole person.” become a medical doctor at a time when the Many times this is fol owed by silence, a tim-basic therapy with inhaled glucocorticoids id smile and a moment of happiness – both had already been introduced, although the the patient’s and mine in my role of a thera-knowledge about the mysteries of inhalers and pist. Because we have succeeded, both the pa-inhalation techniques was far from being as tient and my team. clear as it is today. This was a proper revolu- My belief is that in addition to a perfect- tion in asthma treatment. Now, in the area of ly organized “micro-environment” in which biologics, we – the therapists – are probably in the patients are treated, a good professional the middle of the second revolution in asthma outcome also requires professional consensus treatment. But despite all these steps forward, at a national level, which has actual y been we can see that it is still not possible to pre-achieved in numerous fields. The cherry on vent, at least in some patients, a need for sys- the cake is surely our participation at the in- temic glucocorticoids in maintenance or spo- ternational level, both regional y and at the radic treatment. These patients might have level of the European Respiratory Society. a huge systemic glucocorticoid burden, they The idea to launch the Severe asthma forum have greater mortality and they need a special was born in cooperation with prof. Peter Ko-care. They are vulnerable, and they have my rošec who is an exceptional authority on ba-special attention since they need a multidis- sic asthma principles. Our cooperation with ciplinary approach: it means that they need him was a great privilege and the opportuni-not only a pulmonologist, but also gastroen- ty for excel ent brainstorming debates. Inter- terologist, endocrinologist, diabetologist and national cooperation provides opportunities https://doi.org/10.26493/978-961-293-157-5.13-14 for verification of our own knowledge, pro-Because treating a patient with severe fession and organization. It also mirrors the asthma is not just a therapy, it is also a bit of quality of our work. The SHARP initiative art. (Severe Heterogeneous Asthma Research Good luck! col aboration, Patient-centred) is an excel- lent example of this kind of work and I thank prof. Ratko Djukanović for invitation to this working group. And I am real y happy about some- thing else – the inquisitiveness of young peo- 14 ple that I have the honour to teach, who easi- ly fol ow, who notice something that I do not and respectful y let me know, and who have the courage for new and difficult beginnings. They feel with these patients who are some- how specific nonetheless. sw The present monograph has taken a ie v long time and a lot of thought to emerge. As la a matter of fact, the idea was first expressed ic in the company of my friends, prof. Zvonka inl c Zupanič Slavec and prof. Jonatan Vinkler. dn In this safe “spirit” it sailed on. I enjoyed a the course of its creation because of the re- sica sponses and efforts of the authors. And be- - ba cause of their sense of responsibility which mh could be felt throughout the more than one st a year of our work. This monograph consists er of six basic chapters. The basic principles of ev asthma pathogenesis are fol owed by a chap- 1: se ter on the long path of glucocorticoids in the mu treatment of asthma, which summarizes r both the historical aspect and development of foa treatment, as well as highlights the problem mh of side effects and the burden of oral gluco- st a corticoids. The story in the monograph then ere evolves with multidisciplinary approaches vse to the treatment, diagnostic and therapeu- tic chal enges and asthma phenotypes, and ends with stil existing contradictions and di- lemmas. I would especial y like to thank prof. Sanja Popović-Grle and prof. Mitja Košnik for their excel ent performance. We wished to write professional texts and let them be read by fel ow doctors and their teams who are al- ready trained in the art of asthma, and those who are yet to become so. If the present mon- ograph helps them in this, our purpose will be achieved. 1 Basic Principles in Severe Asthma Endotypes and Immune Cel s in Severe Asthma 1.1 Matija Rijavec1,2 and Peter Korošec1,3 1 University Clinic Abstract of Respiratory and Allergic Severe asthma accounts for a small proportion of asthma prevalence, however due to high re-Diseases Golnik, Slovenia quirements for treatment the majority of medical resources are directed toward those patients. 2 Biotechnical Faculty, Asthma is a highly heterogeneous disease, an umbrel a diagnosis for several diseases with var-University of Ljubljana, Ljubljana, Slovenia iable clinical presentations (phenotypes) and distinct mechanistic pathways (endotypes), and its pathophysiology is not yet completely understood. Thus despite similar clinical symptoms, 3 Faculty of Pharmacy, University of Ljubljana, asthma patients may respond very differently to the same therapeutic interventions. Asthma Ljubljana, Slovenia endotypes are currently regarded as type 2 high (T2-high) or non-T2. Th2 cel s, innate lymphoid cel s, eosinophils and mast cel s are the most important cell types associated with T2-high asthma, on the other hand neutrophils, Th1 and Th17 cel s are involved in non-T2 asthma. As more and more innate and adaptive immune cel types and mediators are identified as important drivers of asthma, asthma endotype definitions are stil fluid and continue to evolve. The identification and understanding of the molecular mechanisms of different asthma endotypes, that reflect a highly variable response to different treatments, will lead to more precise asthma management and better outcomes in patients. Keywords: severe asthma, endotype, phenotype, immune cel s, eosinophils, innate lymphoid cel s, mast cel s, basophils Introduction immunologic, and environmental factors that Severe asthma remains a worldwide problem. contribute to asthma risk, pathogenesis and Even though accounts for a small proportion underlying asthma endotypes have been de-of asthma prevalence affecting a minority of termined6,17,18. The identification and under-patients, it is characterized by high require- standing of the molecular mechanisms of dif- ments for treatment to partly or completely ferent asthma endotypes, that reflect a highly control severe and frequent symptoms, and variable response to different treatments (re-as a result, the majority of medical resourc- lated to certain clinical phenotypes), will lead es are directed toward those patients9,12,14-19. to more precise asthma management and Asthma is a highly heterogeneous disease better outcomes in patients6,13,17,18. and its pathophysiology is not yet complete- ly understood. Large asthma clinical hetero- Phenotypes and Endotypes in Severe geneity and high variability in treatment re- Asthma sponse extend beyond clinical phenotypes, Asthma heterogeneity reflects different un-and over the last two decades several genetic, derlying mechanisms. Asthma is nowadays https://doi.org/10.26493/978-961-293-157-5.17-24 management due to inherent biological ther- apeutic implications8,11,13. As more and more innate and adaptive immune cell types and mediators are identi- fied as important drivers of asthma, it is ev- ident that asthma endotype definitions are still fluid and continue to evolve13. Asthma endotypes are currently regarded as type 2 high (T2-high) or non-T2. Why not adap- tive Th2 high or non Th2 endotypes? Recent- 18 ly, a substantial body of evidence has proven that group 2 innate lymphoid cel s (ILC2s) also play an equal y critical role in type 2 im- mune responses. ILC2s are particularly high in airway tissues and produce large quanti- s ties of IL-5 and IL-13 in response to alarm- wie ins, mediators released from epithelial cel s in vl Figure 1. Association between phenotypes response to stressors, such as infection or in- aic and endotypes in severe asthma. Severe asthma flammation. In asthma, ILC2s appear to play inl is considered an umbrel a diagnosis linked to spe-c an early and key role in augmenting the type d cific pathogenesis. There are many possible pheno-n 2 responses in the airway. Together, Th2 cel s a types (clinical presentations) and each phenotype (adaptive) and ILC2s (innate) are the prima-sic is associated with distinct endotypes (distinct mecha anistic pathways) that can be targeted with person-ry regulators of T2 immunity and express the - ba alized therapy. Adapted from Fitzpatrick & Bacha-master transcription factor GATA3. There- mh rier, 2019. fore, Th2-high inflammation is label ed as st a type 2 (or T2) inflammation, to account for ere considered an umbrel a diagnosis for sever- the role of both adaptive Th2 and innate v al diseases with variable clinical presenta- ILC2 immune cel s5,7,11,13. 1: se In T2-high asthma, there is an interplay m tions (phenotypes) and distinct mechanis- ur tic pathways (endotypes) (Figure 1)13. Hence, of several individual pathways and cel s (Fig-fo ure 2). Alarmins, like TSLP, IL-25 and IL-33 a phenotypes are defined as „observable char- m are airway epithelial-derived mediators that h acteristics that result from a combination of st respond to infection and inflammation. IL-33 a hereditary and environmental influences“ er and IL-25 mainly activate ILC2s, while TSLP e such as clinical presentation, symptoms, trig- v also primes dendritic cel s (DCs), and conse- se gers and allergic features. However, the strat- quently B- and T-cel s. Recent data suggest egy was recently evolving to associate molec- that IL-33 appears to be the most potential ular mechanisms to phenotype and asthma amplifier of T2-high asthma1. Alarmins serve endotypes describe these distinct pathobio-to activate ILC2s. ILC2s are lineage-nega- logical pathways at a cel ular and molecular tive cel s that lack lymphocyte surface mark-level. Thus despite similar clinical symptoms, ers and antigen-specific receptors and pro-asthma patients may respond very differently duce 10-fold more IL-5 and IL-13 compared to the same therapeutic interventions. Why? with activated Th2 cel s. On the other hand, Because of distinct endotypes (mechanistic adaptive pathways involve al ergens-activated pathways). Furthermore, the precise defini-DCs that induce the expression of a Th2 path- tion of these endotypes is central to asthma ogenic signature in the presence of the master 19 amh st aerev Figure 2. Mechanisms of T2-high asthma. Eos, Eosinophils; GATA3, GATA3 transcription factor; MC, se mast cel s/basophils; SM, smooth muscle cel s; Th, T helper cel s. Adapted from Corren, 2019. inslle ce transcription factor GATA-3. Th2 cel s then fibroblasts. Very important from the thera-nu stimulate type 2 immunity through the se- peutic target, IL-5 plays a pivotal role for eo- m cretion of the cytokines IL-4, IL-5, and IL- im sinophils (differentiation and survival)5,7,11,13. dn 13. Importantly, both IL-4, as well as IL-13, While the role of mast cel s degranula- as utilize a common IL-4Rα chain. IL-5 plays pe tion in acute asthma exacerbation is well es- yt a pivotal role in promoting the differentiation tablished especial y in al ergen driven ex-od and maturation of eosinophils, as wel as their n acerbations, the functional significance of e subsequent mobilization and survival. Fur- thermore, T2 cytokines have effects on gob- basophils in asthma has recently gained at- let cel s (mucus), fibrogenic functions (remod- tention. Notably, it was shown that basophils have been recruited in the bronchial wal s of el ing), and hyperresponsiveness5,7,11. Eosinophils are the hal mark cell type as- T2-high asthma. Moreover, it is well known sociated with T2-high asthma and have plei- that in humans basophils are one of the major otropic effects on various inflammatory cel s. producers of IL-4 and can thus directly mod-Upon stimulation, they release a myriad of ulate T2 inflammation. IgEs, which on mast inflammatory mediators chemokines, and cy-cel s and basophils through FcεRI mediate tokines including IL-5, IL-13, eotaxin, cystei- immediate hypersensitivity response to al er- nyl leukotriene (CysLT), major basic protein gens, can also facilitate and modulate antigen (MBP), eosinophil peroxidase (EPX), and eo-presentation by dendritic cel s and response sinophil cationic protein (ECP). CysTL is a to viruses. Additional y, recent data strongly potent bronchoconstrictor that acts in syner-suggest that an altered functional subtype of gy with IL-33 and further drives the self-am- mast cel s may have greater potential to gen- plifying loop that characterizes T2 inflam- erate PGD2. These PGD2-high mast cel s mation. Eosinophils also activate bronchial strongly predict poorly control ed T2-high 20 swie vlaic Figure 3. Mechanisms of non-T2 (T2-low) asthma. PMN, polymorphonuclear cel ; Th, T helper cel s. inl Adapted from Corren, 2019. cdn a asthma and are associated with more severe be inefficacious in these patients but may ex-sica disease (targeting CRTH2)5,7,11,13. acerbate the underlying inflammatory state - ba Non-T2 (T2-low) asthma is typified by through increased Th1 recruitment. High mh the absence of markers of T2-high disease. Th17 is marked by increased levels of IL-st a It is general y characterized by neutrophilic 17A, IL-17F, and IL-22 and IL-17F frequent ere (sputum neutrophils > 40–60%) or pauci- exacerbator endotype has been recently de- v granulocytic (i.e., normal sputum levels of scribed. Additional y, IL-6 has been recent-1: se both eosinophils and neutrophils) inflam- ly shown to cause systemic inflammation in a mur mation and a lack of response to corticos- subgroup of asthma patients with obesity and fo teroid therapy. Mechanisms underlying re- severe disease5,7,11,13. amh cruitment and maintenance of neutrophilic Currently, due to the availability of ther- st airway inflammation are yet unknown: the a apies targeted toward T2 cytokines, the ap- er role of the neutrophil itself is in debate. It has proach is to divide patients into those with ev been linked with the Th1 and/or Th17 cel s, T2-high and non-T2 (T2-low) asthma. se cytokines IL-17A, IL-17F, IL-22, IFN-γ, There continue to be critical unanswered TNF-α, IL-1β, IL-6, IL-8, and NLRP3 in-questions in severe asthma, mainly since our flammasome. It is also possible that some understanding of the inflammatory microen-non-T2 endotype are label ed as such only vironment in the lower airway and the con-because steroid therapy has masked the T2 tributions to the clinical expression of the signature (Figure 3)5,7,11,13. disease remains incomplete. Recent advanc- High Th1 is marked by the produc- es have provided further insight into molecu- tion of IFN-γ. Elevated IFN-γ was associ- lar mechanisms underlying steroid resistance, ated with high airway resistance, increased tissue remodelling, and disease exacerba-inflammatory infiltrates, and corticosteroid tions. The accurate translation of discoveries refractoriness. Corticosteroids may not only from these studies will require careful clinical characterization for the design of clinical tri- Innate Lymphoid Cells als and the development of new biologic ther- It is 12 years since the discovery of innate apies13. lymphoid cel s (ILCs)3. ILCs reside at bar- rier surfaces and regulate tissue homeosta- Immune Cells Drivers of Severe Asthma sis, immunity, and disease pathology. Cy- tokine-producing ILCs are divided into 3 Eosinophils groups, group 1 ILCs (ILC1s), group 2 ILCs Eosinophils have been widely considered to (ILC2s), and group 3 ILC3 (ILC3s), based play a prominent role in the pathogenesis of on their functional similarities to the main T2-high asthma and have pleiotropic effects groups of adaptive T helper (Th) cel s. ILC1s on various inflammatory cel s. Eosinophils are the innate equivalents of Th1 cel s and are implicated in several pathologic processes produce IFN-γ and TNF-α. ILC2s are the including epithelial damage, smooth muscle innate equivalents of adaptive Th2 cel s. On hypertrophy, neural plasticity, and impaired activation, they secrete type 2 cytokines in-tissue repair processes, promoting chronic cluding Il-4, IL-5 IL-9, and IL-13. They also 21 airway remodel ing and airflow obstruction. produce amphiregulin and IL-10. ILC3s are am Additional y, blood eosinophilia or an in- the innate equivalents of Th17 cel s. ILC3s h produce IL-17A/F and IL-22. st creased number of eosinophils in blood posi- ae tively correlated with increased disease sever- Recent data suggest that ILC2s might be re highly important in the pathogenesis of asth- v ity, worse disease control, and increased risk se of severe exacerbations. Eosinophilia results ma3. They respond rapidly to al ergen expo-ins from the stimulation of eosinophil produc- sure and environmental insults in mucosal lle tion from hematopoietic stem and progeni- organs, producing type 2 cytokines. It was ce shown that epithelium-derived cytokines IL- n tor cel s. The differentiation and survival of um eosinophils involve signal ing by IL-3, IL-5, 25, IL-33, and TSLP activate ILC2s result-im ing in eosinophilia, mucus hypersecretion, d and GM-CSF. Of these three cytokines, IL-5 n plays the most critical role, which is very im- and remodel ing of mucosal tissues. Increased as ILC2s have been reported in blood and BAL pe portant from a therapeutic view as a target. yt from patients with asthma as compared with o Tissue recruitment involves the activation of d healthy controls, and in blood and induced n their surface integrins in response to chem- e otactic factors including eotaxins and lipid sputum of patients with severe asthma in mediators. Once infiltrated, eosinophils may comparison with mild asthma. The number undergo activation. Upon stimulation and of circulating ILC2s correlated with eosino-activation, eosinophils release a myriad of phil counts in induced sputum and blood and signature mediators, chemokines, cytokines ILC2s frequencies were also increased in in-and growth factors including ECP, eosino- duced sputum of pediatric patients with se- vere asthma. Regarding the activation sta- phil-derived neurotoxin (EDN), EPX, MBP, tus of circulating ILC2s subjects with severe IL-5, IL-13, eotaxin, CysLT, and transform-asthma or uncontrol ed asthma had increased ing growth factor (TGF)-β1. Among these numbers of IL-5+ and IL-13+ ILC2s cel s. factors are several key actors of T2 immuni- Besides IL-25, IL-33, and TSLP cytokines ty and tissue remodel ing, most notably IL-4, eicosanoids likely play a critical role in pro-IL-13, and TGF-β1. Furthermore, CysTL is a moting migration and activation of ILC2s in potent bronchoconstrictor that acts in syner-asthma. Involvement of ILC2s was also ob- gy with IL-33 and further drives the self-am- served with viral triggers of asthma besides plifying loop that characterizes T2 inflam- al ergens, both in respiratory syncytial virus mation13,20. infection in mice and experimental rhinovirus infection in humans. Recently, studies have secretory products, serine proteases tryptase, been initiated to elucidate the effects of asth-chymase, and carboxy-peptidase, can interact ma treatment on ILC2s and to modulate with various cell types and direct their activ-ILC2s as a potential treatment option for ity via protease-activated receptors and other asthma as ILC2s may contribute to steroid re-processes4. On the other hand, the function- sistance and persistent airway pathology. Fur- al significance of basophils in the pathogene- ther studies using anti-IL5 and IL4/13 bio- sis of asthma has gained attention only recent- logics likely will provide useful information ly. Similarly, as mast cel s, IgEs on basophils to dissect the roles of ILC2s and innate type through FcεRI mediate immediate hypersen-2 responses in the pathophysiology of asth- sitivity in response to al ergens, and can also 22 ma and, at the same time, wil help to develop facilitate and modulate antigen presentation novel treatment strategies for asthma by tar-by dendritic cells and response to viruses. Ba- geting ILC2s3. Further studies are also need- sophils are recruited in the bronchial walls of ed to elucidate the possible role of ILC1s and T2-high asthma. Basophils and eosinophils ILC3 responses in asthma. appear to be closely linked by directly or in- s directly influencing each other since they are wie Mast Cells and Basophils responsive to similar cytokines and chemok- vla The evidence that mast cel s degranula- ines10. Basophils activation leads to the release ic tion fol owed by the release of various medi- of immunoregulatory and effector mediators, inl c ators represent important contributors to the including IL-4 and IL-13, histamine, and dn pathogenesis of asthma is strong. Mast cel s LTC4. Moreover, it is well known that human a normal y reside in the lungs, and on activation basophils are one of the major producers of sica by IgE-dependent or other mechanisms, they IL-4 and can thus directly modulate T2 in- - ba can release a diverse spectrum of mediators flammation4,5,7,11,13. mh that in turn can rapidly induce local effects The pathophysiologic mechanisms driv- st a on blood vessels, nerves, and mucous glands, ing corticosteroid insensitivity and severe ere as well as on epithelial cel s, airway smooth asthma are still unclear and evidence sug-v muscle cel s, and immune cel s4. Among the gests that mast cel s and basophils might have 1: se mast cel s secreted mediators histamine, pros- a role in it. In vitro studies using various cell mur taglandin (PG) D2, and leukotriene (LT) C4 types showed that different mediators pro-fo are capable of inducing bronchoconstriction, duced by activated mast cel s and/or baso-am mucus secretion, and mucosal oedema, al phils, including cytokines, can interfere with h st asthma characteristics. Additional y, recent the therapeutic action of corticosteroids. Meaer data strongly suggest that an altered function- diators released by activated mast cel s have ev al subtype of mast cel s may have greater po- been shown to decrease the anti-inflammato- se tential to generate PGD2. These PGD2-high ry action of glucocorticoids in airway smooth mast cel s strongly predict poorly control ed muscle cel s by reducing the expression of an-T2-high asthma and are associated with ti-inflammatory genes. Mast cel s infiltra-more severe disease (targeting CRTH2)5,7,11,13. tion and interactions have been described in Besides, mast cel s also synthesize and se-different compartments of the airways, in- crete a large number of proinflammatory cy- cluding epithelium, submucosa and airway tokines (including IL-4, IL-5, and IL-13), smooth muscle. Therefore, mast cel s‘ airway which regulate both IgE synthesis and the infiltration, release of mediators and interac-development of eosinophilic inflammation, tion with lung structural cel s may contrib-and several profibrogenic cytokines, includ- ute to the corticosteroid insensitivity in severe ing TGF-β. Furthermore, major mast cel s‘ asthma2,4. Conclusion to better asthma management options For many years, severe asthma has been rec- for al ? J Al ergy Clin Immunol. 2019 ognized as a subset of asthma that is poor- Jul;144(1):25-33. ly managed by standard therapy for asthma. 7. Custovic A, Siddiqui S, Saglani S. Con-Nowadays asthma is considered an umbrel- sidering biomarkers in asthma disease la diagnosis for several diseases with variable severity. J Al ergy Clin Immunol. 2022 clinical presentations (phenotypes) and dis- Feb;149(2):480-7. tinct mechanistic pathways (endotype). The 8. Fitzpatrick AM, Bacharier LB. One step precise definition of these endotypes and de-forward, 2 steps back: The enigma of ciphering the complex interplay of several in- preschool wheeze. J Al ergy Clin Immu- dividual pathways and immune cel s is cen- nol. 2019 May;143(5):1734-5. tral to asthma management due to inherent 9. Global Initiative for Asthma. Global biological therapeutic implications. The iden-Strategy for Asthma Management and tification and understanding of the molecular Prevention [Internet]. [updated 2020; mechanisms of different asthma endotypes, 23 accessed 2022 Feb 2]. Available from: that reflect a highly variable response to dif- https://www.ginasthma.org. a ferent treatments, will lead to more precise m 10. Iype J, Fux M. Basophils orchestrat- h asthma management and better outcomes in st ing eosinophils’ chemotaxis and func- a patients. er tion in al ergic inflammation. Cel s. ev 2021 Apr 14;10(4):895. doi: 10.3390/ se References cel s10040895. ins 1. Altman MC, Lai Y, Nolin JD, et al. Air- l 11. Kaur R, Chupp G. Phenotypes and en- le way epithelium–shifted mast cell infil- dotypes of adult asthma: Moving to- ce tration regulates asthmatic inflamma- n ward precision medicine. J Al ergy Clin um tion via IL-33 signaling. J Clin Invest. Immunol. 2019 Jul;144(1):1-12. im 2019 Nov 1;129(11):4979-91. d 12. King GG, James A, Harkness L, et n 2. Alzahrani A, Hakeem J, Biddle M, et al. a al. Pathophysiology of severe asthma: s Human Lung Mast Cel s Impair Cor- pe We’ve only just started. Respirology. yt ticosteroid Responsiveness in Human o 2018 Mar;23(3):262-71. d Airway Smooth Muscle Cel s. Front ne Al ergy. 2021 Dec 2;2:785100. doi: 13. Kuruvil a ME, Lee FEH, Lee GB. 10.3389/falgy.2021.785100. (2019). Understanding Asthma Pheno- 3. Bartemes KR, Kita H. Roles of in- types, Endotypes, and Mechanisms of nate lymphoid cel s (ILCs) in al ergic Disease. Clin Rev Al ergy Immunol. diseases: The 10-year anniversary for 2019 Apr;56(2):219-33. ILC2s. J Al ergy Clin Immunol. 2021 14. Lee Y, Quoc QL, Park HS. Biomarkers May;147(5):1531-47. for severe Asthma: Lessons from longi- 4. Bradding P, Wal s AF, Holgate ST. The tudinal cohort studies. Al ergy Asthma role of the mast cell in the pathophysiol- Immunol Res. 2021 May;13(3):375-89. ogy of asthma. J Al ergy Clin Immunol. 15. Peters MC, Kerr S, Dunican EM, et 2006 Jun;117(6):1277-84. al. Refractory airway type 2 inflam- 5. Corren J. New Targeted Thera- mation in a large subgroup of asthmat- pies for Uncontrol ed Asthma. J Al- ic patients treated with inhaled corticos- lergy Clin Immunol Pract. May-Jun teroids. J Al ergy Clin Immunol. 2019 2019;7(5):1394-403. Jan;143(1):104-13. 6. Custovic A, Henderson J, Simpson A. 16. Peters SP, Busse WW. New and Antic- Does understanding endotypes translate ipated Therapies for Severe Asthma. J Al ergy Clin Immunol Pract. 2017 Sep-Oct;5(5S):S15-S24. 17. Rijavec M, Krumpestar T, Škrgat S, et al. T2-high asthma, classified by spu- tum mrna expression of L4, IL5, and IL13, is characterized by eosinophil- ia and severe phenotype. Life. 2021 Jan 27;11(2):92. doi: 10.3390/life11020092. 18. Schoettler N, Strek ME. Recent Ad- vances in Severe Asthma: From Pheno- 24 types to Personalized Medicine. Chest. 2020 Mar;157(3):516-528. 19. Šokić Kopač M, Rijavec M, Korošec P, et al. Heterogeneous Response of Airway Eosinophilia to Anti-IL-5 Biologics in Severe Asthma Patients. sw J Pers Med. 2022 Jan 7;12(1):70. doi: ie v 10.3390/jpm12010070. la 20. Van Hulst G, Bureau F, Desmet CJ. Eo- icin sinophils as drivers of severe eosinophil- l c ic asthma: Endotypes or plasticity? Int dn a J Mol Sci. 2021 Sep;22(18):10150. doi: sic 10.3390/ijms221810150. a - bamh st aerev 1: semur foamh st aerevse 2 Long Journey of Corticosteroids The Story of Corticosteroids in Asthma 2.1 Stylianos Vittorakis1, Chrysa Kontogianni2, Anastasia Levounets2, Eleftherios Zervas2 and Mina Gaga2 1 Private Practice, Chania, Abstract Greece Asthma is a common respiratory disease affecting patients of all ages and races. Up to the mid-2 7th Respiratory Medicine dle of the 20th century there was scarce knowledge regarding the biology of the disease and Department and Asthma asthma was a potential y lethal disease with very limited therapeutic options. The introduction Center, Athens Chest Hospital “SOTIRIA”, Athens, Greece of corticosteroids revolutionized the management of asthma and improved the lives of mil ions of patients. Parental and later oral administration was the first treatment with remarkable effects on asthma symptoms and exacerbations but led to serious systemic effects. The invention of inhaled forms of corticosteroids that had minimal systemic absorption and adverse reactions, the enhancement of their efficacy by LABAs and the understanding of asthma pathophysiology were only a few of the significant advances in asthma management over the last 60 years. In this review we present these life-changing advances in asthma treatment, focusing οn the evolutionary role of corticosteroids. Keywords: asthma history, asthma treatment, OCS, ICS, LABA Introduction: Historical Overview writings of Hippocrates, however, the term Asthma is a chronic inflammatory airway dis- probably refers to asthma as a symptom and ease affecting patients of all ages and races. not to the disease we know today. Ιn the begin-It is characterized by heterogeneity which is ning of the 19th century, asthma was defined defined by different underlying disease proas an airway disease characterized by bron- cesses and pathophysiological characteristics chospasm fol owing invention of the stetho- (phenotypes).1 This heterogeneity is reflect- scope by Laennec (1781-1826).3 The first re- ed in therapeutic interventions that have been ports of asthma as an extrinsic or intrinsic extensively evaluated during the last 20 years disorder caused by stress or animal dander or so. are attributed to Henry Hyde Salter in 1860. The term asthma is a Greek noun, άσθμα, In his treatise “On Asthma: its Pathology and which derives from the verb ασθμαίνω mean-Treatment”, Salter describes asthma as a dis- ing to exhale with open mouth, to pant. The ease in which the airways narrow as a re-first written record of asthma appears around sult of contraction of their smooth muscle.4 2700 years ago in Homer’s Iliad. The earli- A few years later Paul Ehrlich (1854-1915) est text where the word asthma is found as a described eosinophils and mast cel s in asth-medical term is in the writings of the school matic sputum using eosin and toluidine blue of Hippocrates of Kos (460-360 B.C.).2 In the staining.5 Sir Wil iam Osler (1849-1919), https://doi.org/10.26493/978-961-293-157-5.27-36 often mentioned as the Father of Modern selective β2- bronchodilators, were devel-Medicine, made a more precise definition of oped for inhaled use. Long-acting beta-ago-asthma connecting pathology, physiology, nists (LABAs - e.g., formoterol, salmeterol), symptoms, and clinical findings, in the first introduced in middle ‘90s as an important edition of his Textbook Principles and Prac-drug in asthma management. They demon- tice of Medicine.6 Thus, it was in the 19th cen- strate a clear benefit in reducing asthma-re- tury that asthma was described as a distinct lated symptoms and improving lung function lung disease with specific etiology, clinical but only when used in combination with an findings, and treatment. anti-inflammatory agent.17 28 Early Therapeutic Interventions The Introduction of Corticosteroids Therapeutic options for asthma were limited on Asthma Management until the middle of 20th century and asthma The story of corticosteroids in asthma be-was treated largely as a disease of broncho- gins in the early 1950s, when cortisone was spasm.7 Regimens containing anticholiner- first administered to treat asthma successful y. s gics were the first aetiologic treatment admin-Case series reporting the benefits of parenter- wie istered for asthma. Paul Ehrlich proposed al administration of cortisone in patients with vl black coffee for the treatment of broncho- allergic asthma were published: In 1950, Car- aic spasm, as this beverage contains theophyl- ryer presented 3 patients with seasonal asth- inl c line and its derivative theobromine.8 Hen- ma and hay fever who received sequential- dn ry Hyde Salter discusses “Asthma cigarettes” ly 100 mg cortisone or cholesterol suspension a containing dried leaves and flowering of D. daily over a 4-week period in a blinded man-sica Stramonium as a treatment for asthma in his ner. All three patients experienced prompt re- - ba 19th century work.9 Datura Stramonium con- lief from symptoms of asthma and hay fever, mh tains alkaloids of bel adonna which has anti- which lasted a few days post administration.18 st a cholinergic action. Wil iam Osler in his eight In 1953, Burrage W. presented 14 cases of se-ere edition of his textbook in 1914 suggests hy- vere bronchial asthma treated with a mean v podermic injections of pilocarpine for asth- daily dose of 50mg cortisone for a prolonged 1: se ma treatment.10 Adrenergic bronchodilators period. The author mentioned that “the use mu were introduced as treatment for asthma in r of cortisone in severe asthma involves a treat- fo the beginning of 20th century. Initial y both ment of an as yet imperfectly understood dis-am adrenaline and ephedrine were used subcu- ease with a potent hormone, whose mode of h st taneously at repeated intervals during asth- action remains a mystery” and that “no pa- ae tient has remained asthma free on less than r ma attacks.11 In 1947, in Cecil’s Textbook of ev Medicine, Rackemann presented the inhaled 25mg of cortisone daily”.19 Several other re-se administration of ephedrine to relieve asthma ports of parenteral administration of corti-symptoms.12 Since then, inhalers were wide- sone in patients with asthma were published ly available for asthma and bronchodilators over the fol owing years.20-22 such as isoprenaline and orciprenaline.13,14 The difficulties of parenteral adminis- The widespread use of those nonselective tration and the relapse of symptoms fol ow-bronchodilators led to an increased ratio of ing discontinuation of treatment were extin-deaths among asthmatics in England and guished with the initiation of oral therapy. Wales in the 1960s, possibly due to their car- In January 1951, Scwartz E. reported 3 cas- diovascular adverse effects or as a result of in- es of “intractable” asthma successful y treat- adequately treated asthma. In the 1970s, sal- ed with cortisone acetate tablets at initial butamol15 and terbutaline16, relatively more doses of 50-100mg with gradual tapering to maintenance dose of 25mg daily.23 Sidney treated with re-initiation of treatment. The and Alex Friedlaender described a series of 12 medical community had not yet linked asth-patients who received an average daily dose ma with inflammation of the airways, so the of 150 to 200mg oral cortisone which pro-author discusses a probable mechanism of duced a comparable effect to that obtained cortisone action as fol ows: “The direct appli-with intramuscular administration. Interest- cation of cortisone to the bronchial mucosa ingly they mentioned reduction in eosinophil may either interfere with the union of anti-counts.24 Savidge R. and Brockcbank studied gen and antibody or inhibit the liberation of 24 asthmatics with remarkable limitation in histamine in the site of shock organ (lung)”.35 their daily activities in 1954: Using a partial- Inhaled dexamethasone in a study of 64 pa- ly blinded methodology, they started with an tients resulted in withdrawal of oral steroids initial dose of 100mg cortisone daily or place-in 29 of these patients for a period from 2 to bo, gradual y tapering by 12.5mg every four 120 months.36 In the early 60s, the first stud-to six weeks in an effort to avoid side effects. ies evaluating the effects of inhaled steroids 29 In al patients, there was remarkable improve- in lung function with the use of spirometry ment in symptoms and patient could return to were published.36 Unfortunately, despite these am their daily activities.25 Αt that period, oral cor- advances, the systemic absorption of agents h st tisone for asthma treatment was administered such as dexamethasone, even when admin-a as long-term or intermittent basis with an ef- istered by inhalation proved an insuperable insid fort to use the minimal needed doses.26 problem. 37 ore The fol owing years, several forms of sto steroids such as hydrocortisone, prednis- The Break-through of ICS in Asthma ict olone, triamcinolone and dexamethasone Treatment ro were used, providing an effective manage- A milestone in asthma treatment was the in- cf ment for a disease that previous to their use, o vention of Beclomethasone dipropionate yr had been life threatening and had detrimen- (BDP) which was patented in 1962 and was o st tal effect on patients’ lives.27,28 Unfortunately, the first inhaled corticosteroid (ICS) marketed eht oral steroids also have side effects. So, in asth- for use in the treatment of chronic asthma.38 ma steroids have always been a double-edged In 1972 Brown H.M, Storey G. and George sword, due to their systemic adverse reac-W.H.S published the results of a study in- tions.29 By 1960 all the systemic toxic effects volving 60 asthmatic patients who received of oral and parenteral treatment of corticoids Beclomethasone dipropionate by means of a had been described and OCS-sparing ef-metered aerosol delivering 50 μg of micron- forts were made in nearly every disease where ized powder per puff.39 (37 of these patients OCS were used, not only due to safety issues had been oral steroid dependent for up to 16 but also to improve outcomes.27,30–34 This ef- years). Two puffs four times daily, giving a to- fort was reflected in many published works tal of 400 μg, was the usual dose, occasional-on the administration of cortisone by inhala- ly increased to three puffs four times a day. tion which started shortly after intramuscu- In 56 cases 400 μg was the optimum dose but lar treatment was made an established choice four remained well control ed on 150 to 200 for severe asthma. In 1951, Maxwel Gelfand μg daily. In 28 out of 37 steroid-depended reported 5 cases of bronchial asthma treat-cases there was complete withdrawal of OCS. ed for two weeks with 5mg nebulized corti- Besides, 19 out of 23 other asthmatics not de- sone inhaled every hour for a period of ten pendent on steroids were also completely con-hours daily. Discontinuation of treatment led trol ed. In that study Beclomethasone was the to relapses, which though, were successful y first inhaled steroid that had no biochemical evidence of adrenal suppression. In other twice daily regimen.51,52 Ciclesonide is a prod-studies Beclomethasone dipropionate proved rug glucocorticosteroid which itself is inac-a safe and effective alternative to oral Prednis- tive and needs to be cleaved by esterases in the olone by means of patients’ preference, use of lung to bind to the glucocorticoid receptor. In rescue medications and lung function (PEFR, the majority of clinical trials, it was adminis-FEV1).37,40 tered as a single dose.53–55 Fluticasone Furoate Budesonide, the second broadly used in-is the newest discovered inhaled corticosteroid haled ICS, was patented in 1973.41 The first that demonstrates prolonged action up to 26 h studies on asthmatic patients showed a comin asthma patients.56 parable action with beclomethasone in asth- 30 ma control in both adults and children.42,43 Pilot Studies In vivo studies have shown different phar-on Asthma Pathophysiology: macodynamic properties and although be- The Role of Inflammation clomethasone has higher receptor affini- Understanding the pathophysiology and in-ty, Budesonide has higher in vitro potency.44 flammatory triggers and processes of asthma s Like Beclomethasone, the introduction of w as well as the effects of ICS on the control of ie Budesonide in corticosteroid dependent pa- v inflammation and bronchial mucosal infiltra- la tients with severe asthma seemed to offer an tion was a milestone in asthma management. ic improvement, al owing substantial reduc- in Laboratory and clinical studies established in- l c tion or withdrawal of oral prednisolone with- haled steroid treatment as the main therapeu- dn out systemic absorbsion.45 Fluticasone pro- a tic option for asthma, dethroning bronchodi- pionate was patented in 1980 and approved sic lator monotherapy. In 1991 Laitinen LA and a for medical use in 1990.46 In a large interna- - b coworkers compared the effect of budesonide a tional study fluticasone propionate 1mg/day m and terbutaline, on clinical symptoms, lung h was as effective as 2mg/day beclomethasone st function, and airway epithelium (on biopsies a dipropionate in the control of severe asthma, e obtained with bronchoscopy) in 14 adult pa- re better effect on lung function with less effect v tients with newly diagnosed asthma. Budes- on adrenal function.47,48 The results were sim- onide improved lung function and bronchi- 1: sem ilar in lower doses of both medications.49 Oth- al hyperreactivity but most importantly was ur er studies also demonstrated that both the dry more effective in ameliorating abnormalities foa powder and aerosolized formulations of fluti- of the bronchial epithelium and decreasing mh casone propionate had twice the efficacy of inflammation in the airways. 57 One year ear-st a beclomethasone dipropionate via a pressur- e lier Haahtela and coworkers had shown that r ized inhaler, introducing an alternative dry ev powder device (Diskhaler) for asthma drug early anti-inflammatory treatment with ICS se delivery.50 in newly detected asthma resulted in greater In the last 30 years, three more inhaled improvement of symptoms and lung function steroid agents were introduced: Mometa-than treatment with terbutaline and that the sone Furoate, Ciclesonide, and Fluticasone improvement lasted through the entire two-Furoate. Mometasone furoate is a highly po- year study period.58 In a fol ow-up study, pa- tent synthetic glucocorticoid initial y used tients who had been assigned to terbutaline as a topical dermatologic agent proved to were assigned to ICS and experienced less be an effective treatment for patients with improvement than those who had started on mild-to-moderate persistent asthma previous-ICS, suggesting that early treatment was more ly taking only inhaled β2-adrenergic agonists effective than delayed treatmen, ie treatment when administered either as a once daily or later into the course of asthma. 59,60 Despite these advances, the information and reduced exacerbations and the need for on whether inhaled corticosteroids prevent rescue medications.63 deaths from asthma remained sparse and in- During the first decade of 21st century, conclusive. Suissa S. and coworkers conduct- effort was made to achieve control of asth- ed a population-based epidemiologic study to ma symptoms and exacerbations with the determine whether and to what extent the use use of ICS and LABA combinations. In the of inhaled corticosteroids prevents death from Gaining Optimal Asthma Control (GOAL) asthma. The cohort consisted of 30596 sub-study, Bateman and col eagues have assessed jects who were fol owed from 1975 through how frequently total asthma control or wel 1997 and the results were published in 2000. control ed asthma control can be achieved. Authors concluded that regular use of low Stepping up the treatment to higher doses of dose inhaled corticosteroids was associat-Fluticasone alone or Fluticasone/Salmeter- ed with a decreased risk of death from asth- ol resulted in a higher proportion of patients ma and that the rate of death from asthma with control ed asthma. Similarly to the FAC-31 decreased by 21 percent with each addition- ET study, more patients rapidly achieved to- tal y or wel -control ed asthma with the com- a al canister of inhaled corticosteroids used in m bination of inhaled salmeterol/fluticasone h the previous year.61 Unfortunately, to this day, st we see patients receiving bronchodilators only and at a lower dose of corticosteroid than a with inhaled fluticasone alone.64 Another op- ins and deaths associated with excessive broncho- id tion for gaining asthma control was the use o dilator use. re of fixed Budesonide/Formoterol combination st both for maintenance and relief, the Sym- o Enhancing Efficacy of ICS with LABA: ict bicort Maintenance And Reliever Therapy r Past and Present o (SMART) approach. In 2007 Bousquet J and cf A major advance in asthma management col eagues showed that in the treatment of oy was also the discovery that LABAs enhance r uncontrolled asthma, budesonide/formoterol o the clinical efficacy of inhaled corticosteroids maintenance and reliever therapy reduced the ste in asthma 62. In 1997 Pauwels R A and cow- h incidence of severe asthma exacerbations and t orkers in the game-changing FACET study, hospitalization/ER treatment with similar evaluated the effects of adding inhaled for-daily symptom control compared to sustained moterol to both lower and higher doses of high-dose salmeterol/fluticasone plus SABA. the inhaled glucocorticoid budesonide and This benefit war achieved with substantial y showed that combining ICS and LABAs, reless ICS exposure.65 Over the fol owing years sulted in better outcomes, required lower dos- several studies supported the MART strategy es of ICS and resulted in better lung function, in asthma treatment. less activity limitation and better quality of Over the last 20 years the combination life. In short, 852 patients treated with glu- of LABA with ICS remained the main op- cocorticoids were randomly assigned to one tion for the treatment of moderate to severe of four treatments (low or high ICS with or asthma.66 On the contrary, guidelines recom-without LABA) given twice daily for one mended, until recently, that most adults and year. The study showed that, in patients who adolescents with mild asthma use regular dai-have persistent symptoms of asthma despite ly low dose ICS as maintenance treatment to treatment with inhaled glucocorticoids, the reduce airway inflammation, symptoms, and addition of formoterol to either the lower or the risk of exacerbations.67 However, in clin-the higher dose of budesonide also improved ical practice patients show poor adherence asthma-symptom scores and lung function to asthma medications, particularly inhaled glucocorticoids and rely on SABAs for symp-Summary tom relief, a phenomenon more intense in The long journey of corticosteroids in asth-mild asthma. However, SABAs do not ad- ma started in early 1950s. Despite their severe dress the underlying inflammatory process adverse effects, the parenteral and oral forms and they do not protect against exacerbations. of these agents were a life changing medica-On the contrary SABA overuse is related to tion for asthmatics, whose treatment options high asthma mortality.68,69 were almost non-existent until then. Twenty SYGMA 1 and SYGMA2 are both mul- years later, the first inhaled steroids proved to ticenter, phase III, randomized, double-blind, be effective and safer, limiting the use of oral agents to more severe stages of disease and 32 52-week, placebo-controled studies, involv- ing asthma patients who were assessed as during asthma exacerbations. Personalized, needing GINA step 2 treatment. In the SYG-phenotype-based treatment approaches using MA 1 study, patients were randomly sepa- combinations of ICS with LABA, newer in- rated into three subgroups: i) terbutaline as halation devices and, when needed, biologics needed group, i ) budesonide-formoterol as for severe asthma are the new reality for al s asthma patients. For the majority of patients, w needed group, and i i) budesonide-formoter- ie the target is to obtain control of asthma with v ol regular maintenance group.70 This study l the least (optimal) dose of ICS that each pa- a showed that, budesonide-formoterol as need- ic tient requires. ICSs combined with LABAs in ed treatment was superior to terbutaline in l c remain the cornerstone of asthma therapy. d outcomes as asthma control and severe ex- n a acerbations and equivalent to maintenance References sic budesonide, but with an 83% lower medi- a 1. Global Initiative for Asthma. Global - b an daily ICS dose. In SYGMA 2, the regu- a Strategy for Asthma Management and m lar use of low dose ICS budesonide plus SABA h Prevention [Internet]. [place unknown]: st as needed was tested against low dose budeso- a Global Initiative for Asthma, c2021. e nide-formoterol as needed in asthmatics with re Available from: https://ginasthma.org/. v mild asthma. In this study, BUD/FORM as needed was non-inferior to BUD alone for re- 2. Marketos SG, Bal as CN. Bron- 1: se chial asthma in the medical litera- m ducing severe asthma exacerbations but re- ur ture of Greek antiquity. J Asthma. fo sulted in 75% lower median daily ICS dose.71 1982;19(4):263-9. am These data resulted in fundamental chang- 3. Cserháti E. The history of bronchi- h es in the treatment of intermittent and mild st al asthma from the Renaissance till the ae asthma, the biggest changes since the ini- r beginning of the twentieth century. ev tial development of GINA recommenda- Acta Physiol Hung. 2005;92(2):181-92. se tions almost three decades ago (1995): The 4. Hide Salter H. On asthma: its pa-2019 guidelines proposed that adults and ad- thology and treatment. London: John olescents with mild asthma should prefera- Churchil ; 1860. bly be treated with ICS-containing regimens: 5. Schwartz RS. Paul Ehrlich’s magas-needed low-dose ICS-formoterol in Step 1 ic bul ets. N Engl J Med. 2004 Mar and as needed low-dose ICS plus as-needed 11;350(11):1079-80. SABA or as-needed low-dose ICS-formoterol 6. Osler W. The Principles and Practice of in Step 2. And this was the last major advance Medicine. New York: D. Appleton and in asthma treatment confirming the essential Company, 1892. 1079 p. role of ICS in treatment even in mild stages of 7. Diamant Z, Diderik Boot J, Chris-the disease.72 tian Virchow J. Summing up 100 years of asthma. Respir Med. 2007 18. Carryer HM, Koelsche GA, Prickman Mar;101(3):378-88. LE, et al. The effects of cortisone on 8. Crompton G. A brief history of in- bronchial asthma and hay fever occur- haled asthma therapy over the last fif- ring in subjects sensitive to ragweed pol- ty years. Prim Care Respir J. 2006 Dec; len. J Al ergy. 1950;21(4):282-7. 15(6):326-31. 19. Burrage WS, Irwin JW, Petersen IG, 9. Jackson M. “Divine Stramonium”: The et al. The role of cortisone in the treat- Rise and Fall of Smoking for Asthma. ment of severe bronchial asthma. N Med Hist. 2010 Apr; 54(2):171-94. Engl J Med. 1953 Apr 16;248(16):679- 10. Chu EK, Drazen JM. Asthma : one 82 hundred years of treatment and on- 20. Randolph TG, Rol ins JP. The effect of ward. Am J Respir Crit Care Med. cortisone on bronchial asthma. J Al er- 2005 Jun 1;171(11):1202-8. gy. 1950 Jul;21(4):288-95. 11. Mel and B. The treatment of spasmodic 21. Rowe A, Rowe AH. Cortisone and cor-33 asthma by the hypodermic injection of ticotropin in al ergic disease. Calif Med. adrenalin. Lancet. 1910;175:1407-11. 1952 Dec;77(6):387-90. am 12. Rackemann FM. Asthma. In: Cecil 22. McCombs RP. Serial courses of corti- h st RL, McDermott W, Wolff HG, editors. cotrophin or cortisone in chronic bron- a Textbook of medicine. 7th ed. Philadel- chial asthma. N Engl J Med. 1952 Jul insid phia (PA): WB Saunders; 1947. p. 533- 3;247(1):1-6. ore 40. 23. Schwartz E. Oral cortisone in intracta- st 13. Lipman WH. The treatment of bron- ble bronchial asthma; preliminary re- oict chial asthma with isuprel. Ann Al ergy. port. J. Al ergy. 1951 Jan;22:1-3 ro 1949 May-Jun;7(3):384-9 24. Friedlaender S, Friedlaender AS. Ef- cf 14. Lowell FC, Curry JJ, Schil er IW. A fect of cortisone administered oral y in oyr clinical and experimental study of bronchial asthma. J Am Med Assoc. o isuprel in spontaneous and induced 1951;146(15):1381-2. steh asthma. N Engl J Med. 1948 Jan 25. Savidge RS, Brockbank W. Long-term t 13;239(2):45-51. control of severe bronchial asthma 15. Choo-Kang YFJ, Simpson WT, Grant with oral cortisone. Lancet. 1954 Oct IWB. Control ed Comparison of the 30;267(6844):889-93. Bronchodilator Effects of Three β-Adr- 26. Brockbank W, Savidge RS, Brebner H. energic Stimulant Drugs Administered Long-term control of severe bronchial by Inhalation to Patients with Asthma. asthma with oral cortisone; second re- Br Med J. 1969 May 3;2(5652):287-89. port. Lancet 1957;2:666-70. 16. Mattila MJ, Muittari A. Effect of bron- 27. Baldwin HS, Dworetzky M, Isaacs chodilator drugs on the peak expir- NJ. Evaluation of the steroid treatment atory flow rate of asthmatic patients: of asthma since 1950. J Al ergy. 1961 oral orciprenaline and terbutaline Mar-Apr;32:109-18. (KWD 2019). Ann Med Exp Biol Fenn. 28. Sheffer AL, Valentine MD. The treat-1969;47(4):298-302. ment of bronchial asthma. Med Clin 17. Walters E, Walters J, Gibson M. In- North Am. 1969 Mar;53(2):239-48. haled long acting beta agonists for sta- 29. Gaga M, Zervas E. Oral steroids in ble chronic asthma. Cochrane Data- asthma: a double-edged sword. Eur base Syst Rev. 2003;(4):CD001385. doi: Respir J. 2019 Nov 28;54(5):1902034. 10.1002/14651858.CD001385. doi: 10.1183/13993003.02034-2019. 30. Begemann H, Kaboth W. [Side-ef- 42. Wil ey RF, Godden DJ, Carmichael J, fects of cortisone derivatives]. Internist et al. Twice daily inhalation of a new (Berl). 1967 Mar;8(3):85-94. corticosteroid, budesonide, in the treat- 31. Deleterious Effect of ACTH and Cor- ment of chronic asthma. Eur J Respir tisone on Tuberculosis. N Engl J Med. Dis Suppl. 1982;122:138-42. 1951 Oct 25;245:662-4. 43. Field HV, Jenkinson PMA, Frame MH, 32. Thayer JM. Side effects of cortisone et al. Asthma treatment with a new cor- and ACTH. Stanford Med Bul . 1952 ticosteroid aerosol, budesonide, admin- Feb;10(1):1-14. istered twice daily by spacer inhaler. 33. Fauci AS, Dale DC, Balow JE. Gluco- Arch Dis Child. 1982 Nov;57(11):864- 34 corticosteroid therapy: mechanisms of 6. action and clinical considerations. Ann 44. El ul‐Mical ef R, Johansson S. Acute Intern Med. 1976 Mar;84(3):304-15. dose-response studies in bronchial asth- 34. Chechani V. Corticosteroids in asth- ma with a new corticosteroid, budes- ma. J Assoc Acad Minor Phys. onide. Br J Clin Pharmacol. 1983 1991;2(3):109-17. s Apr;15(4):419-22. w 35. Gelfand ML. Administration of corti- ie 45. Rosenhall L, Lundqvist G, Adelroth v sone by the aerosol method in the treat- l E, et al. Comparison between inhaled a ment of bronchial asthma. N Engl J ic and oral corticosteroids in patients with inl Med. 1951 Aug 23;245(8):293-4. c chronic asthma. Eur J Respir Dis Suppl. d 36. Arbesman CE, Bonstein HS, Reis- n 1982;122:154-62. a man RE. Dexamethasone aerosol ther- 46. Fischer J, Ganel in CR. Ana- sic apy for bronchial asthma. 1963 Jul- a logue-based drug discovery. Weinheim: - b Aug;34:354-61. a Wiley-VCH; 2006. 575 p. m 37. Lal S, Bhal a KK, Singhal SN, et al. h 47. Barnes NC, Marone G, Maria GUDi, st Comparison of beclomethasone dipro- a et al. A comparison of fluticasone pro- e pionate aerosol and prednisolone in re- re pionate, 1 mg daily, with beclometh- v versible airways obstruction. Br Med. 1972 Aug 5;3(5822):314-7. asone dipropionate, 2 mg daily, in the 1: se treatment of severe asthma. Interna- m 38. Adams NP, Bestall JC, Jones P. Inhaled u tional Study Group. Eur Respir J. 1993 r beclomethasone versus budesonide for fo Jun;6(6):877-85. a chronic asthma. Cochrane Database m 48. Fabbri L, Burge PS, Croonenborgh L, h Syst Rev. 2002;2002(1):CD003530. st et al. Comparison of fluticasone propi- a doi: 10.1002/14651858.CD003530. er 39. Brown M, Storey G, George WHS. Be- onate with beclomethasone dipropion- ev clomethasone Dipropionate: A New ate in moderate to severe asthma treat- se Steroid Aerosol for the Treatment of ed for one year. International Study Al ergic Asthma. Br Med J. 1972 Mar Group. Thorax. 1993 Aug;48(8):817- 4;1(5800):585-90. 23. 40. Clark TJH. Effect of beclomethasone 49. Gustafsson P, Tsanakas J, Gold M, dipropionate delivered by aerosol in pa- et al. Comparison of the efficacy and tients with asthma. Lancet. 1972 Jun safety of inhaled fluticasone propi- 24;1(7765):1361-4. onate 200 micrograms/day with in- 41. Domeij B. Pharmaceutical patents in haled beclomethasone dipropionate Europe. The Hague: Kluwer Law In- 400 micrograms/day in mild and mod- ternational; 2000. (Stockholm Studies erate asthma. Arch Dis Child. 1993 in Law; volume 3). 350 p. Aug;69(2):206-11. 50. Lundback B, Alexander M, Day J, et of an inhaled corticosteroid, budeso-al. Evaluation of fluticasone propionate nide, and a beta 2-agonist, terbutaline, (500 micrograms day-1) administered on airway inflammation in newly di- either as dry powder via a Diskhaler in- agnosed asthma: a randomized, dou- haler or pressurized inhaler and com- ble-blind, paral el-group control ed pared with beclomethasone dipropion- trial. J Al ergy Clin Immunol. 1992 ate (1000 micrograms day-1) admin- Jul;90(1):32-42. istered by pressurized inhaler. Respir 58. Haahtela T, Järvinen M, Kava T, et al. Med. 1993 Nov;87(8):609-20. Comparison of a beta 2-agonist, terbu- 51. Bernstein DI, Berkowitz RB, Chervin- taline, with an inhaled corticosteroid, sky P, et al. Dose-ranging study of a budesonide, in newly detected asthma. new steroid for asthma: mometasone N Engl J Med. 1991 Aug 8;325(6):388- furoate dry powder inhaler. Respir 92. Med. 1999 Sep;93(9):603-12. 59. Haahtela T, Järvinen M, Kava T, et 52. Kemp J P, Berkowitz RB, Mil er SD, 35 al. Effects of reducing or discontinu- et al. Mometasone furoate admin- ing inhaled budesonide in patients with a istered once daily is as effective as m mild asthma. N Engl J Med. 1994 Sep h twice-daily administration for treat- st 15;331(11):700-5. a ment of mild-to-moderate persistent 60. Chu EK, Drazen JM. Asthma: one ins asthma. J Al ergy Clin Immunol. 2000 id hundred years of treatment and on- o Sep;106(3):485-92. re 53. Manning P, Gibson PG, Lasser- ward. Am J Respir Crit Care Med. st 2005 Jun 1;171(11):1202-8. o son, TJ. Ciclesonide versus placebo ict 61. Suissa S, Ernst P, Benayoun S, et al. r for chronic asthma in adults and chil- o Low-dose inhaled corticosteroids and c dren. Cochrane Database Syst Rev. f the prevention of death from asthma. N oy 2008 Apr 16;2008(2):CD006217. doi: r Engl J Med. 2000 Aug 3;343(5):332-6. o 10.1002/14651858.CD006217.pub2. 62. Greening AP, Ind PW, Northfield M, et ste 54. Taylor DA, Jensen MW, Kanabar V, et h al. Added salmeterol versus higher-dose t al. A dose-dependent effect of the nov- el inhaled corticosteroid ciclesonide corticosteroid in asthma patients with on airway responsiveness to adeno- symptoms on existing inhaled corti- sine-5’-monophosphate in asthmat- costeroid. Al en & Hanburys Limit- ic patients. Am J Respir Crit Care Med. ed UK Study Group. Lancet. 1994 Jul 1999 Jul;160(1):237-43. 23;344(8917):219-24. 55. Postma DS, Sevette C, Martinat J, et 63. Pauwels RA, Löfdahl CG, Postma DS, al. Treatment of asthma by the inhaled et al. Effect of inhaled formoterol and corticosteroid ciclesonide given either in budesonid on exacerbations of asthma. the morning or evening. Eur Respir J. Corticosteroids Establishing Therapy 2001 Jun;17(6):1083-8. (FACET) International Study Group. N 56. van den Berge M, Luijk B, Bareil e P, et Engl J Med. 1997 Nov 13;337(20):1405- al. Prolonged protection of the new in- 11. haled corticosteroid fluticasone furo- 64. Bateman ED, Boushey HA, Bousquet ate against AMP hyperresponsiveness J, et al. 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Chal enges of Systemic Glucocorticoids Taper in the Treatment of Severe Asthma 2.2 Sabina Škrgat1,2, Peter Kopač,3 Natalija Edelbaher4 and Tomaž Kocjan2,5 1 Department of Pulmonary Abstract Diseases and Allergy, University Asthma is a chronic airway inflammatory disease, characterized by reversible airway obstruc-Medical Centre Ljubljana, Ljubljana, Slovenia tion and airway hyperresponsiveness. It affects 1-18% of population in different countries and approximately 5–10% of the overall asthma population has severe asthma. Systemic gluco-2 Faculty of Medicine, University of Ljubljana, Slovenia corticoids still represent a significant burden due to treatment of asthma exacerbations and severe forms of asthma. Monoclonal antibodies are powerful anti-inflammatory agents with 3 University Clinic of Respiratory and Allergic Diseases, Golnik, glucocorticoid-sparing properties. With the increasing use of biologics, tapering and cessation Slovenia of maintenance systemic glucocorticoids have become much more common. Personalized ap-4 Department of Pulmonary proach to tapering and careful assessment for adrenal insufficiency in all patients are recom-Diseases, University Medical Centre Maribor, Maribor, Slovenia mended by the experts. 5 Department of Endocrinology, Diabetes and Metabolic Diseases, Keywords: severe asthma, glucocorticoids, side effects, adrenal insufficiency University Medical Centre Ljubljana, Ljubljana, Slovenia Introduction treatment of asthma exacerbations and of se- Asthma is a chronic airway inflammatory dis- vere asthma4,6. ease, characterized by reversible airway ob- The many systemic effects associated struction and airway hyperresponsiveness1. It with long-term systemic GC use have been affects 1-18% of population in different coun- well studied and described7. The most com-tries2. Approximately 5–10% of the patients mon serious systemic GC-associated comor-have severe asthma3, which remains uncon- bidities include osteoporotic fractures, dia-trol ed despite adherence to maximal opti- betes, obesity, cardiovascular disorders, and mized therapy and treatment of contributory hypothalamic-pituitary-adrenal (HPA) axis factors and comorbidities2. suppression. In addition, use of systemic GC Systemic glucocorticoids (GC) became has been associated with psychiatric symptoms such as insomnia, mania, depression, available in 1956 and they have provided ef- anxiety, or aggressive behavior. Dyspepsia, fective treatment of asthma ever since4. Their hypertension, dyslipidemia, opportunistic in-widespread use led to the recognition that fections, muscle atrophy, cataracts, glauco-long-term systemic GC use is associated with ma, bruising, cushingoid appearance, skin significant adverse events5 and to introduc- striae and change in appetite can also oc-tion of inhaled GC in 1972 as maintenance cur5,8,9. Moreover, there is published evidence treatment for asthma4. However, there is still suggesting that even brief (3–7 days), but re-a significant burden of systemic GC due to petitive courses of systemic GC can provoke https://doi.org/10.26493/978-961-293-157-5.37- 42 significant negative outcomes for patients, have similar systemic effects to 5 mg of pred-such as bone density loss, hypertension, gas- nisone13, which might be also true for 2500 μg trointestinal bleeding, and have negative im- of budesonide14. Therefore, high doses of in- pact on mental health7. haled GC should potential y be considered as harmful as low doses of systemic GC15 and Evidence from European Registries their effects are accumulative on top of sys- The European Respiratory Society (ERS) Se- temic GC7. vere Heterogeneous Asthma Research col ab- oration (SHARP) was set up in 2018 to har- Approaches to Systemic GC Taper After monize severe asthma management across 38 Introduction of Monoclonal Antibodies Europe and to unravel underlying heteroge- Monoclonal antibodies are powerful anti-in- neity in a patient-centered way10. The current flammatory agents with GC-sparing proper-project involves the first structured assess- ties16-19. Their availability represents a corner- ment and comparison of national severe asth- stone for systemic GC taper and withdrawal ma registries that are part of SHARP to dis- in severe asthma, which is becoming a com- s cover strengths/weaknesses in those registries w mon scenario in clinical practice with the in- ie and to evaluate severe asthma and its treat- v creasing use of biologics. However, a specific la ment across Europe. guidance on how to proceed is lacking20. ic Across-sectional retrospective analysis of in Accordingly, over 130 international ex- l c aggregated patients’ characteristics and their perts employed a modified Delphi method to dn treatments before starting biologicals from 11 a develop a consensus statement on appropriate national SHARP affiliated severe asthma reg- sic systemic GC use and tapering in patients with a istries showed that patients were treated dif- asthma, adverse effects, patient–physician - ba ferently between countries. Their mean in- shared decision-making, and future research mh haled GC daily dose (fluticasone equivalent) domains21. The paper provided a broader st a ranged from 700 μg in Slovenia to 1335 μg in e guidance on when and how to taper system- re Poland when starting anti-interleukin (IL)-5 ic GC in patients with asthma, regardless of v antibody and from 772 μg in Slovenia to 1344 whether biological therapy has been initiated. 1: se μg in Spain in those starting anti-IgE, respec- According to consensus, tapering should be mu tively. Maintenance oral GC use ranged from r individualized and attempted in all patients fo 21.0% (Belgium) to 63.0% (Sweden) and with asthma receiving maintenance systemic am from 9.1% (Denmark) to 56.1% (the UK) in h GC therapy, regardless of comorbidities. The st patients starting anti-IL-5 and anti-IgE, re- a recommendations generated support for min- er spectively11. The reasons for these differenc- imizing systemic GC use as much as possible. ev es are not entirely clear. Potential explana- Global Initiative for Asthma (GINA) recom- se tions, which would require a focused study by mendations restrict systemic GC use to those the SHARP clinical research col aboration, patients who are ineligible for biologic treat-might include the cost of treatment and the ment and define the lowest acceptable system-fear of high-dose treatment-related side-ef- ic GC maintenance daily dose at less than 7.5 fects11. mg of prednisolone2. On the other hand, the Indeed, a recent systematic review and Delphi expert consensus considered a daily meta-analysis has suggested that the majori-dose of less than 5 mg of prednisolone as ac- ty of oral GC-sparing effect of high-dose in- ceptable, if no alternative treatment is avail- haled GC was likely to be due to their sys- able21. However, even merely 5 mg of pred- temic effects12. Regarding the effects on HPA nisolone a day contributes to a cumulative axis, 1000 μg of fluticasone propionate might dose of more than 1.8 g per year. Additional awareness is therefore needed, if we consid- - dose or duration of systemic GC er the evidence that a lifetime cumulative sys- treatment is cause for concern, temic GC load of 0.5-1 g was associated with - asthma control is achieved (especial- diabetes, while most other adverse effects ly with biologics), emerged at 1 to less than 2.5 g5. - there is a reasonable likelihood of Therefore, a routine screening using a HPA axis recovery. minimal checklist for adverse effects and co- morbidities is recommended in all patients Table 2. Consensus information on systemic GC tapering and suggested tapering speeds according with asthma on systemic GC treatment (Ta- to current systemic GC (methylprednisolone) dose21 ble 1). Daily dose ≥ 16 mg Daily dose 8-16 mg Daily dose 4-8 mg Table 1. Minimal checklist for glucocorticoid adverse effects screening21 Faster pace Medium pace Slower pace Reduce by 8 mg/ week or 30-50 % Reduce 2-4 mg Reduce by 1-2 mg 39 Glycemic control every 2-4-weeks every 1-2 weeks every 1-2 weeks a Bone mineral density mh Blood pressure st During systemic GC tapering patients Cataracts and glaucoma ae should be continuously evaluated for adrenal r Weight change ev Fracture risk assessment (e.g., FRAX) insufficiency (AI), comorbidities, and asthma se symptoms. If GC taper is intolerable, tapering f ot Definition of abbreviation: FRAX=Fracture Risk attempts should be stopped and postponed to ne Assessment Tool. a later date. Return to previous efficacious mta dose is also recommended. When symptoms er are mild, current GC dose should be main- t According to the expert consensus sys- eh temic GC tapering should be initiated only tained and tapering speed should be reduced. t Proceeding toward GC cessation is sug- in when it is considered appropriate for the clini- r gested when: pe cal situation and asthma phenotype. a t - daily systemic GC dose is ≤ 4 mg of s Three common baseline clinical scenari- id methylprednisolone, o os were provided21: ict - a sparing strategy has been initiated, ro 1. Do not attempt tapering in EGPA (eosin- - the patient has agreed to cessation, co ophilic granulomatosis with polyangi - c - there is no evidence of EGPA/ABPA, lu tis) and ABPA (al ergic bronchopulmo- - there is no evidence of adrenal insuffi- gic nary aspergil osis) that relapses during ciency. me tapering and no other changes can be st AI is very common among users of sys- proposed. syf temic GC after tapering22 and experts21 agreed o 2. Tapering with caution in cases with: se that this condition is insufficiently assessed or g - history of life-threatening attacks, n underrecognized. Risk factors for develop- el - systemic GC dependence for extend- l ment of GC-induced AI include the duration ah ed period (e.g., more than 6 months), c of GC therapy, mode of administration (e.g., - in patients with comorbidities that oral vs. inhaled), GC dose and potency, con-respond to systemic GC. comitant drugs that interfere with GC me- 3. Tapering should be done if: tabolism, and individual susceptibility. Im- - systemic GC result in no asthma im- portantly, the risk of developing GC-induced provement and/or side effects, AI is difficult to predict on an individual basis Methylprednisolone dosage 4 mg daily for 4 weeks Check basal morning cortisol (8 a.m-9 a.m) Normal Intermediate values Complete adrenal insufficiency > 350 nmol/L 100-350 nmol/L < 100 nmol/L 40 Continue tapering Delay tapering and repeat test 3 months later swie v Short Synacthten (cosyntropin) test la (intravenous; cortisol value at 0 and after 30 min) icinl cdn a sica - b Normal Partial adrenal insufficiency Complete adrenal insufficiency am > 500 nmol/L 250-500 nmol/L < 250 nmol/L h st aerev Continue tapering Slow tapering Delay tapering 1: sem and repeat test 3 months later ur foam Figure 1. Recommended evaluation for adrenal insufficiency in severe asthma patients, previously treated h st with systemic GC (adapted from Menzies-Gow et al., 2021) aerevse and low threshold for HPA axis evaluation is cessful y authenticated a personalized system-advised if clinical suspicion of AI exists. Use ic GC reduction algorithm with incorporated of basal morning cortisol is general y rec-HPA axis integrity assessment . The investi- ommended for this purpose with short Syn- gators recommended evaluation for AI after acthen (cosyntropin) testing to fol ow in the patients had been receiving 5 mg of predni-case of intermediate results23. solone (equivalent to 4 mg of methylpredniso- Successful systemic GC dose reduction lone) daily for 4 weeks, as shown in Figure 1. in patients with severe asthma after initiation Clinicians should be aware that such pro- of biological therapies, using preset tapering tocols can serve as a guide only and that re-protocols, has been recently demonstrated. al-life management should be tailored on Specifical y, the PONENTE study24 has suc-an individual basis. Moreover, cut-offs vary according to the cortisol assay used and local and prevention [Internet]. Fontana, practices. For example, basal morning corti- WI: Global Initiative for Asthma; 2021 sol that excluded AI varied between 336 and [cited 2021 Sep 30]. Available from: 506 nmol/L when measured by three differ- https://ginasthma.org. ent immunoassays. Therefore, the cut-offs 3. Chung KF, Wenzel SE, Brozek JL, et proposed here should be seen as a direction al. International ERS/ATS guidelines only. Additional y, patients should be test- on definition, evaluation and treatment ed at least 24 h after the last dose of exoge- of severe asthma. Eur Respir J. 2014 nous GC, because (methyl) prednisolone can Feb;43(2):343-73. interfere with immunoassays and cause false- 4. Alangari AA. Corticosteroids in the ly elevated cortisol values. To completely ex- treatment of acute asthma. Ann Thorac clude this possibility, patients could be also Med. 2014 Oct;9(4):187-92. switched to a replacement dose of hydrocorti- 5. Price DB, Trudo F, Voorham J, et al. sone, a short-acting GC, before testing serum Adverse outcomes from initiation of sys- temic corticosteroids for asthma: long- 41 cortisol23. In the case of AI, the switch to hydrocor- term observational study. J Asthma Al- am tisone replacement therapy was general y pre- lergy. 2018 Aug 29;11:193-204. h 6. Bengtson LGS, Yu Y, Wang W, et al. st ferred by the experts to continued predniso- ae Inhaled corticosteroid-containing treat- r lone, but the consensus was not reached25,21. e ment escalation and outcomes for pa- v Theoretical y, its shorter half-life might ac- se tients with asthma in a U.S. health f celerate the recovery of HPA axis by negative o care organization. J Manag Care Spec t feedback, especial y when avoiding late after- ne Pharm. 2017 Nov;23(11):1149-59. m noon exposure to hydrocortisone23. Switch t 7. Price D, Castro M, Bourdin A, et ae to hydrocortisone is also recommended from r al. Short-course systemic corticos- t practical reasons, for instance when low- e teroids in asthma: striking the bal- h strength GC tablets, such as (methyl) predni- t ance between efficacy and safety. Eur in solone 1 mg tablet, are not available. r Respir Rev. 2020;29(155):190151. doi: pea 10.1183/16000617.0151-2019. ts Conclusions 8. Younes AK, Younes NK. Recovery of ido Modern anti-inflammatory treatment with steroid induced adrenal insufficiency. ict biologics is changing lives of many patients r Transl Pediatr. 2017 Oct;6(4):269-73. oc with severe asthma who had to rely on sys- 9. Poetker DM, Reh DD. A comprehensive oc temic GC and cope with their potential y se- review of the adverse effects of systemic lu rious side effects in the past. However, clini- g corticosteroids. Otolaryngol Clin North icm cians should be aware that life-threatening Am. 2010 Aug;43(4):753-68. e st AI is common among systemic GC users and 10. Djukanovic R, Adcock IM, Ander-sy should familiarize themselves with correct f son G, et al. The Severe Heterogene- os GC tapering and cessation. ous Asthma Research col aboration, egn Patient-centred (SHARP) ERS Clin- ell References ical Research Col aboration: a new ahc 1. Holgate ST, Wenzel S, Postma DS, dawn in asthma research. Eur Respir et al. Asthma. Nat Rev Dis Primers. J. 2018 Nov 29;52(5):1801671. doi: 2015 Sep 10;1(1):15025. doi: 10.1038/ 10.1183/13993003.01671-2018. nrdp.2015.25. 11. van Bragt JJMH, Adcock IM, Bel 2. Global Initiative for Asthma. Glob- EHD, et al. Characteristics and treat- al strategy for asthma management ment regimens across ERS SHARP severe asthma registries. Eur Respir Am J Respir Crit Care Med. 2021 Apr J. 2020 Jan 9;55(1):1901163. doi: 1;203(7):795-6. 10.1183/13993003.01163-2019. 21. Suehs CM, Menzies-Gow A, Price D, et 12. Maijers I, Kearns N, Harper J, et al. al. Oral Corticosteroids Tapering Del- Oral steroid-sparing effect of high-dose phi Expert Panel. Expert consensus on inhaled corticosteroids in asthma. 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Oral corticosteroid elimina- icin 15. Bourdin A, Suehs C, Charriot J. Inte- tion via a personalised reduction algo- l c grating high dose inhaled corticosteroids rithm in adults with severe, eosinophilic dn a into oral corticosteroids stewardship. asthma treated with benralizumab (PO- sic Eur Respir J. 2020 Jan 2;55(1):1902193. NENTE): a multicentre, open-label, a - b doi: 10.1183/13993003.02193-2019. single-arm study. Lancet Respir Med. am 16. Braunstahl GJ, Chlumský J, Peachey 2021 Jan;10(1):47-58. h G, et al. Reduction in oral corticoster- 25. Iqbal K, Halsby K, Murray RD, et al. st ae oid use in patients receiving omalizum- Glucocorticoid management of adrenal re ab for al ergicasthma in the real-world insufficiency in the United Kingdom: v setting. Al ergy Asthma Clin Immunol. assessment using real-world data. Endo- 1: se 2013;9(1):47. doi: 10.1186/1710-1492-9- cr Connect. 2019;8(1):20-31. mur 47. foa 17. Bel EH, Wenzel SE, Thompson PJ, et mh al. Oral glucocorticoid-sparing effect of st a mepolizumab in eosinophilic asthma. N er Engl J Med. 2014 Sep 25;371(13):1189- ev 97. se 18. Nair P, Wenzel S, Rabe KF, et al. Oral glucocorticoid-sparing effect of benrali- zumab in severe asthma. N Engl J Med. 2017 Jun 22;376(25):2448-58. 19. Rabe KF, Nair P, Brussel e G, et al. Ef- ficacy and safety of dupilumab in glu- cocorticoid-dependent severe asthma. N Engl J Med. 2018 Jun 28;378(26):2475- 85. 20. Boulet L-P, Godbout K. Oral corti- costeroids tapering in severe asthma. 3 Multidisciplinary Approach in Severe Asthma The Multi-Disciplinary Team Approach to Specialist Adult Difficult Asthma Care 3.1 Ramesh J Kurukulaaratchy1,2,3,4 and Chellan Eames4 1 Clinical and Experimental Abstract Sciences, University of Difficult-to-treat (or difficult) asthma presents a chal enging multidimensional model of Southampton, Southampton, UK chronic disease that imposes a significant burden at both individual patient and wider societal 2 David Hide Asthma and Allergy levels. Within that model of disease there is increasing understanding of the diverse range of Research Centre, Isle of Wight NHS Trust, Isle of Wight, UK asthma phenotypes that might be encountered. There is also the growing realisation that these do not occur in isolation but exist within a wider multimorbidity disease framework. Identify-3 NIHR Biomedical Research Centre, University Hospitals ing these other treatable traits that exist within the setting of difficult asthma has shown capa-Southampton NHS Foundation Trust, Southampton, UK bility to improve patient outcomes. In that context, application of structured approaches to patient assessment have shown good efficacy, both at more general as wel as specialist care levels. 4 Asthma, Allergy and Clinical Immunology, University Hospitals So too have multidisciplinary team approaches to difficult asthma care. The combined roles Southampton NHS Foundation of the Asthma Specialist Physician, Asthma Nurse Specialist, Asthma Pharmacist, Speech & Trust, Southampton, UK Language Therapist and Asthma Dietitian in that regard are evolving rapidly. In this chapter we review the multimorbidity model of difficult asthma and how best to approach that via multi-disciplinary team working approaches when undertaking specialist management of adult difficult asthma in clinical practice. Keywords: difficult asthma, multi-disciplinary team, multimorbidity, treatable traits Introduction – Burden, Disease dependency, higher treatment needs and po- Mechanisms, and Definitions of Difficult- tential mortality risk. Though representing a to-Treat Asthma small proportion of the asthma population, Asthma is a common but heterogeneous subjects with more severe disease account for a chronic inflammatory airway disease respon- disproportionate burden imposed by this dis-sible for associated symptoms of breathless- ease. They are estimated to account for at least ness, chest tightness, wheeze and cough. It is 50% of asthma-associated healthcare costs3. estimated to affect over 300 mil ion people Therefore there has been a concerted effort in global y across the life course1. Most people recent years to better understand the nature with asthma can attain good disease control and driving mechanisms behind more severe with standard inhaled therapies administered asthma and develop effective treatments for it. in line with conventional guideline-based ap- Our current pharmacotherapeutic ap- proaches2. However, around 5-10% of peo- proach to asthma is moulded to the Type 2 (T2) ple with asthma have more complex and inflammation pathophysiological paradigm difficult-to-control disease that is associat- of asthmatic disease. This concept of “T2-ed with greater disease morbidity, healthcare high” and “T2-low” asthma inflammatory https://doi.org/10.26493/978-961-293-157-5.45- 65 endotypes4 defined by the presence or absence ly clinical practice. Thus there is also a grow-of T2 inflammatory processes has become ing understanding that problematic asthma is the central polarizing lens through which we seldom purely severe asthma in isolation but view asthma pathophysiology. T2 inflamma-often part of a wider constel ation of adverse tion may be driven by either (CD4+) Type 2 health issues. Attempts to highlight this by helper (Th2) lymphocytes or innate lymphoid adoption of specific terminology with discrete cel s group 2 (ILC2).5 Th2 lymphocytes pro-definitions for “difficult-to-treat (or difficult) duce critical “asthma-genic” cytokines in- asthma” and “severe asthma” have been pro- cluding interleukin (IL)-4, IL-5 and IL-13. posed as outlined by the Global Initiative for IL-4 promotes IgE production by B lympho-the management of Asthma (GINA)13. Using 46 cytes, increases low-affinity CD23 (F RII) Cε that perspective, difficult asthma describes IgE receptor expression on B lymphocytes and asthma in which aggravating co-morbidi-macrophages while directing class switching ties, inadequate treatment, suboptimal in-of naïve CD4 T-helper lymphocytes to the T2 haler technique and/or poor adherence may type.6 IL-13 shares a common receptor (IL-individual y or col ectively impede good asth- s 4Rα) with IL-4 and shows similar effects in- ma control. This broad definition also encom- wie cluding promoting IgE production and CD23 passes the subset of patients with truly severe vl expression.7,8 IL-4 and IL-13 also induce gob- asthma that remain sub-optimal y control ed aic let cell metaplasia and MUC5AC produc- despite optimised treatment of both asthma inl c tion, driving mucus production too.8 IL-5 is and contributory factors13-17. Severe asthma dn a key driver of eosinophilic processes, respon- has been defined by the ERS/ATS as asthma a sible for eosinophil migration into the asth- which requires treatment with guideline sug- sica matic airway where they are a predominant gested medications for GINA steps 4–5 asth- - ba cell type in T2 disease.9 Eosinophils are now ma (high dose ICS & long acting beta agonist mh commonly regarded as the prime target for a (LABA) or leukotriene modifier/theophyl-st a range of evolving asthma treatment options line) for the previous year or systemic steroids ere from newer inhaled corticosteroids (ICS) and for > 50% of the previous year to prevent it v other prophylactic medications to monoclonal from becoming ‘ uncontrol ed’’ or which re-1: se antibody biologic treatments. The last 5-years mains ‘ uncontrol ed” despite this therapy18. mur have seen a proliferation of higher level bio- For this definition, uncontrol ed asthma was fo logic asthma treatments enter clinical practice defined as at least one of: poor symptom con-am global y with undoubted improvements in pa- h trol (as measured by standard measures such st tient outcomes. These include agents such as a as Asthma Control Questionnaire or Asth- er Omalizumab, Mepolizumab, Reslizumab, ma Control Test), frequent severe exacerba-ev Benralizumab and Dupilumab. Yet not al tions (2 or more bursts of systemic steroids se patients respond well to biologic treatments10. for at least 3 days at a time in the past year), Furthermore, recent studies have also shown serious exacerbation (at least 1 asthma hos-that fol owing a thorough characterization, pitalisation in the past year), or airflow lim-most patients with more problematic asthma itation (pre-bronchodilator FEV , Forced Ex-1 fall into the T2 category of disease suggest- piratory Volume in 1 second <80% predicted ing the need to look beyond that simple patho- alongside reduced FEV /FVC [Forced Vital 1 physiological paradigm in the future11,12. Capacity] defined as less than the lower lim- As our understanding of the pathophysi- it of normal). In paral el there is increasing ology of more severe asthma has grown, so has emphasis on thorough and holistic assessment our recognition of the context in which that of patients with more difficult asthma. With disease exists in patients encountered in dai-such approaches it is becoming evident that fol owing comprehensive assessment, a large patients with problematic asthma have poten-proportion of patients with more problematic tial y modifiable treatable factors if those are asthma actual y fall into the category of dif-identified through an appropriate compre- ficult rather than severe asthma. Two recent hensive and holistic assessment process. European studies have highlighted this point. In a study of 1034 asthma patients attending Difficult Asthma as a Multimorbidity 4 respiratory clinics in Denmark, 17% were Difficult Breathing Syndrome classified as having difficult asthma fol ow- – The Concept of Treatable Traits ing application of ERS/ATS criteria for dif- Clinicians readily acknowledge that a pro- ficult asthma based on treatment levels. In portion of patients with asthma do not attain those subjects after a systematic assessment good asthma control despite full optimisation process, only 12% fulfil ed the stringent crite-with currently available asthma treatments. ria for severe asthma in isolation, while 56% This concerning fact was the focus of a Lan-fell into the category of difficult asthma and cet 2017 Commission “After asthma: redefin-47 32% had overlapping features of both19. In ing airways disease”.21 In addition the realisa-e a Dutch pharmacy database study of adult tion is dawning that poorly control ed asthma ra asthma patients, 17.4% met criteria for hav- seldom occurs as an isolated health problem. ca ing difficult asthma. Fol owing an Innovative m In particular at the more “difficult-to-con- h Medicine Initiative (IMI) definition based on st trol” end of the spectrum asthma often con- a adherence and good inhaler technique to dis- stitutes part of a multimorbidity constel ation ltu tinguish those with severe refractory asthma, of conditions best regarded as a “Difficult only 20.5% of these difficult asthmatics were iffic Breathing Syndrome” rather than “severe d deemed to have severe asthma20. These find- asthma” alone (Figure 1). This has led to ltud ings col ectively signal the point that most the need to adopt a more holistic perspective a istliac speo thcao ppr amae tyrain ipl isc i-d ltu meht Figure 1. The “Difficult breathing syndrome” in difficult asthma. Abbreviations: T2 – Type 2 inflammation, ABPA – Al ergic Bronchopulmonary Aspergil osis, SAFS – Severe Asthma with Fungal Sensitisation, COPD – Chronic Obstructive Pulmonary Disease, GORD – Gastro- oesophageal reflux disease. 48 swie vl Figure 2. Comorbidities in the Wessex AsThma CoHort of difficult asthma (WATCH) study. aic Abbreviations: GORD – Gastro-oesophageal reflux disease. inl cdn a to understand the numerous chal enges faced An important new taxonomic approach sic by patients with problematic asthma. to airways disease based on identifying and a Real-world studies clearly demonstrate managing component factors rather than ge- - ba the significant level of ongoing comorbidity neric disease labels such as asthma was re-mh seen in patients with difficult asthma. For ex- cently proposed by Augusti et al to provide st ae ample in the Wessex AsThma CoHort of dif- structure to this understanding of multimor- re ficult asthma (WATCH) study based in the bidity in airways diseases like difficult asth-v tertiary referral Difficult Asthma Clinic at ma.23 Such potential y modifiable factors, 1: se Southampton, United Kingdom (UK), high m known as “treatable traits” are broadly cat- ur prevalence of physical comorbidities like rhi- egorised as pulmonary, extrapulmonary and fo nitis and gastro-oesophageal reflux disease a behavioural in nature and occur concurrent- m (GORD) were noted. But so too were psycho- h ly in combinations that may be specific to an st physiologic comorbidities like anxiety, depres- a individual patient. Pulmonary traits might in- er sion, dysfunctional breathing patterns and in- clude fixed airflow limitation, small airways ev ducible laryngeal obstruction/vocal cord disease, pattern of airway inflammation (eo-se dysfunction (Figure 2). Recent findings from sinophilic, neutrophilic, mixed inflammatory, the WATCH study have also demonstrat-paucicel ular), al ergic fungal airways disease, ed differing associations of these various co- aspirin exacerbated respiratory disease, bron- morbidities with difficult asthma phenotypes chiectasis, airway infections and dual COPD. based on age of asthma onset/sex which merit Extrapulmonary traits could include rhinitis, wider understanding.22 In particular, psycho-chronic rhinosinusitis (with or without pol- physiologic comorbidities and obesity tended yps), gastro-oesophageal reflux disease, obe-to be commoner in females with difficult asth- sity, obstructive sleep apnoea, physical decon- ma in that study highlighting other treatment ditioning, dysfunctional breathing, inducible options beyond asthma pharmacotherapy for laryngeal obstruction (ILO)/vocal cord dys-particular subgroups.22 function (VCD), anxiety, and depression. Behavioural traits include poor inhaler tech-comorbidities in such patients. That in turn nique, poor treatment adherence, distort- has been accompanied by an increasing focus ed symptom perception and smoking. A core on multidisciplinary team (MDT) models of purpose of this structured approach of identi-care centred around a systematic assessment fying treatable traits is to acknowledge the un- process in order to meet the diverse support derlying complexity of clinical presentation in needs of this patient group. Such structured a manner that facilitates more precise asthma models of care will inevitably vary according management which is personalised and ho-to healthcare system and available resource. listic. This a notable shift from the “one size This structured approach lends itself particu-fits al ” approach encouraged by traditional larly well to implementation via specialist care guideline-based management strategies that centres for patients with difficult asthma. In have been the mainstay of clinical manage-countries such as the UK this approach has ment in recent decades. been further aligned to a process of region- Treatable traits are common in diffi- al specialist centres for difficult asthma sup- cult asthma where they may cluster to varia- 49 porting regional networks of care29. These ble degrees in individual patients.16,17,24-26 One centres must meet specified resource require-er study indicated a median number of 3 comor- a ments and are subject to quality benchmark- ca bidities per patient attending a specialist-re- ing on core outcomes. While the UK spe- mh ferral difficult asthma clinic in Melbourne, cialist commissioned framework offers one st a Australia.27 Of note, the burden of treatable systematic approach, data has consistently ltu traits appears to align with worse asthma out- shown that comprehensive assessment with- comes such as exacerbations, asthma control in more specialised difficult asthma care re-iffic d and quality of life.17,23,25 Conversely systematic alises improvements in patient asthma status ltu clinical approaches that incorporate address- regardless of geography or healthcare sys- d a ing treatable traits in asthma has also recently tem.27,30,31 Thus a 3 step systematic approach istl shown clinical effectiveness in improving out- to difficult asthma specialist care based on iac comes for this patient group.27,28 This model of diagnostic confirmation, comorbidity detection and inflammatory phenotyping was as- spe difficult asthma as a Difficult Breathing Syn- o t drome with numerous treatable traits further sessed in Melbourne, Australia.30 This result-hca stimulates the need to engage a systematic ap- ed in significant improvements in comorbid o proach to assess and manage such patients conditions like chronic rhinosinusitis and dys-ppr a and take into account multi-disciplinary ap- functional breathing. It also resulted in signif- ma proaches based on individual patient need. e icant paral el improvements in asthma relat- ty ed outcomes such as asthma control, asthma ra Structured Multi-Disciplinary Team related quality of life and exacerbation fre- in ipl Approaches to Difficult Asthma Care quency. Further work from the same research isc The recognition of difficult asthma as typical- group has more closely focused on asthma pa- i-d ly constituting a multimorbidity disease model tient-related outcome measures.31 This found ltu alongside the growing portfolio of higher level that a systematic assessment framework in me biologic medications has led to a growing con- h difficult asthma specialist care realized sig- t sensus that there is a need to adopt an increas- nificant improvements across multiple asthma ingly structured and holistic approach to care domains. These included a halving of main-for patients with difficult asthma.13,29 A key tenance oral corticosteroid dose (regardless advancement that has accompanied that con-of biologic co-administration) and achieve- sensus has been to both address the asthmat- ment of minimal y important differences for ic component as well as relevant aggravating asthma symptom control and quality of life in over 50% patients. Reduced exacerbations registries and access to relevant supporting re-were found in 64% patients while 40% pa- sources. A structured electronic template to tients improved their FEV by ≥ 100ml. Im- guide severe asthma systematic evaluation 1 provement in at least domain was found in has also been recently created in the form of 87% of patients undergoing that systemat-SAGE (Severe Asthma Global Evaluation) to ic assessment. Of note, the improvements encourage consistency in the systematic as-demonstrated in this study were independent sessment process34. It contains up to 282 input of biologic treatment initiation, highlighting fields but utilises auto-calculations and deci-the value of early adoption of such approach- sion making tools to streamline the process. es in the patient care pathway to ensure focus- The case to base difficult asthma care 50 ing the right treatments on the right patients, on a systematic multidisciplinary assessment at the right time. In that context, structured framework seems entirely logical and wel assessment can be applied at different points supported by an emerging evidence base as along the asthma care pathway, not just in a discussed above. However, that approach specialist centre environment. SIMPLES was is not without potential difficulties at mul-introduced as a tool for use in primary care to s tiple levels as recently highlighted by Majel- w support management of patients with poorly ie lano et al.35 These problems might be down to v control ed asthma.32 The SIMPLES approach l the physician with poor adherence to guide- aic encompassed self-management, education, lines and checklists, alongside underuse of di-inl monitoring, lifestyle (with emphasis on smok- c agnostic tests and available referral pathways. d ing status) in addition to pharmacotherapy. n They may also reflect issues of communica- a The specific assessment domains in SIMPLES tion and different perceptions of management sic comprised smoking status, inhaler technique, a goals between physician and patient. A re- - b monitoring, pharmacotherapy, lifestyle, edu- a cent US study further emphasized the poten- m cation and support. Often ignored facets such h tial discordance in recognition of asthma con- st as regular review and accessibility were also a trol between physician and patient. Of note it e recognised and given prominence. This was re demonstrated a tendency for under perception v coupled to guidance on when to refer from primary to specialist care. Another important of symptoms and asthma control by patients 1: se when assessed by parameters such as Asthma m component to SIMPLES was the early adop- u Control Test or GINA asthma control crite- r tion of digital technologies with web-based fo ria.36 Other critical barriers to optimal multi- a access to both the SIMPLES framework and m disciplinary assessment and care may also oc- h relevant assessment tools. More recently the st cur at an organisational/resource level with a Severe Asthma Toolkit was developed as a er holistic resource to support structured multi- inadequate clinical staffing, clinical space and ev disciplinary care for patients with severe asth- capacity. Such factors may place limitations se ma across the healthcare spectrum.33 Devel- on access to both assess, review and treat pa- oped by a consortium of multidisciplinary tients in a timely and ideal fashion. experts with patient and advocate codesign, this resource was established in the format of The MDT Components of Specialist an easily accessible website. Content included Difficult Asthma Care in a Specialist background information about severe asth-Clinic ma, diagnosis and assessment, management, In a Specialist clinic setting, the assembled MDT medications, comorbidities, living with severe typical y will include a range of healthcare asthma, information on establishing a clini-professionals including Consultant Respirato- cal service, specifics to paediatric and adoles- ry Physicians, Consultant Al ergists, Asthma cent care, advice on specific population needs, Nurse Specialists, Asthma Physiotherapists, Asthma Psychologists, Asthma Pharmacists, endotype to define the core type of asthma Speech & Language Therapists and Dieti-that is present. In paral el, they need to assess tians. Patients referred into such services wil factors such as adherence to treatments and general y undergo comprehensive assessment issues of inhaler technique to identify if such at the point of referral fol owed by appropri-treatment related factors explain why that pa- ate pharmacotherapeutic treatment chang- tient’s asthma is not well control ed. Their es. They then have regular fol ow-up with ap- assessment must also search for all possible propriate members of the MDT as dictated aggravating comorbidities that might a) neg-by individual need. Such MDT’s typical y re- atively impact on asthma control or b) them- view cases on a regular (often weekly) basis in selves drive symptoms of breathing difficulty a meeting setting to achieve group consensus that lead to a misperception of those symp-on appropriate treatment steps culminating in toms as being driven by asthma when they approval for higher level biologic treatments are not. In order to achieve this understand-once the MDT is satisfied that other appropri- ing they will need to undertake and interpret a range of objective measures to aid asthma 51 ate actions have been addressed. This struc- tured pathway meets the important goal of characterization including blood tests (ful er blood count, Total IgE, aspergil us serology), a ensuring that all other facets of patient need c al ergy skin prick tests to a standard aeroal er- a are met rather than simply escalating to high- m gen panel appropriate for that locality, lung h er and higher asthma therapies in the hope of st improving refractory breathing difficulties. function testing (spirometry with bronchodi-alt lator reversibility plus gas transfers), measures u It should therefore maximise the chances of improving healthcare status and facilitate ra- of airway inflammation (Fractional Exhaled iffic tional use of higher-level costly biologic medi- Nitric Oxide [FeNO] +/- induced sputum d differential counts) plus radiological imaging ltu cations where they are truly indicated. d (chest radiography +/- High Resolution Com- a In the fol owing sections we review the puted Tomography [HRCT] chest). They wil ist roles of different MDT members involved in l also need to undertake a range of screening iac difficult asthma care. assessments for comorbid conditions and their spe severity using standardised disease monitor- o The Asthma Specialist Physician th ing tools such as the Nijmegen Questionnaire ca In the Specialist clinic setting, a Consultant (to assess breathing pattern disorder), HADS o (or equivalently experienced) Respiratory (Hospital Anxiety and Depression) score (to ppr a Physician with subspecialist expertise and ex- assess psychological comorbidity status), Ep- mae perience in managing difficult asthma plays worth score (to assess for sleep apnoea) and ty a central role in directing patient treatment r SNOT-22 (to assess for rhinitis).39-42 The use a and overseeing an individualized approach in of such questionnaires as a standard compo- ipl to multidisciplinary patient care. In simple nent of the assessment process has been asso-isc terms they might be viewed as the conductor ciated with significantly better identification i-d of the MDT orchestra. Their role will initial- of asthma-related comorbidities though it can ltu ly focus on establishing that the patient does be time consuming and onerous for the pa-me indeed have asthma. This basic step is impor- h tient in the short-term.43 t tant as it has been shown that after a thor-Fol owing the initial comprehensive eval- ough evaluation process a not insubstantial uation process, the Specialist Asthma Phy-minority of patients (5-12%) may be deemed sician needs to determine appropriate asth-to not have a diagnosis of asthma.37,38 If asth- ma focused pharmacotherapeutic strategies ma seems probable, the Physician then must and establish potential timelines to consider determine patient asthma phenotype and/or higher level biologic asthma therapies should conventional approaches meet with limit-with the patient, gain understanding of their ed success. At the same time they have to ap- hopes and fears and gain their confidence. A propriately consider the need to involve oth- further important nursing role, both initial- er core members of the MDT in patient care ly and then longer term, is to support patient including Nurse Specialist, Physiotherapist, understanding of their condition and the rel-Psychologist, Dietitian and Speech Therapist. evant aggravating factors that need to be ad-Furthermore, they need to consider any need dressed to aid their asthma management. to refer to other specialists to address particu- These might include education on aeroal er- lar comorbidities (e.g. Gastroenterologists and gen avoidance, smoking cessation, mitigat-Otolaryngologists for example). ing exposures to other irritants and measures 52 In addition to a good understanding of such as weight loss and improved physical ac-asthma management, the Specialist Asthma tivity. Another important function of the Spe-Physician must have a good working knowl- cialist Nurse is to support patient manage- edge of managing relevant comorbidities. ment by interlinking with other members of A difficult asthma MDT would also benefit the MDT including the Consultant, Physio-from having multiple Specialist Asthma Phy- s therapist, Psychologist, Speech Therapist, Di- w sicians in order to ensure resilient capacity ie etitian and Pharmacist as well as the patient v to meet the demands placed on that service. l during the course of the patient journey. a That also offers the opportunity to create a ic Ensuring optimal inhaler technique, de- in Specialist team with a diversity of overlap- l veloping sustainable self-management plans cd ping clinical expertise which can then prove n and achieving good adherence to both medi- a helpful in complex case management. In that cations and other aspects of that management sic context having Physicians within the difficult a plan are all activities that Specialist Nurses - b asthma MDT who have added expertise in a also are well placed to deliver. These should m Al ergy, Bronchiectasis, COPD, Sleep Medi- h be addressed at the outset but need regular st cine and ILO/VCD can significantly enhance a reassessment and reinforcement over time as e the effectiveness of that MDT. r improvements in these areas may wane over ev time. In that regard, poor inhaler technique The Asthma Nurse Specialist 1: se is commonplace among asthma patients, po- m Asthma Nurse Specialists sit at the core of any u tential y present to some degree in most pa- r difficult asthma MDT where they fulfil a va- fo tients at some point, and remains an ongoing a riety of key roles at different stages of the pa- m issue that facilitates poor asthma control.44-47 h tient journey as outlined in Figure 3. st A Cochrane database review of studies assess- a When a patient is first assessed in a diffi- e ing impact of strategies to improve inhaler re cult asthma service, the Specialist Nurse may v technique found some benefit for asthma con- se undertake a supportive role with many of the initial objective assessments. These might in- trol and quality of life but general y did not clude performing aeroal ergen skin prick test- result in consistent or important clinical bene- ing, blood sampling and FeNO testing to fits.48 This may in part reflect the heterogene-inform asthma characterization as wel as ad- ity and inherent biases of studies assessed in ministering a range of questionnaires relat- that review. Conversely a recent systematic re- ed to both asthma control and relevant ag- view of critical inhaler errors and their impact gravating comorbidities. These actions are on health outcomes did identify some stud-time consuming. However, that time spent by ies that found beneficial impact of strategies a Nurse Specialist with a new patient at the to improve inhaler technique in relation to outset of their Specialist Care can provide inasthma outcomes.49 There is also a major role valuable opportunity to establish a rapport for the Asthma Nurse Specialist in assessing and addressing issues with suboptimal adher-As Specialist difficult asthma care evolves ence to inhaler treatments in conjunction with with the emergence of a wide portfolio of T2 Asthma Specialist Physician, Pharmacist and targeting biologic asthma therapies, so anoth-sometimes the Psychologist. er significant role for the Asthma Nurse Spe- Self-management is a multicomponent cialist is taking form. This is to supervise the approach that gives patients the confidence administration of these new agents and often to deal with medical management, role man-coordinate that with new modalities of treat- agement and emotional management of their ment delivery such as homecare and self-in-chronic health conditions. Use of an asth- jection. In addition the Asthma Nurse Spe- ma self-management plan, including regu- cialist is central to monitoring of treatment lar monitoring of asthma symptoms and lung response during the initial treatment trial and function, plus clear guidance on appropriate for assessing continued response thereafter, management strategies can significantly em-with surveil ance of need for a switch of bi- power patients to take more effective con- ological therapy should response to the ini- tial biologic drug wane over time. These new 53 trol of their asthma. Specialist Nurses have a crucial role in guiding such strategies. A core biologic agents deliver significant improve-er ments in patient outcome for a majority of pa- a value of self-management in a variable state c tients.56-59 One area of opportunity in biologic a like asthma is recognising worsening features m responders is to significantly reduce mainte- h and guiding early action. Thus self-manage- st nance oral corticosteroid (OCS) burden in a a ment strategies have been shown to improve lt proportion of previously OCS dependent pa- u asthma control, quality of life while reduc- ing exacerbations and acute healthcare us- tients. This has highlighted another impor- iffic tant role for the Asthma Nurse Specialist in d age without increasing healthcare costs.50 lt guiding safe OCS weaning while remaining ud Though self-management should be a core observant for features of secondary adreno-a component of asthma care it is poorly im- cortical insufficiency. istl plemented in routine clinical care despite an A further activity that an experienced iac unacceptable burden of poor asthma out- Asthma Nurse Specialist can undertake is to speo comes.51 Numerous barriers to effective use provide a paral el nurse-led channel of care th of self-management strategies in asthma are with rapid access for designated patients un-cao becoming increasingly understood.52 Build- der a difficult asthma MDT. There is limit- ppr ing on that, development of more versatile ed definitive evidence on such activity in the am setting of difficult asthma. The role of Asth- a and user-friendly asthma self-management e ma Nurse Specialists for asthma in gener- t platforms to aid patients and healthcare pro- yr al was highlighted in a comprehensive re- a fessionals is attracting growing interest and in view which found no significant differences Asthma Nurse Specialists could be integral to ipl in asthma exacerbations, subsequent asthma their oversight and coordination. In particu- isc severity or quality of life between Nurse-led i-d lar, interest on harnessing interactive technol- or Physician-led care.60 That concluded that ltu ogies using patient-friendly digital platforms Nurse-led care was potential y appropriate me is growing. Studies have reported promising h for wel -control ed asthma but suggested the t potential, good patient engagement, usability need to establish the evidence base in those and satisfaction with some approaches.53,54,55. with other levels of asthma control/severi-Therefore, in the future Asthma Nurse Spe- ty. An Asthma Nurse Specialist can provide cialists are likely to need to be able to engage interim review for patients in between their with such new technologies and approaches to Physician appointments during periods of undertake their roles within the MDT. clinical instability or where closer observation is warranted, as in the case of a pregnant dif-discharge outcomes.63 That showed no signifi- ficult asthma patient. Such channels can also cant differences in exacerbations or quality of interlink with acute care pathways and fol-life between the 2 intervention arms, though low-up patients who have had an acute asth- exacerbations remained relatively common ma admission to ensure optimised post-dis- in both. As our own group have subsequently charge care that seamlessly interlinks with shown, a combined MDT approach that links the difficult asthma MDT. An early study in with the difficult asthma MDT may deliver of such post-discharge support identified im-the best results for such post-discharge asthma provements in patient knowledge about their care pathways (see section; Impact of Com-asthma and relevant actions to take which bined Difficult Asthma MDT Approaches).64 54 was accompanied by reduced emergency GP It can be readily appreciated that, as with cal -outs in the fol owing 4 months but no re-the Asthma Specialist Physician, the Asth- duction in hospitalisations for acute asthma.61 ma Nurse Specialist needs to have well devel-That mixed outcome might in part reflect the oped understanding of the nature, assessment nature of the applied intervention. A subse-and management of difficult asthma and rel- s quent study in our own Institution assessed evant comorbidities. Overlapping experience wie impact of Asthma Nurse Specialist patient in other areas of Respiratory Medicine and vl management as part of a Respiratory Physi- in Al ergy are desirable to facilitate these re- aic cian-led pathway for patients with acute asth- quirements. They also need expertise in pa- inl tient education al ied to good communica- c ma in the Acute Medical Assessment Unit.62 dn This intervention led to significant improve- tion skil s, the ability to interact with a range a ments in achieving safe discharge criteria of healthcare professionals and to apply new sica and reduction in 30-day readmission, but at technologies as they emerge. - ba the expense of an extra day in hospital for mh the index admission. The role of an Asth- The Asthma Specialist Pharmacist st a ma Nurse Specialist in such post-discharge As the portfolio and complexity of availa-ere pathways has also been demonstrated in a ble asthma pharmacotherapies expands, the v UK randomised control ed trial comparing Asthma Specialist Pharmacist has become an 1: se nurse-delivered and physician-delivered post increasingly important member of the Asthma mur foamh st aerevse Figure 3. The Multidimensional Role of an Asthma Nurse Specialist. Abbreviations: FENO = Fractional Exhaled Nitric Oxide. MDT. Their role is potential y multidimen-easily interpreted by the Asthma Specialist sional with focused activities including assess- Pharmacist. One obvious drawback of this ment of inhaler adherence, optimisation of approach is that prescription refill does not al-inhaler technique, undertaking patient con- ways equate to actual medication usage. An sultations within the clinical pathway and in- alternative adherence assessment is the FeNO put to providing governance oversight to bio- suppression test used in patients with high logics treatment pathways. baseline FeNO, whereby they undergo daily Suboptimal adherence to asthma thera- FeNO measurement alongside monitored in- pies has long been recognised among patients haler usage.68,69 This has accurately identified with difficult asthma. A UK study over a dec-patients with poor adherence who showed ade ago identified that over one third of such greater fal s in FeNO during the course of the patients had obtained less than 50% of their test. Increasing adoption of electronic tech-prescribed ICS while nearly half of those pre- nologies in healthcare offers opportunities scribed maintenance OCS were found to be with respect to adherence assessment in asth-55 non-adherent to that medication.65 Anoth- ma too. Numerous electronic add-on devices er contemporaneous UK study demonstrat- can yield useful insight into inhaler usage.67,70 er ed that 65% of patients in a difficult asth- a These tools can offer a foundation for dis- ca ma clinic were non-adherent to their asthma cussions with patients on then improving ad-mh medications defined by less than 80% pick herence to inhaled medications. Blood monst a up of prescribed medications.66 In this study, itoring for adherence to OCS has also seen ltu non-adherence was a predictor of poor asth- increasing uptake with development of paired ma outcome including history of needing ven- prednisolone and cortisol assays for use in iffic d tilation for acute severe asthma. A more re- clinical practice for patients on maintenance ltu cent Australian study identified that nearly OCS.71,72 d a 50% of patients assessed in a difficult asth- There are also multiple dimensions to istl ma clinic setting using electronic monitor- non-adherence which might be either a con- iac ing devices were found to have suboptimal sidered intentional act by the patient or a inhaler adherence defined as taking less than non-intentional outcome associated with oth-speo t 75% of prescribed doses. That study also not- er demographic patient factors that influence hc ed that around half of those eligible for cost- a poor medication usage.73 Therefore individ- o ly biologic therapies met non-adherence crite- ualised approaches to addressing adherence ppr a ria for their conventional preventer treatment may be needed dependent on the specific pa-mae regime.67 These studies col ectively highlight tient. An Asthma Specialist Pharmacist may ty a significant problem with non-adherence be well placed to deliver such activity in the ra in this patient population which an Asthma difficult asthma MDT setting, coupled to ac-in Specialist Pharmacist would be well suited to tions such as inhaler training consultations. ipl isc identifying and addressing. However, subjec- Pharmacist delivered asthma inhaler train- i-d tive patient reporting is unreliable and simple ing has been shown to improve both adher-ltu clinical assessment has been shown to be in- ence and asthma control at a general asthma me accurate too.67 Tools such as prescription pick population level.74 Systematic reviews have ht up data and calculation of the medicines pos- demonstrated positive impact of Pharmacist session ratio have gained widespread use.65 delivered interventions on both asthma adher-These probably work best in healthcare set- ence and a range of outcomes.75,76 However, tings with wel -constructed electronic health improved asthma medication adherence may record systems clearly documenting prescrip-not always be fol owed by improved clinical tion issues that can be readily accessed and status in a multimorbid disease model such as difficult asthma. Nevertheless as we trav-demonstrate the efficacy of such methods in erse an era of new biologic asthma therapies, difficult asthma. formal assessment of adherence to conven- Dysfunctional breathing (or breath- tional asthma therapy and optimisation has ing pattern disorder) describes an aberrant become a mandated prerequisite to access-breathing pattern which results in breathing ing biologic therapies in many healthcare sys- difficulty that is often accompanied by other tems such as the UK.29 In such systems, the symptoms including palpitations, chest pain, Asthma Specialist Pharmacist often assumes light-headedness, paraesthesia and anxiety. a central gatekeeping role. It is commonplace among patients with diffi- cult asthma, affecting nearly 50% of subjects 56 The Asthma Physiotherapist in some studies.22,83 Furthermore it may link An Asthma Specialist Physiotherapist can de- with other detrimental comorbidities in diffi- liver 3 important roles in the context of a dif- cult asthma including psychological comor- ficult asthma MDT; chest clearance support, bidities and inducible laryngeal obstruction/ breathing control training and physical exer- vocal cord dysfunction.83,84 An Asthma Spe- s cialist Physiotherapist is central to addressing w cise training. ie this through breathing retraining techniques. v Asthma is a chronic inflammatory dis- l These have shown benefit in the setting of a ease associated with airway epithelial goblet ic asthma in general, as well as in difficult asth- in cell hyperplasia and consequent potential for l c mucus hypersecretion. Some difficult asth- ma.85-88 The high burden of dysfunctional dn breathing in difficult asthma has potential to a ma patients may show a hypersecretory pat- impose significant workload pressures on an sic tern of airways disease with excessive mucus a Asthma Specialist Physiotherapist. It is there- - b production that is associated with airflow ob- a fore encouraging that a digital self-guided m struction and worse asthma control.77 Fur- h breathing retraining intervention has shown st thermore, it is increasingly recognised that a equivalent beneficial impact compared to e overlap airway disease states may arise with r face-to-face Physiotherapist delivered train- ev features of dual asthma, COPD and bron- ing in incompletely control ed asthma.89 chiectasis. Much debate has focused on the 1: se Physical deconditioning and weight gain m concept of an Asthma-COPD-Overlap-Syn- u are recognised features of difficult asthma. r drome that may show bronchitic clinical fea- fo Exercise interventions have potential to im- a tures.78 Bronchiectasis, while complicating m prove asthma control, fitness levels and quality h distinct asthma phenotypes such as al ergic st of life. 90,91 While the evidence base for Pulmo- ae fungal airways disease is estimated to occur in r nary Rehabilitation in COPD is well estab- ev about 1/3 of asthma patients and align with lished, that remains limited in asthma. How-se more severe asthma.79,80,81 Chest clearance ever, a recent study demonstrated positive may be a helpful adjunct tool in the setting effects of such an approach in severe asthma of such dual disease phenotypes. An Asth-with respect to exercise capacity and symp- ma Specialist Physiotherapist may facilitate toms.92 An Asthma Specialist Physiotherapist that by teaching patients techniques such as would be well placed to support these types of active cycle of breathing approaches centred intervention. However, high perceived barrion core components of breath control, thorac- ers to exercise have been documented in dif- ic expansion exercises and forced exhalation ficult asthma in conjunction with associated techniques augmented by use of Positive Ex-comorbidities and airways disease status that piratory Pressure (PEP) devices where appro- can make such management options chal- priate82. There is minimal formal evidence to lenging.93 It can be seen that the Asthma Specialist The Asthma Psychologist Physiotherapist may effectively support a va- Psychological comorbidity such as depression riety of needs for the difficult asthma patient. and anxiety affects at least 1/3 of patients with A recent systematic review has supported that difficult asthma.22 Psychological comorbidity concept demonstrating the benefits of a range in asthma has been shown to associate with of physiotherapy inputs to asthma care.94 worse asthma and psychological outcomes as wel as impaired quality of life.98-103 Clear un- Speech & Language Therapist derstanding of the impact of such health is- Inducible laryngeal obstruction/ vocal cord sues upon the multimorbid disease model of dysfunction (ILO/VCD) is a “middle air-difficult asthma remains to be defined. That it way” disorder characterised by involuntary is likely to have significant impact is suggested narrowing of the vocal folds predominant-by previous findings from our Institution.104 ly during inspiration. It gives rise to symp- In a retrospective study of patients repeatedly toms of breathing difficulty including breath- hospitalised with acute asthma in a 12 month 57 lessness, voice change, and may be associated period, 69.4% had a known psychiatric diag-with the phenomenon of upper airway or nosis alongside frequent other comorbidities era glottic wheeze. It may act as a mimic for asth- including dysfunctional breathing and obesi- ca ma symptoms but has been demonstrated to ty. Such patients accounted for a dispropor-mh be present as an aggravating comorbidity in tionately high number of bed days and associ-st a 15-30% of difficult asthma patients.22,37 Diag- ated healthcare costs. ltu nosis ideal y requires an MDT approach with The Asthma Psychologist can create a input from Asthma Specialist Physician, Asth- personalised approach to support the psycho- iffic d ma Nurse Specialist, Asthma Specialist Phys- logical needs of the difficult asthma patient. ltu iotherapist, Otolaryngologist plus Speech A variety of processes might be utilised in-d a and Language Therapist. Clinical assessment cluding mindfulness therapies and cognitive istl alone might miss the diagnosis which ideal y behavioural therapies. Mindfulness practice iac rests on objective visualisation of the dynam- is centred on non-judgemental acknowledge- ic laryngeal abnormalities at laryngoscopy.95 ment of experiences in order to reduce anx-speo t An alternative empirical diagnostic pathway iety and depression.105 A randomised control hca based around MDT consensus has been pro- trial (RCT) of mindfulness-based stress re- o posed due to restrictions around undertak- duction, found improved quality of life and ppr a ing laryngoscopy during the Covid-19 pan- less perceived stress across 42 patients with mae demic.96 Management approaches remain to mild, moderate and severe asthma (compared ty be validated for ILO in the setting of difficult against a control intervention).106 The feasibil-ra asthma. MDT approaches revolving around ity and positive impact of delivering such in-in the input of a speech and language therapist ipl terventions in a group setting has been shown isc nevertheless show efficacy and are often the in a recent pilot observational study.107 Cogni-i-d mainstay of treatment in centres specialising tive Behavioural Therapy (CBT) provides an-ltu in this condition.97 These typical y employ a other avenue for the Asthma Psychologist to me multicomponent approach that includes pa- h support patients with difficult asthma. This t tient education, strategies to reduce larynge- focuses on stopping negative thought cycles al irritation and tension plus elements of psy- associated with an overwhelming complex is- chological and physiotherapy support where sue such as difficult asthma by breaking that appropriate. down into smal er parts that be more readi- ly addressed. A Cochrane review of CBT in persistent asthma demonstrated some improvements in quality of life, asthma cona framework that can be adapted for future trol and anxiety levels, though wider effects pathways in difficult asthma.113 could not be discerned. Additional y incon- sistent study methodology reduced the degree Impact of Combined Difficult Asthma to which these results could be interpreted.108 MDT Approaches A case series from UK difficult asthma cen- The multimorbid nature of difficult asthma tres il ustrated the potential individual patient ideal y requires an integrated MDT approach benefits that can be obtained using CBT in-to properly address the constituent parts. Sig- terventions.109 nificant benefits from such an approach have A potential role for the Asthma Psy- 58 recently been demonstrated utilising a struc- chologist within a multidimensional interven- tured assessment to identify treatable traits, tion is indicated by the recent demonstration aligned with appropriate MDT involvement of a clustering of extrapulmonary comorbidi-that was coordinated by a nurse case manag- ties in difficult asthma patients with very poor er.28 These included improvements in quality asthma control. These included psychological of life, asthma control and acute primary care s factors such as depression and anxiety plus w asthma visits. Previously an integrated MDT ie obesity and physical inactivity.24 Adequate v approach was established by our Institution la Psychologist resource and time to support the when initiating a tertiary care outreach diffi-ic mental wel being needs of patients under spe- inl cult asthma clinic on the Isle of Wight, UK.114 c cialist services with difficult asthma is likely to d That involved an Asthma/ Al ergy Specialist n become a pressing need within difficult asth- a Physician, Asthma Specialist Nurse, and Al- ma MDT’s. sica lergy Dietitian alongside access to Respirato- - b ry Physiotherapist and Clinical Psychologist. a The Asthma Dietitian m Within 18 months of being under that care h Obesity is a common finding among patients st pathway, difficult asthma patients showed ae with difficult asthma. For example, in the r significant reductions in maintenance OCS e WATCH study the average BMI of patients v use and dosing requirement. In addition sig- was 31, while the prevalence of obesity was 1: se nificant reductions in asthma healthcare uti- m 48%.22 The presence of obesity is associat- u lisation were observed with respect to GP vis- r ed with worse asthma outcomes and greater fo its, Emergency Department visits, Hospital a disease severity. 110 Weight loss strategies can m bed days and Intensive Care Unit bed days. h improve asthma outcomes particularly when st None of the patients in that study received bi- ae combined with other behavioural interven- ologic therapies during the study period. Inte- re tions targeting exercise and/ or mental wel - v grating such MDT approaches to link acute se being.111 The input of a dietitian to support inpatient care and outpatient care can also such interventions could be very impactful but deliver significant benefits for difficult asthma there is little evidence base in the literature on patients.64 An MDT was implemented com-which to guide that role. Another role of the prising Asthma Specialist Physician, Asth-dietitian may be in those asthma patients who ma Specialist Nurse, Respiratory Physiother-have significant food al ergies. The combina- apist and Clinical Psychologist spanned the tion of food al ergy and asthma is mutual y patient journey from inpatient to outpatient detrimental and the role of a skil ed dietitian care. Over the course of 2-years this interven-to establish safe food practices is invaluable in tion reduced repeated asthma admissions by that setting.112 The role of dietitians in allergy 33%, associated bed-days by 52% and associ-practice is wel -established and may provide ated repeat admission costs by 35%. Conclusions 6. Lambrecht BN, Hammad H, Fahy JV. Difficult asthma represents a complex multi- The Cytokines of Asthma. Immunity. morbid disease model with many aspects of Apr 16 2019;50(4):975-91. need that require a wel -structured and high- 7. Ingram JL, Kraft M. 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Ainsworth B., Patel A., Eyles C., et al. t Feasibility and Acceptability of a Group Mindfulness Intervention in a Difficult Asthma Clinic. Mindfulness. 2020 May 15;11:1734-46. 108. Kew KM, Nashed M, Dulay V et al. Cognitive behavioural thera- The Characteristics of Upper Respiratory Tract in the Patients with Asthma and the Patients 3.2 with Episodic Laryngeal Obstruction Irena Hočevar Boltežar1,2 1 University Medical Centre Abstract Ljubljana, Ljubljana, Slovenia Background. Asthma and some other diseases of the upper respiratory tract have similar 2 Faculty of Medicine, symptoms and signs. The signs and symptoms of rhinitis and laryngitis are not unusual in pa-University of Ljubljana, tients with al ergic asthma. Attacks of dyspnea are not characteristic only for asthma but also Ljubljana, Slovenia for some other diseases with pathogenesis in the larynx. Methods. The recent papers on upper respiratory tract characteristics in the patients with asthma and the patients with episodic laryngeal obstruction were reviewed. Results. The connections between the nasal signs and symptoms and asthma are well established what is not the case for laryngeal problems. The laryngeal symptoms and signs in patients with asthma can be caused by the same triggers as asthma. However, they can also be merely the consequences of the asthma signs and symptoms or the asthma treatment. The pathogenesis of the episodic laryngeal obstruction includes a variety of causes which dictate the mode of treatment. In some cases, asthma and episodic laryngeal obstruction can coexist. Conclusions. In order to find the correct diagnosis and proper treatment of the upper respiratory tract problems in patients with dyspnea attacks, a team of different specialists is necessary. Keywords: asthma, rhinitis, laryngitis, al ergy, dyspnea, diagnostics, treatment Upper Respiratory Tract Problems with allergic rhinitis27. The association be- in the Patients with Asthma tween asthma and al ergic rhinitis was exten- sively studied. It is very likely that it is a dis- Nasal Disorders ease occurring simultaneously in both parts The upper and lower respiratory tract share of the respiratory tract11,24,17. In a recent study the same anatomical, functional, pathogen-on molecular mechanisms causing asthma, ic, clinical, and immunological features. The rhinitis and eczema, 15 pathways involved in airborne al ergens activate the similar effec-this multi-morbidity were found2. There are tor cel s in the respiratory tract. Therefore, a limited studies on the risk factors responsible term »the united airway disease« was intro-for the progression of al ergic rhinitis to asth- duced18. It is well known that asthma and al- ma. However, recent data suggest that it is lergic rhinitis appear together in a consider- possible to prevent asthma onset by al ergen able number of patients. In a large study in immunotherapy in the patients with al ergic China, it was confirmed a 29.4% prevalence rhinitis30. of allergic rhinitis in asthmatic patients, and a 20.6% prevalence of asthma in patients https://doi.org/10.26493/978-961-293-157-5.67-74 Laryngeal Disorders of some benign laryngeal lesions46. The third In terms of unified respiratory path (nose, possible way is though the reduction of air middle ear, larynx, lungs), a mediator re-flow coming from the lungs of the asthmatic sponse in one organ can trigger similar re- patient to the vocal folds. Consequently, the sponses along the rest of respiratory tract. available subglottic pressure does not suffice There is a paucity of research on al ergic lar-for good voice quality and causes the speak- yngitis. Some authors even doubt that such er to change the activity of laryngeal muscles entity real y exists. The diagnosis of al er-during phonation in order to compensate for gic laryngitis is a diagnosis of exclusion after the insufficient subglottic pressure46. all other possible diagnoses (laryngopharyn- The fourth possible mechanism of af- 68 geal reflux, retronasal drip as a consequence fecting voice quality is through the influence of sinusitis, laryngeal symptoms due to irri-of asthma treatment on larynx. Dysphonia is tation at working place, etc) are ruled out47. the most common side effect of inhaled cor-Most patients with suspicion of al ergic laryn- ticosteroids treatment. After inhaled steroids gitis complain because of cough, throat clear- exposure the laryngeal findings range from s ing, sensation of a foreign body and excessive vocal fold oedema, erythema, and atrophy to w irregularities of the vocal fold edges, interar- ie mucous in the throat, postnasal drip, and dif- vl ferent voice disorders. When the researchers ytenoid thickening, and supraglottic hyperac-aic studied reaction of laryngeal mucosa to var- tivity19. The vocal fold atrophy results in vo- inl cal folds’ bowing and incomplete vocal folds c ious antigen exposures thick-viscous endola- dn ryngeal mucous and transient or chronic re- closure during phonation. Ozbilen Acar et al. a active vocal folds oedema and hyperaemia proved corticosteroid-associated myopathy sica was noticed in a great majority of the cases39,6. after inhaled corticosteroids treatment by per- - b forming EMG and stroboscopy during thera- a There are several studies showing a link be- mh tween allergic rhinitis and vocal symptoms py and after its cessation. The glottis gap and st a which can improve with increased duration voice disorders improved in several weeks af-er ter the end of therapy35. e of immunotherapy treatment31,44. v Voice disorders are not unusual in the Inhaled corticosteroids produce their af- 1: se patients with asthma. Deteriorated voice fects mostly by local immunosuppression sec-mu ondary to reduced mRNA synthesis35. Lo- r quality was noticed in asthma patients when fo compared to healthy controls with the use calized laryngopharyngeal candidiasis is the am of objective and subjective evaluation meth- most frequently documented infection after h st the use of inhaled corticosteroids. The inci- a ods14. There are several different mechanisms e dence of laryngeal candidiasis associated with r through which the voice quality in asthma pa- ev tients can be affected. According to the theo- dysphonia was estimated at 20% in those se ry of the unified respiratory disease, the vocal taking inhaled steroid therapy50. As a mat-fold mucosa may be affected by al ergic in- ter of fact, the entire microflora of the larynx flammation thus altering the mass of the vocal changes after regular inhalation of corticos-folds and their vibrating characteristics. The teroids, and potential y lead to the occurrence mucous on the vocal folds can give the char-of rare opportunistic laryngeal infections49. acteristic of »wet voice« but also forces the pa- tient to cough. As a matter of fact, cough is Episodic Laryngeal Obstruction one of the most prominent symptoms of asth-Attacks of dyspnea and wheezing are not ma. During cough the vocal folds violently only the typical symptoms of asthma. Sud-strike together causing mechanical trauma, den airway obstruction at the level of the lar-oedema, erythema and even the occurrence ynx was first described as a disturbance in the functioning of the laryngeal muscles in 1842 been reported among individuals with ELO. and was cal ed “hysterical croup”15. Since The authors thought that sudden laryngeal then, more than 70 different names have been closure could be triggered by poorer larynge-used for the problem described. Recently, the al sensitivity or inflammation of the laryngeal terms periodic occurrence of laryngeal ob-mucosa. Another possible explanation could struction or episodic laryngeal obstruction be that the threshold of excitability is lowered, (ELO) have been used, which include the pos-but when it is reached, it triggers a very strong sibility of pathological events both at the lev- reaction in the sense of “all or nothing”13,22. el of the vocal folds and at the level of the su- Some believe that the cause of mainly supra- praglottis9. glottic approximation of structures is the neg- ative inspiratory pressure during rapid deep Etiology breathing which attracts tissues into the lu- The etiology is not entirely clear. Among the men of the larynx. They call it „bottle neck“ possible causes for inducible laryngeal ob- theory based on special laryngeal anatomy 69 struction with breathing disorders many dif- with narrow laryngeal inlet41,40. In the case ferent factors and situations are mentioned: of coexisting laryngopharyngeal reflux from ...a the aerodynamic principles possibly con- the oesophagus, the characteristic oedema of mh nected with age, gender and physical capaci- the laryngeal inlet makes it even more pliable st ty20,45,29,40; alteration of the laryngeal sensibili-and the approximation of aryepiglottic folds ahit ty after stimulation of the supraglottis mucosa is more likely22. ws or direct stimulation of the superior larynge- tn al nerve by laryngopharyngeal reflux, aller- Classification iet gy, infections36,25,40, irritants, temperature and The ELO is divided into three categories ac-paeh humidity of the air in the surroundings26; and cording to the triggering factor: t psychological aspects42,23. in 1. ELO due to irritation (substances from tc Morrison hypothesized that the cause for a the environment, laryngopharyngeal re- r abnormal laryngeal obstruction during inspi- t flux), yr ration is a change in the central nervous sys- o 2. exercise-induced laryngeal obstruction ta tem resulting in hyper-irritable state of the (EILO), sensory and motor pathways. Various patho- spir 3. psychogenic ELO. e physiological processes lead to chronic ir- rr ritation of the laryngeal nerves, and due to In fact, all three forms of ELO can be in- ppe the plasticity of the nervous system, the way tertwined. Airway obstruction can occur at uf the level of the vocal folds or supraglottis, or o the central neurons respond to an incoming sic stimulus may change. Thus, the event trig- at both levels at the same time. In some pa- ist tients, vocal folds’ approach occurs not only r gers a sensory stimulus, and airway obstruc- et during inspiration but also during expiration. c tion occurs due to the hyperexcitable state of ar the neural network in the brainstem that con- Between dyspnea attacks, the patient has no ah trols the functioning of the larynx32. Ayres breathing problems9. ceh and Gabbott believe that the altered balance t of the autonomic nervous system maintained Epidemiology by structures in the central nervous system There are no accurate data on the prevalence plays a role in abnormal vocal folds move-of ELO in the population. ELO is thought ment in patients with ELO5. Frequent prev-to be the real cause of breathing problems in alence of symptoms of laryngopharyngeal re- 10% of patients who are unsuccessful y treat- flux and decreased laryngeal sensitivity have ed for asthma. It is often the cause of breathing problems in patients with certain psychiatric between the two vocal processes of the aryte-disorders (e.g. depression, childhood sexu- noid cartilages9,12. al abuse, obsessive-compulsive disorders)16,4. Women predominate among ELO patients, Diagnostic Procedures with a 3:1 ratio in their favour as reported A group of different specialists should be in-in the professional literature. Problems most volved in the diagnostics of ELO (otorhi-commonly occur between the ages of 20 and nolaryngologist, pulmonologist, gastroenter-40, but patients aged 6 to 83 years have also ologist, neurologist, psychiatrist, psychologist, been described9,23. speech therapist and others according to the clinical picture). The gold standard in ELO 70 More information is available for EILO, one of the subtypes of ELO. EILO occurs diagnostics is a larynx examination using a mostly in adolescent or young adult wom-flexible nasolaryngoscope during the attack en, often top athletes at maximum exercise. of dyspnea. In most cases it is impossible to Among randomly selected young people in have the opportunity to perform the exami-Denmark, at least 7.5% of people with EILO nation and to have the necessary equipment s were identified, and among adolescents with on site. Only in EILO, the diagnostic proce-wie dure can be planned and carried out. Flexible v upper respiratory hyperexcitability, as many la as 26.1% of people with EILO42,8. nasolaryngoscopy is performed during exer- ic cise on a bicycle or treadmill while monitor- inl c ing ECG, lung function, blood oxygen satura- d Symptoms and Signs n tion, and blood pressure fluctuations21,48,40. At a Especial y in EILO, shortness of breath oc- rest or in the period without problems, the la- sica curs and very often also inspiratory stridor ryngoscopic picture is usual y normal. - b during physical exertion, so these patients a In the differential diagnosis of ELO, m are initial y treated for exercise-induced asth- h asthma, especial y stress-induced asthma, st ma33,43. Other symptoms include dysphonia, a anaphylactic and other al ergic reactions, for- er dysphagia, cough, and some patients also re- e eign body in the respiratory tract, angioede- v port a foreign body sensation in the throat ma, laryngospasm, epiglottitis, other upper 1: se or a feeling of discomfort in the chest and respiratory infections, unilateral and bilater-mu throat9. Problems can occur at rest or dur- r al paralysis of the larynx from other causes, fo ing physical exertion, either during the day adductor-respiratory congenital anomalies am or at night. Symptoms of shortness of breath and benign and malignant changes in the lar-h st and inspiratory stridor can be triggered by an ynx, stenosis of the larynx and upper trachea ae identified trigger (e.g. strong odour, irritants r must be mentioned. To exclude other diseas- ev in the air, emotional stress), or they can occur es that can also cause occasional breathing se without any obvious reason. Problems usual- problems and audible breathing, it is advis- ly pass within seconds, minutes rarely lasting able to take a measurement of lung function. longer32. Occlusion at the level of the supra- The flow-volume curve shows a typical de- glottis occurs more frequently. The arytenoids crease in the curve during inspiration dur-descend forward above the entrance to the ing an ELO attack. A methacholine test is larynx, the aryepiglottic folds approach the required to rule out asthma. Positive aller-median line, leaving little room for breathing gy tests, detection of peripheral blood eosin-between them and the epiglottis. In the case of ophils, C1 inhibitor concentrations, and C4 glottis closure, the vocal folds come very close levels distinguish ELO from al ergic mani-together, they can even be practical y com- festations and angioedema9. It is possible that pressed, leaving only a tiny space for breathing exercise-induced asthma and EILO coexist. Among the youth with airway hyperrespon-so it was logical to use proton pump inhibi- siveness, the prevalence of EILO was 26.1%8. tors, ranitidine, and antacids in those patients. The success of such treatment is very good Treatment in those patients in whom reflux has been Team approach is necessary to treat patients demonstrated38,34. with ELO problems. When the correct diag- Surgical treatment also gives good re- nosis is established with appropriate proce- sults, but only in selected patients. The most dures, we can explain the events to the patient commonly used method is to cut the aryepi-in the acute phase and calm him down. In glottic folds closer to the epiglottis and to re-some patients, rapid “dog breathing” is suc- move the mucosa and cuneiform cartilage cessful, in others a slow long breath through from the aryepiglottic fold with the help of a the nose, in others an attempt to smell or pho-laser (supraglottoplasty). The use of a suture nate a high voice / s / or a combination of that pul s the epiglottis towards the root of the these two manoeuvres. Some patients are tongue and lateralization of one vocal cord 71 helped by speaking quickly, loudly, coughing, with a suture is also described28,51. or holding their breath1. Some authors report Pinder and co-workers used a question- ...a the success of diazepine therapy, while oth- naire to determine the long-term course of the mh er authors are not in favour of this method disease. After 15 years of ELO onset, none of st the patients reported deterioration. The con- a of treating acute dyspnea1,9. Christopher and h dition improved or completely recovered in it col eagues were the first to describe the imme- ws diate beneficial effect of inhaling a mixture of 68% of included subjects37. tn helium and oxygen during an attack, and the iet effect of the treatment was not only acute but Conclusions paeh also long-lasting10. Although ELO is benign Respiratory tract acts as a whole. The same t in nature and difficulty breathing ceases af- causes can induce asthma, rhinitis and laryn- int ter a period of time, cases have been described c gitis in some individuals. Some of the larynge- ar where intubation or even tracheotomy was re- al characteristics of the asthma patients can be tyr quired due to severe respiratory distress dur- just the result of asthma symptoms or asthma ot treatment. In others, there are different dis- a ing the attack9. So far, quite a few methods have been eases manifesting the same symptoms of the spire used in the treatment of recurrent problems upper respiratory tract. In some patients, dif-rr with varying degrees of success. Speech ther- ferent pathologies coexist. Therefore, a team ppe apy treatment is based on breathing exercis- of different specialists must be involved in uf o es, exhalation against resistance, strengthen- the diagnostic procedures and the treatment sic ing of inspiratory muscles and relaxation of of asthma, asthma – caused conditions, asth-istr vocal cords9,7. Psychotherapy and counsel- ma-accompanying diseases, and asthma-like et diseases of the upper respiratory tract. c ling help in 30% to 90% of cases, greater suc- ar cesses are of course in the psychogenic form ah of ELO. There are some reports of successful References ceh 1. Adrianopoulus MV, Gal ivan GJ, Gal- t use of hypnosis in the paediatric population3,9. Until a few years ago, experts believed livan KH. PVCM, PVCD, EPL and ir- that gastroesophageal reflux to the level of ritable larynx syndrome: what are we the larynx and pharynx was the main cause talking about and how do we treat it? J of ELO. This is the case in certain patients. Voice. 2000 Dec;14(4):607-18. There are studies that have demonstrated 2. Aguilart D, Pinart M, Koppelman GH, the presence of reflux in patients with ELO, et al. Computational analysis of mul- timorbidity between asthma, ecze- ease. Expert Rev Clin Immunol. 2010 ma and rhinitis. PloS One. 2017 Jun May;6(3):413-23. 9;12(6):e0179125. doi: 10.1371/journal. 12. Chiang T, Marcinow AM, deSilva BW, pone.0179125. et al. Exercise-induced paradoxical vo- 3. Anbar RD. Hypnosis in pediatrics: ap- cal fold motion disorder: diagnosis and plication at a pediatric pulmonary cen- management. Laryngoscope. 2012 ter. BMC Pediatr. 2002 Dec 3;2:11. doi: Mar;123(3):727-31. 10.1186/1471-2431-2-11. 13. Cukier-Blaj S, Bewley A, Aviv JE, et al. 4. Anbar RD, Hehir DA. 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Eur Arch Otorhinolaryngol. 2008 Apr;265(4):485-7. 4 Diagnostic and Therapeutic Chalenges in Severe Asthma Lung Function Tests to be Used in Severe Asthma: Spirometry and Bronchodilator Test, 4.1 Diffusion Capacity for CO, Induced Sputum, Body Plethysmography, Electronic PEF Measurements Matjaž Fležar1,2 3 University Clinic Abstract of Respiratory and Allergic Lung function tests are the cornerstone for asthma diagnostic procedure and patient follow-up Diseases Golnik, Slovenia and is complementary to other phenotyping tools used later for precision diagnosis. Spirome-2 Faculty of Medicine, try and bronchodilator tests are used to define degree and reversibility of airway disease, dif-University of Ljubljana, Ljubljana, Slovenia fusion capacity of the lung for CO is used as exclusion tool for comorbid diseases (particularly COPD), Body plethysmograph is used in small airway asthma to determine the degree of air trapping and hyperinflation, electronic PEF monitoring is used for work-related asthma characterization and targeted sputum examinations (induced sputum protocol) are used in immune phenotyping process. In hands of pulmonologist these tests (not all of them routinely used) are necessary to separate uncontrol ed asthma from severe asthma phenotype. Keywords: lung function tests, severe asthma, work related asthma, asthma phenotyping Introduction histamine vs. al ergen test) BHR can be used Asthma from lung function perspective is a to determine inducible airway constriction, disease detected by smooth muscle hyperres-seen in asthma, COPD, some normal persons, ponsiveness and airway obstruction, which is in children after childhood bronchiolitis, in variable and reversible. All these physiological smokers and in a course of acute bronchitis. hal marks of the disease can be appropriate- The presence of BHR is linked to respiratory ly tested, although the results may vary over symptoms such as chronic cough, nocturnal the course and intensity of the disease. If cho-cough, wheeze, dyspnea on exertion, period- sen in context of a clinical picture of a patient, ic dyspnea at rest, inhalational al ergy-related they can provide most definite diagnostic con-lower respiratory symptoms, etc. firmation of the disease6. In diagnostic procedure of asthma, as- sessment of BHR is in place if pre-test proba- Clinically used Tests and Physiological bility of asthma is at least 30% and not more Background than 70%. It is also not necessary if the patient Smooth Muscle Hyperresponsiveness present with completely reversible airway ob- In case of normal spirometry (no obstruction) struction (normalization of flows, volumes and pretest probability of asthma between 30 and resolution of obstruction – norma-and 70%, a surrogate test to detect airway hy- lization of FEV1/VC ratio) after 400mcg per responsiveness in non-specific or specific of inhaled short acting bronchodilator drug bronchial provocation test (methacholine or (e.g., salbutamol). Proper timing of the test https://doi.org/10.26493/978-961-293-157-5.77-81 is necessary because positive test during the during pol en season and negative dur-acute bronchitis episode and 4-6 weeks after ing wintertime; however, this is more an that could produce false positive result and exemption as a rule. lead physician to false conclusion, that the pa- 2. Workplace-related asthma: the test tient has asthma. Proper timing of the test is could be repeated if new-onset respira- also important in elite sportsmen exercising tory symptoms appear in a patient work- in cold environments (e.g., biathlon runners) ing in asthma-risk workplace; 3-5 years and in diagnostic procedure of work-related after complete removal from workplace, asthma. if test was positive (e.g., in retirement).1,8 BHR test has a high (over 95%) nega- 78 tive predictive value – to exclude asthma. The Repeatability of the test in the same per-positive predictive value varies very much in son within a week is within two doubling con-relation to provocation dose of inhaled agent centrations of the provoking agent. However, and has over 50% of »false positives« in a inter-laboratory repeatability can reach up to range above 2mg cumulative methacholine 300% difference. That methodological issue makes the interpretation of repeated test even s dose. Therefore, if the test is negative at the w more difficult. ie time when the patient has symptoms, we can vl be sure that the patient does not have asthma. a Bronchial Hyper Responsiveness ic BHR is linked to different genetic loci inl on our chromosomes as is atopy. Current ev- vs. Bronchial Reversibility cd idence suggests, that BHR has two compo- Those terms could not be used interchange- n a nents: »inducible« – linked to the level of air- ably since they do not necessary represent sica way inflammation (due to either IgE-mediated the same process within the airways. How- - b and/or neutrophilic-mediated) and »constitu- ever, many epidemiological studies, looking am for population-based bronchial hyper respon- h tive« – linked to the level of airway remode- st siveness have used a significant BD response a ling, hypertrophy of bronchial smooth mus- e as a surrogate marker of BHR. Therefore, r cles and intrinsic properties of smooth muscle ev cel . In that concept, it is understandable, that large population cohort data are hard to interpret. Some patients can have a positive BD 1: se the first part of BHR could be diminished or m test (defined by increase in FEV1 over 12% u even abolished by proper anti-inflammato- r and 200mL) and negative broncho provoca- fo ry treatment of airway mucosa and the sec- a tion test, while other with documented BHR m ond being more inaccessible to treatment. In h most of asthmatic patients their BHR exists could have negative BD response (e.g., COPD st a patients). As already stated, both BD response e over the entire lifetime, even though the level re of BHR may vary significantly and is linked as BHR are dynamical y changing variables vse to expression of their symptoms. over time, depending both on underlying air- Repeated test for BHR is not useful in way inflammation and structural changes. clinical practice. If the first test is done in a proper time, its positive value can be consid- Structural Changes in Airways Linked ered significant. Repeated BHR is also not to BHR recommended to assess the success of medical Airway Smooth Muscle (ASM) treatment (e.g., inhalation drugs for asthma). However, the test could be repeated in certain Human studies in alternations of airway circumstances: smooth muscle function require bronchial bi- opsy and are therefore limited. However, ep- 1. Periodic asthma (al ergen driven sea- ithelial damage of any kind can result in al- sonal asthma): the test could be positive tered smooth muscle function and thickening of basal membrane. ASM hyperplasia (me-of disease and are ideal tools for studying indi- diated through growth factors, epithelial in- viduals who have or are suspected to have ex- flammatory mediators, and extracel ular ma- ercise-induced bronchoconstriction3. trix components) is a key mechanism, most The response to bronchoprovocation probably irreversible with treatments availa- agent is dose (or concentration) dependent. ble nowadays5. Since it is clinical y not feasible to test both hyperreactivity and hypersensitivity (due to Epithelial Damage and Inflammation possibility to induce severe obstruction in for- Epithelial damage (e.g., in viral bronchi- mer), arbitrary point of decease of FEV1 is tis)10 can be a reason for dysfunction in air- chosen as 20% of drop of FEV1 comparing way smooth muscle innervation (particularly the FEV1 after inhalation of normal saline parasympathetic and NANC-non-cholinergic (0.9% NaCl). Patterns of response are shown non-adrenergic) and consequently causing a on Figure 1. transient BHR9,11. In COPD and smokers’ air- Airway obstruction is a term that is derived from spirometric flow-volume curve 79 ways that mechanisms are even more prom- inent. Repair process could lead to col agen and is defined as a decrease of Index Tiffene- ... au (FEV1/VC ratio) for 12% below lower st deposition, basal membrane thickening and e limit of normal. Decrease of expiratory flows t permanent airway narrowing12. r per-se (FEV1 or PEF) is not sufficient for con-ota firmation of obstructive ventilatory defect but il Techniques to Measure Bronchial d can be used (after we define obstruction) as a oh Hyper Responsiveness marker of degree of obstruction (mild, mod- cno Direct and Indirect Bronchial Challenge erate, severe). Since in many cases asthma br (as predominantly large/medium airway dis- d Tests n ease) can affect small airways too, impulse ay ‘Direct’ BPTs measure airway smooth mus- r oscil ometry and/or body plethysmography et cle function, whereas the ‘indirect’ tests re- m measurement are used to define the degree of o flect airway inflammation. Airway caliber is important in determining response to di- bronchial system involvement. : spir Variability of airway obstruction usual y a rect stimuli2. Therefore, the direct chal enges m (but not always i.e., in non-eosinophilic asth- h function best to exclude current asthma when st ma) paral els the intensity of airway asthmat- a they are negative. By contrast, all the indirect e ic inflammation. The variability should be as- re chal enges (exercise, eucapnic voluntary hy- v sessed over time; the best tool is to use PEF perpnoea, hypertonic saline, adenosine mono se measurements for at least 2 weeks, three times in phosphate (AMP) and mannitol) critical y de- d daily at home environment in the period, se pend on the presence of airway inflammato- when the patient describes asthmatic symp- u ry cel s4. Many of the indirect chal enges are be toms. Diary of those measurements (best pro- o dose limited meaning that it is not possible t vided by electronic PEF meter, since compli- s st to push the dose beyond a certain limit that ance of a patient with ordinary PEF meter is e t is limited by physiology (exercise, eucapnic n less than 30%) is assessed day by day and ex- io voluntary hyperpnoea) or solubility (AMP). t cess variability is determined by more than cn Comparative studies have demonstrated that 20% fluctuation of PEF. fu the indirect chal enges are highly specific but g Reversibility of obstruction is assessed by n have a relatively low sensitivity compared bronchodilator test. Improvement of airway lu with methacholine7. Due to their high speci- obstruction after short-acting bronchodilator ficity (and low sensitivity), indirect chal enge (in Slovenia standard is 400mcg of salbuta-tests function best to confirm the presence mol) for at least 200ml increase on either FVC 80 swie vlaicinl cdn a sica Figure 1. Patterns of response to Broncho provocation agent. - bamh st or FEV1 PLUS 12% of pre-bronchodilator scan be repeated, and dynamic changes are ae value is considered positive. In some cases, used as a support for diagnosis as for appro-rev both FVC and FEV1 increase simultaneous- priate treatment. Pre BD spirometric meas- ly – in those patients we should think about urement should always be used in outpatient 1: sem small airway asthma (increase on FVC can be fol ow-up; BD reversibility can detect degree ur due to decrease in air trapping after BD and of current airway inflammation. In latter foa consequently more air available for expiration case, exhaled FENO values are valuable in ti-mh before airway close during expiration). trating anti-inflammatory treatment. st ae Workplace asthma can be either true oc- re cupational asthma (that developed due to al- v Conclusions se Intrinsic airway disease (smooth muscle and lergens at workplace in a previously non-asth-epithelial damage due to asthmatic inflam- matic person) or workplace-exacerbated mation) can be assessed using lung function asthma (usual y in known asthmatic due to ir-measurements. The scope of test differs in re- ritants at workplace – »dirty workplace« asth- spect of timing and activity of disease process ma). Long-term measurements of flows at (i.e., methacholine testing is used in stable dis-workplace (electronic PEF) are necessary, best ease, with normal spirometry; BD test is used in a period on/off place when the patients are in acute exacerbation, longitudinal PEF meas-symptomatic1. urements are used in induced-variability envi- Results of lung function tests should be ronments (e.g., workplace)). Since the disease reproducible. Therefore, standardization of is very variable over time and place, most test procedure in lung function lab is necessary. Screening results (done by spirometry on the 10. Busse WW. Respiratory infections field, e.g., GP office, etc.) should be confirmed and bronchial hyperreactivity. J Al er- and assessed further at the pulmological level. gy Clin Immunol. 1988 May;81(5 Pt 1):770-5. References 11. Hirota S, Hel i PB, Catal i A, et al. Air- 1. Trivedi V, Apala DR, Iyer VN. Occu- way smooth muscle excitation-contrac- pational asthma: diagnostic challenges tion coupling and airway hyperrespon- and management dilemmas. Curr Opin siveness. Can J Physiol Pharmacol. 2005 Pulm Med. 2017 Mar;23(2):177-83. Aug-Sep;83(8-9):725-32. 2. Hargreave FE, Sterk P, Adelroth EC, et 12. Pascual RM, Peters SP. Airway remod- al. Airway responsiveness to histamine eling contributes to the progressive loss or methacholine: advances in measure- of lung function in asthma: an over- ment and interpretation. Respiration. view. J Al ergy Clin Immunol. 2005 1986;50 Suppl 2:72-6. Sep;116(3):477-86; quiz 487. 3. Melil o G, Cocco G, Balzano G, et al. 81 Evaluation of non-specific bronchi- ... al hyperreactivity in different respira- ste tory diseases. Eur J Respir Dis Suppl. tr 1986;147:282-5 ota 4. Bundgaard A, Feilberg V. Bronchial hy- ild perreactivity in al ergic subjects. Eur J ohc Respir Dis Suppl. 1986;143:28-30. no 5. Widdicombe JG. Cel ular basis of bron- br chial hyperresponsiveness. Control dn mechanisms: introduction. Bull Eur ayr Physiopathol Respir. 1986;22 Suppl etm 7:109-11. o 6. Britton J, Tattersfield AE. Does meas- : spir urement of bronchial hyperreactivity am help in the clinical diagnosis of asthma? h st Eur J Respir Dis. 1986 Apr;68(4):233-8. ae 7. Sekizawa K, Sasaki H, Shimizu Y, et rev al. Dose-response effects of methacho- se line in normal and in asthmatic subjects. ind Relationship between the site of airway se u response and overall airway hyperres- be ponsiveness. Am Rev Respir Dis. 1986 o ts Apr;133(4):593-9. ste 8. Cartier A, L’Archevque J, Malo JL. Ex- tn posure to a sensitizing occupational iot agent can cause a long-lasting increase cn in bronchial responsiveness to histamine fug in the absence of significant changes in n airway caliber. J Al ergy Clin Immunol. lu 1986 Dec;78(6):1185-9. 9. Casale TB. Neuromechanisms of asth- ma. Ann Al ergy. 1987 Dec;59(6):391-8. Biomarkers in Severe Asthma 4.2 Marina Lampalo Clinic for Lung Diseases Abstract Jordanovac, Zagreb, Croatia Asthma is the most common chronic respiratory disease, affecting both children and adults. It is an umbrel a term, encompassing multiple phenotypes. Asthma phenotypes may also be identified as clusters of measurements from different dimensions of the disease, and are partly genetical y determined. The mechanisms leading to the disease are complex and it is still a chal enge to choose suitable biomarkers, which have become especial y important with the introduction of biological asthma treatment. Asthma can be broadly divided into T2-high and T2-low molecular endotypes. Early-onset asthma is typical of al ergic phenotype and has so far been the most extensively investigated. The prevalence of adult-onset asthma i si increasing because of the ageing population. This asthma phenotype can be divided into two types considering the existence of eosinophilic inflammation. Various other asthma phenotypes, for instance, exercise-induced, and obesity or smoking-associated asthma, should be taken into account when evaluating the patient. Severe asthma,with the prevalence of 5-10% of all asthma patients, remains a clinical chal enge. Various biomarkers are thus under investigation in the hope of helping researchers and clinicians in better disease evaluation since the individual approach and personalized medicine are imperative. Keywords: asthma phenotype, clusters, biomarkers, eosinophils Introduction Phenotype is by definition an observ- Asthma is the most frequent chronic respira- able disease characteristic which is the re- tory disease1 , with almost 1 in 8 children and sult of gene-environment interaction. These 1 in 12 adults affected2. Since 2016, the Glob-characteristics can be disease symptoms, trig- al initiative for asthma (GINA) has stated that gers, body shape and weight, age of asthma onset, etiology, atopic status, response to the asthma is a heterogeneous disease3. Asthma smoking habit, laboratory findings, biomark-phenotyping is needed for a more precise pa- ers, lung function parameters and presence of tient approach and a better understanding chronic airflow obstruction, bronchodilator of asthma diversity. Asthma heterogeneity is reversibility, reaction to drugs or substances, seen in diverse clinical presentations, different response to treatment, level of asthma con-responses to treatment, and different patho- trol, number of exacerbations, severity and physiological features and findings due to var- speed of asthma deterioration, need for hos- ious pathogenic mechanisms, which lead to pitalization or intensive care unit treatment, multiple asthma phenotypes. including mechanical ventilation, duration https://doi.org/10.26493/978-961-293-157-5.83-89 of quiescent state of asthma, involvement of There is no perfect biomarker, and unlike for upper respiratory airways and/or nasal pol-some other disorders, biomarkers for asth- yps etc. The topic concerning asthma phe- ma are less precise, and still not completely notypes is very important as personalized, known. General y, based on these markers, individual y tailored treatment adjusted to asthma can be divided into two groups, T2-the understanding of underlying phenotype high asthma, and T2-low (or non-T2) asth-mechanisms yields much better results in ma11,10. asthma patients4,5. Continuous improvement of asthma phe- Asthma phenotype description dates notypes and their identification has led to an from the mid-20th century, with Rackeman’s individualized, targeted approach in asthma 84 idea from 1947 about extrinsic and intrinsic therapy, especialy in severe cases. Biomarkers asthma, emphasizing the triggering role of al-are the key to understanding and recognizing lergens in asthma6. After the enthusiasm for phenotypes, and accordingly the key to thera-inhaled corticosteroid treatment in asthma in py and treatment assessment. the’80s of the previous century, and the intro- Type 2 high-inflammation asthma is characterized by eosinophilic airway inflam- s duction of LABAs (long acting beta agonists) w mation, while type 2 low-inflammation asth- ie in asthma treatment in the ‘90s7, with much vl better achievements in asthma control, the ma includes neutrophilic and paucigranulo-aic first decade of the new mil ennium brought a cytic asthma. A larger proportion of cases of inl severe asthma are type 2-high asthma17,18. c rise in the asthma heterogeneity awareness8. d A high level of type 2 cytokines is charac- n However, observable characteristics are a not enough, because of many overlapping teristic of T2-high asthma, and those areIL-5, sica symptoms of the disease, so the common un- IL-4, IL-13, IL-25, IL-33, and thymic stro- - b mal lymphopoietin (TSLP). Biomarkers of a derlying pathophysiological mechanism in m type 2 inflammation have proven valuable for h asthma is important. Due to these facts, a new st a term was developed - asthma endotypes9. endotyping in asthma17,18. ere Biomarkers are specific measurable dis- v ease characteristics. These are quantifiable Biomarker: Type 2 Inflammation 1: se factors distinguishing between physiological m Blood Eosinophils u and pathological processes and could be used r Eosinophils are specialized leukocytes pro- fo as a pathway for therapy selection and ther- a duced in the bone marrow, primarily found in m apeutic response monitoring10. The mecha- h tissues and in the respiratory system, airway st nisms leading to the disease are complex and it a mucosa, and airways, which promote inflam- e is still a chal enge to choose suitable biomark- r mation by releasing an abundance of inflam- ev ers to adequately stratify patients, which be- matory mediators. These mediators, together se came especial y important with the introduc- with those released from T2 cel s, cause eosin- tion of biologicals in asthma treatment11. The ophilic inflammation, bronchoconstriction, key point is biomarkers for the endotypic (and and airway remodel ing. Blood eosinophil phenotypic) criteria. The right combination counts are a potential surrogate biomarker of various biomarkers in different phenotypes for eosinophilic inflammation in asthma and is under investigation hoping to help research-are relatively easy to obtain. However, their ers and clinicians in better disease evaluation levels depend on the time of sampling (high-since the individual approach and personal- est at midnight, lowest at midday), time since ized medicine are imperative11,12. Today, de- eating, exercise, and therapy (corticosteroids fining a severe asthma phenotype is a pro- reduce eosinophilia)13. Although studies of cess based on a biomarker-driven approach10. blood eosinophil count, as predictors of high sputum eosinophils in eosinophilic asthma, mechanism and role of periostin in the patho-have yielded somewhat mixed results, blood physiology of asthma are still unclear. Mouse eosinophil counts have been useful in the se-models suggest that periostin plays a role in lection of patients for eosinophil-targeting mucus production, eosinophil recruitment, agents. The exact cut-off value is still debat-and subepithelial fibrosis. able, but the cut-off used in the clinical tri- In a recent study conducted by Taka- als to define high blood eosinophil counts has hashi et al., it was presented that serum per-ranged between 150 and 300 cel s/μL. Some iostin levels were good predictors of blood eo-studies showed that patients with eosinophil sinophilia (r = 0.36), which could mean that counts above 300 cel s/_L have more frequent periostin levels serve as a biomarker of eosino-exacerbations and acute respiratory events13. philic airway inflammation21,22. 50 ng/L is considered the cut-off in most Markers of Eosinophil Activation studies while values above 50 ng/L are con- The predominant mediators in the eosinophil sidered high periostin levels. The limitation 85 granules are cytotoxic cationic proteins, such of periostin is that it is also secreted by oste-oblasts and the levels can be elevated in some a as eosinophil cationic protein (ECP), and eo- m tumours (brain tumours, bony metastasis), h sinophil-derived neurotoxin (EDN), major st basic protein (MBP), and reactive oxygen spe- and growing children23. aer cies (ROS). Some of these mediators can be ev measured in blood and used as a guide in bet- Dipeptidyl Peptidase-4 - DPP4 se ter asthma clustering, but also as a potential Dipeptidyl peptidase-4 (DPP-4) is expressed insr treatment target. High ECP levels are detect- in a variety of lung epithelial and endotheli- ek al cel s and submucosal glands, however, the r ed in the blood and sputum of severe asthma am patients (mostly atopic), compared to those role in the pathophysiology of asthma is un-bio with non-severe asthma. ECP is associat- certain. DPP-4 can be found in bronchoalve- ed with bronchospasm and airway resistance olar lavage (BAL) and correlates with airway and is elevated in asthma exacerbation, and inflammation in rat models. Studies relat-its levels are reduced after therapy induction. ed to DPP-4 are limited; IL-13 is thought to It is assumed that ECP can be used as a mark-stimulate DPP-4 production, and, like peri- er for corticosteroid induction and dosage, but ostin, DPP-4 can be measured in serum and this needs to be confirmed. EDN is another can be used as a guide to induce anti-IL-13 marker of eosinophilic disease and persistent therapy18,24. airflow limitation in severe asthma patients; it can be measured in serum, urine, and other Immunoglobulin E body fluids14-16. An utterly important predominant biomark- er in patients with asthma is al ergen specific Periostin IgE. IgE is a product of B lymphocytes in re- Periostin is an extracel ular matrix protein se- action to a foreign antigen25. Serum IgE levels creted by bronchial epithelial cel s and lung fi- have been shown to correlate with the severi- broblasts in response to Th2 cytokines, IL-13, ty of asthma. In the case of severe asthma exand IL-4. acerbations, total IgE levels rise, after which In addition to its role in cell prolifera- they fal , and stable levels are reached within tion, invasion and angiogenesis, periostin also 1-1.5 months after the onset of severe exacer-plays a significant role in the development of bations26. Different specific immunoglobulin inflammatory processes, as well as the devel-E and their interactions may be an impor- opment of the T2 phenotype19,20. The exact tant causal mechanism in the development of asthma27. Nevertheless, with the advent of notably increased risk of severe exacerbations targeted asthma therapy, it gained a key role in the year preceding FeNO measurement38. in tailoring individual therapy as well as mon- A recent study by Brooks, Massanari, itoring its effectiveness. Depending on blood Hanania and Weiner found that the imple-levels, total IgE may also indicate other co- mentation of FeNO into pre-omalizumab morbidities (including allergic bronchopul- treatment assessment decreases the expected monary aspergil osis, certain primary im- per-patient cost by almost 50% from the mo- munodeficiencies, infections and infestations ment of omalizumab initiation into therapy, (parasites), inflammatory diseases, and ma-and the same trend continues during the first lignancies)28. year of the omalizumab treatment. Authors 86 point to the obvious benefit of using FeNO for detecting omalizumab responders (prior Fractional Exhaled Nitric Oxide Concentration (FeNO) to initiating a 12-week trial of omalizumab)39. Fractional exhaled Nitric Oxide (FeNO) is used to detect active airway eosinophilic in- Induced Sputum and Airway Inflammation s Studies have demonstrated the usefulness of w flammation, measured by solely non-invasive ie induced sputum to guide asthma treatment v tests35. la Due to its immense importance in the and showed that normalizing airway eosino-ic philic inflammation al owed better control of in differential diagnostic process, fractional ex- l c asthma with reduced exacerbations and hos- d haled nitric oxide concentration (FeNO) has n pital admissions29. The technique of induced a a distinctive role among all biomarkers. Ni- sputum that al ows non-invasive collection sic tric oxide (NO) is normal y found in exhaled a of airway cel s is considered the gold stand- - b breath while patients with asthma often ex- a ard to identify inflammatory asthma phe- m hibit higher levels of NO in their exhaled h notype30. In one study performed using in- st breath, which is thought to be due to the up- a duced sputum, it was shown that compared e regulation of inducible nitric oxide synthase re to the paucigranulocytic phenotype, eosino- v (NOS2) in airway epithelial cel s, the enzyme philic, neutrophilic and mixed granulocyt-1: se in charge of epithelial NO production36. Giv- ic phenotypes were characterised by a poorer mu en that NO levels can be measured relative- r lung function. Eosinophilic phenotype exhib- ly easily, and the test itself is non-invasive and fo ited a higher frequency of atopy, higher lev- am easily repeatable, FeNO has enormous poten- els of IgE, higher bronchial hyperresponsive- h tial in everyday clinical practice. st ness to methacholine, higher FeNO levels and ae The American Thoracic Society recom- r lower asthma control compared to paucigran- ev mends clinical y significant cut-off points for ulocytic. The mixed granulocytic phenotype se FeNO: (1) <25 ppb (<20 ppb in children), and had higher levels of fibrinogen, the lowest lung (2) >50 ppb (>35 ppb in children)37. function and the highest degree of bronchi- FeNO is a biomarker of T2 response (or al hyperresponsiveness to methacholine31. As airway eosinophilia) but does not correlate far as the sputum neutrophilic phenotype is with sputum eosinophils. A FeNO level >50 concerned, there was a weak correlation be-ppb suggests a steroid-responsive inflamma- tween sputum and blood neutrophil count tion, while patients with a FeNO level around taken in percentage. In a study conducted by 25 ppb are less likely to respond to steroids37. Ntontsi et al., it was found that paucigranu- A recent study by Price et al., found that locytic asthma was most likely to be a benign people with a combination of high FeNO asthma type, related to good treatment re-and high blood eosinophils were prone to a sponse32. Smokers did not have a significantly higher proportion of neutrophils in their spu-is no perfect endotype classification. Multiple tum than ex-smokers or never smokers30. In- biomarkers are superior to a single biomark- dependent predictors of sputum eosinophil er. Despite significant improvement in asthma count ≥3% were the percentage of blood eo-understanding, there is still a long way to go sinophils, low FEV1/FVC, and high FENO to resolve the asthma problem in most persons and IgE levels. A cut-off value of 220/mm3 suffering from asthma syndrome. or 3% for blood eosinophils performed equal- ly to FeNO50 ppb to identify the presence of References a sputum eosinophil count ≥3%. Independent 1. Soriano JB, Abajobir AA, Abate KH, predictors of sputum neutrophilia were ad-et al. Global, regional, and nation- vanced age and high FRC, while blood neu- al deaths, prevalence, disability-adjust- trophil count was not31. Sputum eosinophils ed life years, and years lived with disa- >3% can only distinguish eosinophilic vs neu- bility for chronic obstructive pulmonary trophilic, mixed or paucigranulocytes asthma disease and asthma, 1990-2015: a sys- 87 phenotype 33. Using blood eosinophilia per se tematic analysis for the Global Burden as a biomarker for eosinophilic asthma is dif- of Disease Study 2015. Lancet Respir amh ficult due to the daily fluctuations of blood eo- Med. 2017 Sep;5(9):691-706. st sinophils, with or without treatment34. In the 2. Lambrecht BN, Hammad H. The imaer study by Agache et al., serum IL-5 and IL-13 munology of asthma. Nat Immunol. ev were identified as the best blood eosinophilia 2015 Jan;16(1):45-56. se predictors, with a good reproducibility at re- 3. Reddel HK, Bateman ED, Becker A, et insr al. A summary of the new GINA strat- e peated testing after 6 weeks34. kr egy: a roadmap to asthma control. Eur am Conclusion Respir J. 2015 Sep;46(3):622-39. bio Asthma is a complex heterogeneous condi- 4. Fajt ML, Wenzel SE. Asthma phe- tion, and under this broad term, severe asth- notypes and the use of biologic med- ma itself covers several subgroups with spe- ications in asthma and al ergic dis- cific characteristics, symptom profiles and ease: the next steps toward personal- biochemical mechanisms of the disease. A ized care. J Al ergy Clin Immunol. 2015 biomarker is objectively measured and eval- Feb;135(2):299-310; quiz 311. uated as an indicator of normal biological 5. Chung KF. Precision medicine in asth-processes, pathogenic processes, or pharma- ma: linking phenotypes to targeted cologic responses to a therapeutic interven- treatments. Curr Opin Pulm Med. 2018 tion. In severe asthma, biomarkers could be Jan;24(1):4-10. used for diagnosis of phenotype or endotype, 6. Rackemann FM. A working classi-can also be predictive of clinical outcomes fication of asthma. Am J Med. 1947 or response to therapy, and may be dynamic Nov;3(5):601-6. with time or therapy. Ful y determining phe- 7. Greening AP, Ind PW, Northfield M, notype or endotype of severe asthma will re- et al. Added salmeterol versus high- quire the interpretation of combinations of er-dose corticosteroid in asthma patients commercial y available biomarkers. Today, with symptoms on existing inhaled cor- defining a severe asthma endotype is a pro- ticosteroid. Al en & Hanburys Limit- cess based on a biomarker-driven approach. ed UK Study Group. Lancet. 1994 Jul There is no perfect biomarker. Biomarkers for 23;344(8917):219-24. asthma are less precise, and still not complete- 8. A plea to abandon asthma as a dis- ly known. With no perfect biomarkers, there ease concept. Lancet. 2006 Aug 26;368(9537):705. doi: 10.1016/S0140-tial as a diagnostic or therapeutictarget. 6736(06)69257-X. Respir Res. 2015 May 17;16(1):57. doi: 9. Lotvall J, Akdis CA, Bacharier LB, et 10.1186/s12931-015-0218-2. al. Asthma endotypes: a new approach 20. Bentley JK, Chen Q, Hong JY, et al. to classification of disease entities with- Periostin is required for maximal air- in the asthma syndrome. J Al ergy Clin waysinflammation and hyperrespon- Immunol. 2011 Feb;127(2):355-60. siveness in mice. J Al ergy Clin Immu- 10. Tiotiu A. Biomarkers in asthma: state nol. 2014 Dec;134(6):1433-42. of the art. Asthma Res Pract. 2018 Dec 21. Takahashi K, Meguro K, Kawashima 21;4:10. doi: 10.1186/s40733-018-0047- H, et al. Serum periostin levels serve as 88 4. a biomarker for both eosinophilic air- 11. Fajt ML, Wenzel SE. Asthma phe- way inflammation and fixed airflow notypes and the use of biologic med- limitation in wel -control ed asthmatics. ications in asthma and al ergic dis- J Asthma. 2019 Mar;56(3):236-43. ease: the next steps toward personal- 22. Wagener AH, de Nijs SB, Lutter R et ized care. J Al ergy Clin Immunol. 2015 al. 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Clinicoecon Outcomes Res. sre BMC Pulm Med. 2016 May 10;16(1):74. 2019 Apr 17;11:301-7. kra doi: 10.1186/s12890-016-0232-2. m 32. Ntontsi P, Loukides S, Bakakos P, et al. bio Clinical, functional and inflammato- ry characteristics in patients with pauci- granulocytic stable asthma: Compari- son with different sputum phenotypes. Al ergy. 2017 Nov;72(11):1761-7. 33. Korevaar DA, Westerhof GA, Wang J, et al. Diagnostic accuracy of minimal y invasive markers for detection of airway eosinophilia in asthma: a systematic re- view and meta-analysis. Lancet Respir Med. 2015 Apr;3(4):290-300. 34. Agache I, Akdis C, Jutel M, et al. Un- tangling asthma phenotypes and endo- types. Al ergy. 2012 Jul;67(7):835-46. 35. Neelamegan R, Saka V, Tamilarasu K, et al. Clinical Utility of Fractional ex- haled Nitric Oxide (FeNO) as a Bio- marker to Predict Severity of Disease and Response to Inhaled Corticosteroid (ICS) in Asthma Patients. J Clin Diagn Res. 2016 Dec;10(12):FC01-FC6. doi: 10.7860/JCDR/2016/20656.8950. 5 Asthma Phenotypes and Therapeutic Possibilities Asthma and Aspirin Exacerbated Respiratory Disease 5.1 Peter Kopač1,2 and Mihaela Zidarn1,2 1 University Hospital Abstract of Respiratory and Allergic Aspirin exacerbated respiratory disease (AERD) is a disease characterized by the triad of asth-Diseases, Golnik, Slovenia ma, chronic rhinosinusitis with nasal polyposis, and respiratory reaction to cyclooxygenase 1 2 Faculty of Medicine, inhibitors. The prevalence of AERD is estimated is reported to be: 7% in patients with asthma, University of Ljubljana, Ljubljana, Slovenia 15% in patients with severe asthma, 24% in patients with life-threatening asthma, 10% in patients with nasal polyposis, and 9% in patients with unspecific chronic rhinosinusitis. Aspirin and other nonsteroidal anti nflamatory drugs (NSAID) can cause hypersensitivity by different immunological mechanisms that can be classified into 5 categories: NSAID exacerbated cutaneous disease, NSAID induced urticaria or angioedema, single NSAID anaphylaxis, aspirin-exacerbated respiratory disease, single NSAID induced delayed reaction. The clinical picture, pattern of cross-reactivity, disease course, and course of desensitization may also be quite different. It is important to diagnose which disease phenotype is involved. This can be determined in most cases by history. Due to distinctive symptoms, the diagnosis of AERD could often be based on reliable history. In patients with adult-onset asthma, recurrent nasal polyposis and multiple (two or more) reactions after a single NSAID or reactions after two different NSAIDs in the last 5 years the diagnosis could be based on history alone. However, in some cases, further diagnostic tests are necessary to avoid underdiagnosing or over-diagnosing the disease. Cross reactivity between NSAIDs in AERD is not associated with similarity of chemical structure, as it is in IgE mediated hypersensitivity, but it is associated with the strength of COX-1 inhibitions therefore the patient with AERD must avoid all the other drugs which are strong COX-1 inhibitors. Aspirin desensitization in AERD could be performed for two purposes: aspirin tolerance in cardiovascular indication or symptoms improvement in severe cases of chronic rhinosinusitis with nasal polyposis. Keywords: aspirin, asthma, drug hypersensitivity, nonsteroidal anti nflamatory drugs Introduction 19221. Since then this condition has been giv- Aspirin exacerbated respiratory disease en many different names from “Morbus (AERD) is a disease characterized by the tri-Widal”, “Samter’s triad”, “ASA induced asth- ad of asthma, chronic rhinosinusitis with na- ma with nasal polyposis” and “NSAID-Exac- sal polyposis, and respiratory reaction to erbated Respiratory Disease - NERD”. Var-cyclooxygenase 1 inhibitors. It was first de- ious specialists, including pulmonologists, scribed in the literature as a case report by otorhinolaryngologists, and al ergists, treat French professors Widal and col eges in patients with this condition. https://doi.org/10.26493/978-961-293-157-5.93-103 It is important to diagnose if the patient for several days. It is important to distinguish has an AERD, as NSAIDs are widely used these symptoms from anaphylaxis. In NECD as analgesic, antipyretic and cardio-protec- there are only cutaneous symptoms present, tive drugs. NSAID asthma exacerbations in without systemic involvement. The intensi-these patients may occur unexpectedly and ty and the threshold dose for the reaction are may be severe2. Also, aspirin-associated asth-changing through time and the course of the ma is a specific phenotype of eosinophilic disease. The severity of the symptoms is also asthma and with a different treatment deci-dose-dependent. Usual y, NSAIDs are wel sion. Asthma control can be improved by ad- tolerated when chronic spontaneous urticaria ditional treatment with antileukotrienes and, is in remission. Sometimes there are addition-94 in selected cases, by desensitization to aspirin. al co-factors, such as viral disease, psychical Therefore, it is important to define the tolera-or physical stress present, which aggravate the bility of NSAIDs in all patients with asthma disease, and patients better tolerate NSAID and nasal polyposis. without these co-factors. Therefore it is some- times difficult to confirm the diagnosis with a drug provocation test, as results are not al- s NSAID Hypersensitivity w ways replicable. Skin tests have no diagnos- ie Prevalence of hypersensitivity to NSAID v tic value in NECD. NSAID exacerbated cu- la is reported to be 1.6%3. Aspirin and other taneous disease is unpleasant, but it is not life ic NSAIDs can cause hypersensitivity by differ- in threatening. Patients with NECD usual y wel l c ent immunological mechanisms. Therefore, d tolerate selective COX-2 inhibitors and also n the clinical picture, cross-reactivity, disease a the lower dose of aspirin (eg 100 mg as in an- course, and course of desensitization may also sic tithrombotic treatment). However, desensiti- a be quite different. It is important to diagnose - b zation to aspirin is rarely successful in NECD a which disease phenotype is involved. This can m patients and patients should avoid all COX-1 h be determined in most cases by history. st inhibitors in therapeutic dose5,6. a NSAID hypersensitivity can be classified e NSAID induced urticaria or angioede- re into 5 categories: NSAID exacerbated cuta- v ma (NIUA) occurs in patients without the neous disease (NECD), NSAID induced urti- underlying cutaneous disease, but similar to 1: se caria or angioedema (NIUA), single NSAID m NECD patients develop isolated skin symp- ur anaphylaxis, aspirin-exacerbated respiratory toms up to 24 hours after ingestion of at least fo disease (AERD), single NSAID induced de- a two chemical unrelated NSAIDs. Again, m layed reaction (SNIDR)4-7. Mixed pattern, h there is no systemic involvement, in contrast st cal ed “blended reactions” represent the sec- a to IgE mediated anaphylaxis. Sometimes er ond most frequent entity in NSAID hyper- NIUA occurs in patients several years before ev sensitivity simultaneously involving skin and they develop chronic spontaneous urticarial, se airways8 Immunological and clinical charac- but this is not always the case. Cross reactivity teristics of various types of NSAID hypersen- is associated with the strength of COX-1 inhi- sitivity are summarized in Table 1. bitions and not with the chemical structure of NSAID exacerbated cutaneous disease NSAID. Also these patients tolerate wel selec- (NECD) occurs in patients who are suffer- tive COX-2 inhibitors. In contrast to NECD ing from chronic spontaneous urticaria. Ap- patients, desensitization with aspirin is rare- proximately 12-30% of patients with chron- ly successful in NIUA patients. When desen- ic urticaria have worsening of their disease sitized to aspirin, patients do tolerate also oth-and occurrence of generalized hives and/or er NSAIDs5,6. angioedema within 1-6 hours after applica- Single NSAID anaphylaxis is dif- tion of NSAID. Skin symptoms may persist ferent from both phenotypes of NSAID Table 1. Immunological and clinical characteristics of various types of NSAID hypersensitivity. Aspirin-exacerbat- NSAID exacerbat- NSAID induced Single NSAID Terminology ed respiratory dis- ed cutaneous dis- urticaria or Single NSAID induced delayed ease (AERD) ease (NECD) angioedema anaphylaxis (NIUA) reaction (SNIDR) Pathophysiology COX-1 inhibition COX-1 inhibition Unknown, probably COX-1 inhibition IgE mediated T-cell mediated Underlying disease Asthma, nasal polyposis Chronic urticaria none none none Cross reactivity NSAID Cross NSAID Cross NSAID Cross reactive reactive reactive selective selective Timing 30-180 min 1-6 h up to 24h immediate (up to 1h) delayed Bronchial obstruc- tion, nasal conges- Symptoms tion and/or rhin- Urticaria Urticaria orrhea, wheezing, and/or angioedema and/or angioedema Anaphylaxis Various delayed reactions coughing, dyspnea 95 Desensitization Successful Rarely successful Rarely successful Successful Contraindicated in most cases sea ise hypersensitivity described above. The mech- drug reaction, Steven Johnson syndrome, tox- dy anism is IgE mediated immediate al ergy. ic epidermal necrolysis, drug induced nephri-ro Therefore classical symptoms of anaphylaxis, t tis, pneumonitis, etc. The pathomechanism a with pruritus, flush, hives, angioedema, and include specific T cel stimulation. Diagnostic spire systemic involvement with bronchospasm, tests are specific and different for each clin-rd hypotension, and gastrointestinal symptoms ical manifestation. Desensitization to aspirin eta occur immediate, or within 1 hour after ex- is contraindicated in case of a severe delayed bre posure to NSAID. The severity of the disease reaction5,6. ca is usual y not dose dependent. Patients usual- x e ly react to other NSAIDs with similar chem- in Clinical Characteristics of AERD ical structures (and not with similar strength spir of COX-1 inhibition). Skin tests and also ba- The symptoms of AERD do not develop im- ad mediately after taking NSAIDs, but some- n sophil activation tests may be useful in di- a what later, on average 30-180 min after ad- a agnosing this disease. Drug provocation test mh can confirm the diagnosis of al ergy to cul- ministration9. This can sometimes make it sta prit drug, but it is contraindicated in case of difficult to identify the culprit of the reaction. a very severe reaction. Drug provocation test The reaction starts with upper respiratory is useful to confirm tolerance of alternative tract symptoms like nasal congestion and/or NSAID. Desensitization to culprit NSAID rhinorrhea, fol owed by lower airway symp-is possible, but usual y not recommended as toms like wheezing, coughing, and shortness there are many alternatives on the market5,6. of breath. In patients with not, wel control ed Single NSAID induced delayed reaction asthma symptoms usual y occur much quick-is rare. It occurs in patients with no underly- er with more severe bronchospasm which may ing skin or respiratory disease. The onset of even lead to a fatal outcome10-12. The onset the disease is delayed, usual y more than 1 and severity are dose-related, lowest dose pro-day up to weeks after exposure to the NSAID. voking a reaction for individual patients vary It has various clinical manifestations and var-between 100-300 mg ASA11-13. ious organ involvement such as maculopap- Patients also frequently have chron- ular exanthema, drug reaction with eosino- ic symptoms such as recurrent nasal polyp- philia and systemic symptoms (DRESS), fixed osis with the need for frequent surgery, loss of smel , and also similar upper and lower re-nasal polyposis and multiple (two or more) re- spiratory symptoms after intake of alcohol11,12. actions after a single NSAID or reactions after Symptoms usual y appear 1-5 years before two different NSAIDs in the last 5 years the asthma develops14. diagnosis could be based on history alone11,12. However, in some cases, further diagnostic Epidemiology tests are necessary to avoid underdiagnosing The prevalence of AERD is estimated is re- or over diagnosing the disease. ported to be: 7% in patients with asthma, As the disease is not IgE mediated skin 15% in patients with severe asthma, 24% in tests or measurements of specific IgE are not applicable. Several other approaches have 96 patients with life-threatening asthma, 10% in patients with nasal polyposis, and 9% in been proposed and researched (like sulfido-patients with unspecific chronic rhinosinusi- leukotrienes release assay, 15-HETE test, ba- tis5,15,16. Reported prevalence is likely to be un- sophil activation test) but are not used in clin- derestimated due to low awareness of the dis- ical practice25-25. Therefore, unfortunately, ease. there is currently no other clinical y applicable s in vitro test available to confirm the diagnosis. w Symptoms of AERD usual y appears in ie This means that the only testing available is v patients with adult onset asthma between the l drug provocation testing, which is time-con- a age of 20-40 years17,18. AERD in children is ic suming, complicated, and potential y danger- in rare. The ratio of male to female patients is l c ous, and should therefore only be carried out d 1:217. AERD was previously not associated n in experienced centers by experienced physi- a with atopy or any other respiratory al ergy, cian and trained nurse. Emergency treatment sic although some newer studies report a higher a equipment should be at hand. Indications for - b prevalence of atopy in these patients19,20. Non a performing drug provocation test with aspi- m steroidal anti-inflammatory drugs that most h rin in suspected AERD are confirmation of st common cause respiratory reactions are: aspi- a AERD in patients with unreliable history and er rin (80%), ibuprofen (41%), naproxen (4%)13. assessment of provocation dose before oral ev desensitization procedure12,26. Absolute con- 1: se Pathophysiology traindication for drug provocation tests are mu NSAIDs inhibit cyclooxygenase 1, increas- the history of severe anaphylactic reaction r fo ing leukotriene production and decreasing the after any NSAID, unstable asthma, FEV1 ≤ am production of anti-inflammatory prostaglan- 70%, recent respiratory infection, pregnan- h st dins. Patients with AERD have higher levels cy, severe underlying disease such as cardio-ae of leukotrienes due to inflammation mediat- vascular, renal or liver disease12,26. There are rev ed by neutrophils, monocytes, and basophils, different routes of aspirin administration for se eosinophils, and mast cel s. Increased leukot- provocation tests: inhaled intranasal, oral and riene production with NSAID ingestion leads intravenous. Most commonly used are nasal to bronchoconstriction, eosinophilic inflam-and oral provocation tests27. Both have their mation, increased mucus production in the advantages and disadvantages. Nasal inhala-bronchi. Also in nasal polyps tissue, there are tion of lysine-aspirin is safer and less time con-elevated concentrations of leukotrienes21,22. suming in comparison to standard oral prov- ocation tests. The nasal provocation test has Diagnostics a lower sensitivity (80-87%) compared to the Due to distinctive symptoms, the diagnosis oral test, which has a sensitivity of 89-90%. could be often based on reliable history. In However, the specificity of both tests is high patients with adult-onset asthma, recurrent (93-100%)12,26 28-32. Inhalation chal enge with lysine-aspirin is as sensitive as oral one, but during provocation testing. It is also recom-safer and faster to perform11. mended that if AERD is suspected, spirome- Nasal provocation is useful in patients try or at least a PEF measurement should be with severe and unstable asthma and is at performed before the next dose. The test is higher risk for severe obstruction. On the oth-positive if at least one or more objective symp- er hand, it is not useful in patients with se-toms are present, such as upper respiratory vere nasal obstruction due to massive nasal tract reaction (rhinorrhoea, nasal congestion, polyposis as this reduces the sensitivity of the sneezing, lacrimation), bronchospasm (dysp-test26. At first, the test should be done with in- noea, wheezing), laryngospasm, a drop of tranasal saline to exclude unspecific hyper- 20% in FEV1 or PEF. At the slightest symp- sensitivity. Then lysine aspirin up to 80 uL is tom onset, the test should be stopped immedi-instal ed into each nostril33. Assessment of the ately and treated aggressively with antihista-reaction includes a combination of objective mines, nasal decongestants, bronchodilators, symptoms such as rhinorrhea, sneezing, na-and adrenaline. There are several different 97 sal congestion, and objective reduction of na- protocols for oral aspirin provocation. The in- sal flow measured with acoustic rhinometry, itial dose is typical y 10-20 mg. The number sea active anterior rhinomanometry, and peak of steps also varies, mostly in 5-8 steps. When ise AERD is suspected, it is important to remem- d nasal inspiratory flow33. As the sensitivity of yr ber that a reaction can occur up to 3 hours o nasal provocation is low, negative test should t after the aspirin dose and therefore a longer a be fol owed by oral provocation. Oral provo- observation period is required. In contrast spir cation test is considered the gold standard in e to immediate IgE-mediated hypersensitivi- r drug hypersensitivity. Although it has a high de ty testing where reactions usual y occur im- t specificity, it still does not have 100% sensi- ab mediately or within the first hour after drug r tivity, so in some cases, even a negative prov- ec administration, so observation up to 2 hours a ocation test cannot completely rule out drug x after the last dose is usual y sufficient. There- e hypersensitivity. Drug provocation test is in time-consuming, complicated, and potential- fore, most protocols provide for a 2-day prov- spir ly dangerous. It needs to be performed in a sit- ocation protocol with aspirin. The median ad cumulative dose at which symptoms occur is n uation where emergency treatment is availa- a 68-157 mg34,35. Upper respiratory tract symp- a ble, as wel as intensive care unit. Medications mh for anaphylaxis, adrenaline, and antihista- toms and lacrimation are usual y the first to sta mines should be available on site. It should occur. Bronchospasm is described in 35-90%. be performed under the supervision of expe- In addition to these, gastrointestinal symp- rienced and trained personnel. When select- toms (abdominal pain, nausea, vomiting), ing an appropriate protocol for drug testing, it skin signs (erythema, pruritus, urticaria), and should be borne in mind that inadvertent de-even hypotension have been described26,36. sensitization to the drug may occur during the Risk factors predicting a more severe test, resulting in a false-negative result. There- bronchial reaction include: patients not re- fore, the doses and the interval between doses ceiving additional anti leukotriene therapy, should be careful y selected. Ideal y, the inter-AERD symptoms lasting less than 10 years, val between doses of an oral drug provocation reduced FEV1 already before the start of test-test should be 60 min and the amount of drug ing, history of asthma exacerbations requiring administered should be at least 2 times, but an emergency room visit37. There are also pa-preferably 10x the previous dose. tients with a high clinical pretest probability Vital parameters, blood pressure, pulse, of AERD but in whom the aspirin chal enge and saturation should be careful y monitored test is negative. According to some studies, the sensitivity of the provocation test is only 90%. other equivalent alternatives. It can be used In these patients, it is reasonable to repeat test-for IgE-induced hypersensitivity (eg anaphy- ing with a higher cumulative dose of aspirin at laxis after antibiotics, monoclonal antibodies, the time of discontinuation of antileukotriene or chemotherapeutics), for non-immune-me-therapy and systemic steroids. diated hypersensitivity (eg aspirin angioede- ma), or infusion reactions (eg chemotherapy Management of AERD or monoclonal antibodies). Desensitization Cross reactivity between NSAIDs in AERD is also possible for mild delayed reactions (eg is not associated with similarity of chemical maculopapular rash after antibiotics)43,44. structure, as it is in IgE mediated hypersensi- The exact mechanism of action of de- 98 tivity, but it is associated with the strength of sensitization is not yet fuly understood. In COX-1 inhibitions. A patient must avoid al vitro studies have shown that during desen-the other drugs which are strong COX-1 in- sitization both basophils and mast cel s are hibitors: acetylsalicylic acid, piroxicam, sulin- temporarily unresponsive to desensitized an- dac, fenoprofen, oxazopirin, mefenamic acid tigen, while these cel s may stil respond to an-s indomethacin, ibuprofen, naproxen, ketopro- other antigen. w fen, diclofenac, ketorolac, etodolac, nabu- ie It has been suggested that aspirin vl metone. Metamizole (dipyrone) is considered desesnitization fol owed by maintenance of a aic as week COX-1 inhibitor8. But majority of pa- daily dose of aspirin improves deregulation of inl tients with AERD develop respiratory exac- c arachidonic acid metabolism which leads to dn erbation with metamizole38. Patients should decreased airway inflammation and to clini-a carry with them information about their drug cal improvement45. The state of anergy to an sica hypersensitivity. antigen is temporary, the cel s are responding - ba Weak COX-1 inhibitors such as par- after about two half-lives of the al ergen. De- mh acetamol, meloxicam, and selective COX- sensitization can be performed in all patients st a 2 inhibitors (celecoxib, etoricoxib, parecox- with immediate hypersensitivity to the drug er ib) are wel tolerated by most AERD patients. e that have no alternative choice. It can theoret- v Central analgetics such as tramadol and opi- ical y be administered for any drug. The rela- 1: se ates are also safe alternative12,39. Some patients tive contraindications for desensitization are: mu also have respiratory symptoms after alco- unstable patient, uncontrolled asthma, severe r fo hol ingestion so alcohol avoidance should be heart failure, pregnancy. In these cases, it is am advised to AERD patients40. Some patients necessary to evaluate risks and benefits. De-h st even report respiratory symptoms after us- sensitization is also not recommended when ae ing spearmint flavored food like chewing gum proper patient supervision and safety cannot rev or toothpaste, cows milk, and salicylate rich be ensured43,44. se diet41. Patients with AERD do benefit with Different protocols exist for performing additional antileukotriens for asthma symp- desensitization, but all include the adminis- toms42. tration of ascending doses of aspirin at inter- vals of 90-120 minutes until a reaction or the Aspirin Desensitization in AERD target dose is reached within 1-3 days46. An Drug desensitization is a method of induc- example of desensitization protocol used in ing a temporary tolerance and safely admin- University Clinic Golnik is presented in Ta- istering the drug to a patient who is al ergic ble 2. Aspirin desensitization in AERD could to it. The procedure is potential y danger-be performed for two purposes: aspirin toler- ous and time-consuming and it is suitable ance in cardiovascular indication or symp-for the selected patient in which there are no toms improvement in severe cases of chronic Table 2. Aspirin desensitization protocol used effects on nasal polyposis, reducing the need in University Clinic Golnik. for surgeries and nasal steroid use, however, there was no effect on NSAID hypersensitiv- Step Interval (min) Aspirin dose ity17,52. 1 0 1 mg 2 30 2 mg Summary Aspirin, NSAIDs and pyrazolones should be 3 60 4 mg avoided in patients with history of reaction af- 4 90 8 mg ter any of these drugs until al ergy workup. 5 120 16 mg Safe alternatives are paracetamol and opioids. 6 150 32 mg Most patients tolerate COX-2 inhibitors, but 7 180 64 mg this should be confirmed with drug provoca- 8 210 100 mg tion test. In patients with asthma, nasal polyposis 99 rhinosinusitis with nasal polyposis. In the first or chronic rhinosinusitis and convincing his-case is the target dose of 100 mg of aspirin, tory of multiple reactions to Aspirin, NSAIDs sea in the second case, the target dose varies from or pyrazolones, no further diagnostic proce-ise dures are needed and strict avoidance is nec- d 325 mg up to 1300 mg47,48. In both cases, the yr essary. In patients with chronic urticaria, di- o selected aspirin dose must be taken daily to ta maintain tolerance. If the dose is missed for agnostic provocation tests should only be performed in patients with indication for an-spir more than 48 hours, desensitization must be e r carried out again. In the majority of the pa- ti-inflammatory effects of NSAID as in rheu- det tients, desensitization is successful, although matologic diseases. ab Aspirin is the drug of choice in some r up to one-quarter of the patients have reac- ec emergency situations (e.g. acute myocardial a tions during the procedure47. Factors associat- x infarction). Patients with history of reaction e ed with successful desensitization are female in sex, high blood eosinophil count, low sputum after single NSAID and no history of asthma spir neutrophils, severe nasal symptoms49. If the and/or chronic urticaria, should be offered ad Aspirin provocation test. If Aspirin is tolerat- n reaction occurs, the patient should be treat- aa ed, and then the desensitization process can ed, patient could be offered further provoca-mh be continued. The most common long term tion tests with alternative NSAID. In patients sta adverse effect is gastric irritation. with ischemic heart disease and NSAIH hy- Aspirin desensitization in AERD is asso- persensitivity, confirmation of tolerance or ciated with beneficial effects mainly in symp- desensitization up to 100 mg is usual y pos- toms of chronic rhinosinusitis. Use of intra- sible also in patients with asthma or chronic nasal corticosteroid and recurrence of nasal urticaria. polyps are reduced, and there is also less need Patients with asthma, especial y severe for revision surgery in these patients. Aspi- asthma and concomitant nasal symptoms and rin desensitization is less effective in reducing unknown tolerance to Aspirin, NSAID and asthma symptoms, although one study did pyrazolones should be warned of the poten-confirm minor improvement in FEV1, symp- tial for development of AERD later in life. tom and medication score46,50. There are several studies researching the References effect of biological therapies on AERD with 1. Widal F, Abrami P, Lermoyez J. First various outcomes. Omalizumab, anti-IL5 complete description of the aspirin idi- treatment, and dupilumab do have clinical osyncrasy-asthma-nasal polyposis syn- drome (plus urticaria)--1922 (with a 10. Yoshimine F, Hasegawa T, Suzuki E, note on aspirin desensitization). By F. et al. 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Omalizumab treatment in Samter’s tri- ad: case series and review of the liter- ature. Eur Rev Med Pharmacol Sci. 2019 Sep;23(18):8124-9. 103 sea ise dyrota spire rdetabrecax ein spir adn aamh sta T2-low Asthma 5.2 Žarko Vrbica1,2 1 University of Dubrovnik, Abstract Dubrovnik, Croatia T2-low asthma represents between 30-40% of severe asthma patients. It is less well defined 2 Dubrovnik general Hospital, compared to the al ergic and eosinophilic asthma (T2-high asthma). There are no specific bi-Dubrovnik, Croatia omarkers for T2-low asthma but is often connected with the smoking, air pol ution and obesity. Most of the patients have late onset asthma with more symptoms that are induced by exercise and cold exposure with frequent infective exacerbations and bronchiectasis. The responce to inhaled steroid treatment is poor, so the available therapeutic options and the targeted therapies effective in both T2-high and T2-low asthma like new anti-TSLP monoclonal antibody tezepelumab are discussed. Ongoing trials with sophisticated transcriptomic and proteomic characterisations of different T2-low asthma patients should provide us tools to better characterise these patients and choose the precise therapeutic approaches. Keywords: T2-low asthma, neutrophylic asthma, paucigranulocytic asthma Introduction airway inflammation will be a mixture of Non-eosinophilic (T2-low) severe asthma is both pathways with either T2 or the non-T2 somewhat an „orphan“ entity in the severe being dominant, and possibly reflecting a asthma spectrum1. Severe asthma is a heter-therapeutic target for greater disease control2. ogeneous disease involving diverse pathobio- logical mechanisms (endotypes) with differ- Clinical Characteristics ent clinical presentations (phenotypes). While T2-low asthma represents between 30-40% the allergic asthma and non-allergic eosino- of severe asthma patients. Persistently non-eo- philic asthma (T2-high asthma) are better sinophilic asthma prevalence has been report-defined and their pathobiology is better de- ed up to 47% but most patients (>90%) con- scribed with increasing number of specific sidered to have neutrophilic bronchitis may treatment options, non-eosinophil ic (T2-low have a re‐emergence of sputum eosinophils asthma) is less defined, different mechanisms when their steroid doses are tapered for long are involved in its pathobiology. The path-enough3. ways are likely different in individual pa- T2-low asthma is more frequent in the tients, vary over time and circumstances, and late-onset asthma patients, obese females and are more complex than a simple division into high symptomatic patients and has a poor re-arbitrary groups: T (Type) 2 and non-T2 in- sponce to inhaled steroid treatment. Neutro- flammation. More likely, the end product of philic inflammation is frequently associated https://doi.org/10.26493/978-961-293-157-5.105-113 with smoking, air pol ution, obesity, very late host-environment interactions and mech-onset (>50 or > 65 years of age), exercise and anisms of disease (RNA Transcriptomics - cold induced asthma, infective asthma exac- study of gene expression and metabolom- erbations and bronchiectasis1,4. ics - measurement of mediators or metabolic products). Minimal y invasive analytic tools Pathophysiology have been reported for asthma, using blood, Non-type 2 inflammation (T2-low) mediat- sputum, or bronchial brushings1. The omics ed asthma is difficult to define due to lack of approach has been helpful in understanding signature biomarkers. It exists in the absence the molecular mechanisms of T2-low asthma. of T2-high or eosinophilic inflammation and The potential chemosensory and remodeling 106 includes neutrophilic and paucigranulocytic signatures recently described in asthmatic subtypes. Several cell types and cytokines, in-airways may point to new endotypes relevant cluding Th1, Th17, IL-6, and IL-17, contrib- in T2-low patients7-9. ute to mechanisms of non-T2 asthma5. Beside the inflammation, some structur- In response to industrial pol utants, in- al abnormalities of the airway smooth mus- s fectious agents, tobacco smoke, and other cles and heightened neuronal dysfunction can wie lead to the increased cough reflex sensitivity nonspecific stimuli, injured airway epithelial vl connected with the poor asthma control10. a cel s release a multitude of factors that initi- ic ate innate and adaptive immunity with sub- There is a negative correlation between inl c sequent release of tol ‐like receptors (TLRs). airway cytotoxic T cel s (CD8+) and body dn TLR2 and TLR4 are innate immune recep- mass index in severe asthma patients. Des- a tors that are inducing the shift toward Th1 reased expression of CD8+ cytotoxic T cel sica and Th17 response so the dominant T cel s in network in individuals with T2-low asthma11 - ba T2-low asthma are Th1 and Th17 that gen- is strongly related to obesity and systemic in- mh erate pro‐inflammatory cytokines as IL‐8, flammation. A primary function of CD8+ T st a IFN‐γ, IL‐6, IL‐17A/F, TNF‐α and IL‐1ß. T cel s is host defense against viral infection and ere helper 17 (Th17) cel -derived cytokines and an impaired immune response to viral infec-v immune factors mediate neutrophilic influx tions could be a mechanism of exacerbations 1: se to the airways. Th17-secreted interleukin-17A in T2-low asthma. mu Airway mucus hypersecretion is asso- r (IL-17A) is an independent risk factor for se- fo vere asthma that impacts airway smooth mus- ciated with greater asthma severity, reduced am cle (ASM) remodeling. Transforming growth lung function, increased number of exacerba-h st factor-β1 (TGF-β1) correlates with enhanced tion and is a predictor of a poorer response to ae anti-inflammatory treatment with glucocor- r Th17 activity and is essential to Th17 differ- ev entiation and IL-17A production. Vice versa, ticoids. Mutations or polymorphisms in the se IL-17A enhance activation of TGF-β1 sign- cystic fibrosis transmembrane conductance aling pathways augmenting the immune re- regulator (CFTR) gene were detected in hy- sponse6. persecreting patients with neutrophilic asth- The application of cluster analysis in ma, bronchiectasis, pansinusitis and recurrent asthma has gained increasing attention respiratory infections12. as a departure from traditional hypothe- Depending on the cel ularity, T2-low sis-based approaches to phenotyping asthma. asthma can be further classified into neutro-This analysis is accomplished through “om- philic and paucigranulocytic but there are no ics” methods, which refers to a large data- strict borders between those groups. set derived from a single sample to gain in- sight into previously unrecognized molecular Neutrophylic Asthma either activate a pro‐inflammatory cascade Key cytokine involved in T2-low asthma, or differentiate into immunomodulatory role. IL‐17, promotes neutrophil migration by in- This knowledge is crucial in programming ducing IL‐6 and IL‐8 release from bronchi- the treatment strategies because the treatment al epithelial cel s. IL‐8 (CXCL8) is the most not adapted to the specific underlying patho-potent chemoattractant in the lung that cor- biology may lead to undue adverse effects16. relates with both increased neutrophil per- centage and absolute neutrophil counts. Impact of Corticosteroids on Sputum Moreover, neutrophils have also been demon-Neutrophilia strated to secrete IL‐8 creating a positive feed- Th1 cell activation leads to production of back loop that promotes further neutrophilic IFN‐γ which in combination with the low se-inflammation. cretory leukocyte protease inhibitor (SLPI) Receptor for advanced glycation end‐ expression leads to high airway resistance and products (RAGE) is a pattern‐recognition re- ceptor that interacts with various endogenous corticosteroid refractoriness. Use of corticos-107 ligands involved in host response to injury, in- teroids (ICS and OCS) has been even shown to contribute to sputum neutrophilia17 be- a fection, and inflammation. Asthmatics with mh neutrophilic inflammation have a deficiency cause the corticosteroids, while they promote st apoptosis of eosinophils, have been demon- a in soluble form of RAGE (sRAGE). sRAGE wo serves as a decoy receptor by sequestering strated to inhibit neutrophil apoptosis. Sputum neutrophil count was higher in patients 2-lt RAGE ligands and thus inhibiting RAGE de- pendent cel ular responses. It is not known receiving moderate‐to‐high dose ICS than whether that deficiency is causative factor or those receiving low‐dose ICS. the result of neutrophilic inflammation13. It is wrong to consider neutrophils as Paucigranulocytic Asthma only negative cel s in asthma. Activated neu-Paucigranulocytic asthma encompasses pa- trophils can eliminate pathogens by phagocy- tients with absence of airway inflammation tosis, degranulation or formation of neutro- (eosinophilia and neutrophilia) with persis- phil extracel ular traps (NETs). Because of tent symptoms and evidence of AHR5. Acti-their role in mediating persistent inflamma- vation of Type 1 ILCs with excessive IFN‐γ tion and causing airway damage, they have production leads to reduced numbers of eo-been thought of as primitive kil ers. How- sinophils and neutrophils resulting in pauci- ever, they can have immunomodulatory ef- granulocytic inflammation. Mechanisms of fects and play a role in tissue repair and heal- this endotype can be changes in ASM or in- ing through production of anti‐inflammatory flammation not reflected in the bronchial lu-cytokines like IL‐1RA, IL‐10, TGFß1 and men. TGFß2. High extracel ular DNA concen- Numerous stimuli, including inflamma- trations in sputum mark a subset of patients tory cytokines, pol utants, altered airway mi-with more severe asthma who have NETs and crobiome and mechanical strains, can pre-markers of inflammasome activation in their dispose ASM to become nonspecifical y airways14,15. hyper‐responsive. The particular effect of the neutrophils is AHR independent of inflammation can dependent on location of the cel s, comorbid- be caused by the altered neuronal control ities and surrounding inflammatory milieu of ASM contractility. Nerve growth factor and nowadays we can recognise multiple neu- (NGF) can induce AHR, activate inflamma- trophil phenotypes with distinct morpholog- tory cel s and cause airway remodeling. Neu- ical and functional characteristics. They can roimmune cross‐link dysregulation of critical signaling molecules, including G protein‐cou-cases, investigations of transcriptome and pled receptors, transmembrane proteins, and proteome in sputum may lead to the better growth transcriptional factors, can be possi-differentiation of T2 high and T2 low asth- ble mechanisms promoting AHR independ- ma. ent of airway inflammation. Secretion of mast cell mediators could Non-pharmacological Treatment lead to bronchial obstruction, airway remod-Active or passive smoking can induce neutro- eling and AHR so the mast cell infiltration in philic inflammation, so the first measure in ASM can play a role in the pathogenesis of those patients is to promote smoking cessa-this asthma phenotype. tion. 108 Some patients may show both Th17 and Low-fat diet should be tried especialy in Th2 mediated inflammation and mixed gran-obese patients. The high-calorie and high-fat ulocytic inflammation might be a transition meal can increase the neutrophil recruitment between neutrophilic and eosinophilic phe-in the airways. Because of that, in obese pa- notypes. tients weight reduction program with weight s loss can lead to significant improvement in wie Management of T2-low Asthma asthma control and forced vital capacity, re- vl No specific therapies have shown any clinical duction in symptom days, rescue‐medication aic benefits in patients with asthma that is asso- use and emergency room visits18. inl c ciated with a non‐T2 inflammatory process. Bariatric surgery can be considered in dn It remains to be seen if such an endotype tru- morbid obese patients If there is no effect of a ly exists and to identify treatments to target weight reduction programs. sica that endotype. There is a high unmet need in Bronchial thermoplasty (BT) can im- - ba the endotype-driven approach for the T2-low prove asthma control, peak expiratory flow, mh asthma1. quality of life, symptom‐free days and de- st a Meanwhile, identifying intense airway crease the rescue medication use, severe ex-ere neutrophilia as an indicator of airway infec- acerbations, emergency department visits and v tion and airway hyperresponsiveness as an days missed from work/school. BT should 1: se indicator of smooth muscle dysfunction, and be reserved for uncontrol ed asthmatics with mu persistent symptoms, frequent exacerbations r treating them appropriately, and not increas- fo ing glucocorticosteroids in patients who do and severe AHR19. One limitation of bron-am not have obvious T2 inflammation, seem rea- chial thermoplasty is the difficulty of predict- h st ing clinical responders, so the discussion with a sonable3. er First, we should confirm the T2-low na- experts about the feasibility and necessity of ev ture of asthma with documented AHR and bronchial thermoplasty is adviced20. se the absence of T2 inflammation (normal Mucus clearance procedures: In the pa- blood or sputum eosinophils, serum IgE or tients with mucus hypersecretion, smoking FeNO) or high sputum neutrophil. This is im-cessation, physiotherapy in different body portant because most of such patients (with positions with high-frequency chest wall os-the exception of mast-cell mediated disease) cil ation and eduaction about deep breath-may not benefit from increasing the dosage of ing with effective coughing can improve mu-maintenance ICS. cus clearance and al eviate the symptoms. In Neutrophilic bronchitis can mask the un- addition, intermittent positive end-expirato- derlying eosinophil ic component so it is im- ry pressure (PEEP) can dilate the small air- portant to recheck the cell counts after the way, reduce small airway obstruction, pro-blood neutrophilia has resolved. In unresolved mote the sputum drainage and accelerate mucus clearance. Inhalation therapies should Theophyl ine in vitro promotes apoptosis be prefferentialy administered via humidi- of neutrophils, inhibits neutrophils from gen- fied inhalation or aerosol inhalation in order erating reactive oxygen species and causes a to moisturize the airway, dilute sputum and decline in neutrophil chemotaxis29. facilitate expectoration21. Roflumilast, a phosphodiesterase‐4 in- hibitor, can cause the reduction of neutrophil Pharmacological Treatment counts and TNF‐α levels and can improve ICS could be discontinued or reduced in two FEV1 in mild to moderate asthmatics when thirds of non-eosinophilic asthma patients added to ICS30. with no worsening of asthma control or ex- Antifungal treatment should be consid- acerbation. Sometimes that reduction can re- ered in the patients with the persistent pres- veal an eosinophilic inflammation and lead to ence of Aspergil us in the respiratory tract31,32. the change in patient classification and treat- Immunoglobulin replacement therapy: ment22. Patients with severe asthma and recurrent res- 109 Tezepelumab is an anti-TSLP monoclo- piratory infections should be screened and (if nal antibody that binds human TSLP, pre- a appropriate) treated for immunoglobulin de- m vents interaction with its receptor and, con- h ficiency since that can improve asthma out- st sequently, inhibits multiple downstream a comes33. w inflammatory pathways. Blocking of this o pathways can improwe the severe asthma A proposal of algorithm to T2 low asth- 2-lt control in both T2 and non-T2 asthma23. ma approach is shown in the Figure 1. Long acting bronchodilators (LAMA and LABA) can be effective in increasing the Investigational Products time to first exacerbation and improving lung Because of an unmet need for new therapeu-function and symptoms24. tic agents in T2-low asthma, there are plenty Antibiotic treatment can be effective in of investigational products in development for patients with recurrent infective exacerba-that indication3,34. tions. Molecular microbiology and mycolo- CXCR2 antagonists in preliminary stud- gy with extended cultures, including 16s deep ies showed significantly reduced sputum and sequencing, may be considered to direct the blood neutrophilia in patients with severe treatment. neutrophilic asthma and decreased number Immunoglobulin replacement may im- of mild exacerbations. prove asthma control in patients with infec- Etanercept blocks TNF and in a smal tive exacerbations and immunoglobulin defi- study demonstrated improvement in AHR, ciency25. FEV1, and symptoms. Other investigated Azithromycin in long-term non-antibi- anti‐TNF‐α compounds showed unacceptable otic doses of (250 mg daily three times per toxicity, mainly increased risk of infections. week) can result in decrease of severe asthma Antibody against IL‐17 receptor did not exacerbations frequency, improvement of the result in any statistical y significant benefit quality of life and reduced frequency of res-uptill now. piratory infections with no significant adverse Anakinra (IL‐1 receptor antagonist) in events26. healthy volunteers significantly reduced spu- Selective antagonists of cysteinyl leukot- tum neutrophilia and caused the rise of spu- rienes receptors in vitro can inhibit superox-tum IL‐1β, IL‐6, and IL‐8 levels. ide generation, production of LTB4 and re- Anti‐IL6 b locking might be a poten- lease of elastase by activated neutrophils27,28. tial therapeutic target in T2-low asthma, but 110 swie vlaicinl cdn a sica - bamh st aerev 1: semur foamh st aerevse Figure 1. A proposal of algorithm to T2low asthma approach. 16S sequencing: 16S rRNA gene (DNA sequence corresponding to rRNA encoding bacteria, which exists in the genome of all bacteria) CFTR gene: gene for a Cystic Fibrosis Transmembrane conductance Regulator protein LABA: Long-Acting Beta Agonists LAMA: Long-Acting Muscarinic Antagonists BMI: Body Mass Index AHR: Airway Hyperresponsiveness there is no clinical trial data available for in-management of these risk factors may con- tervention in asthma. tribute to improved asthma outcome36. Nebulized IFN‐β treatment at the on- set of viral upper respiratory tract infections Conclusion shown to improve morning peak flow, in-Lately, the heterogeneity of asthma pheno- crease in serum CXCR10 and reduced spu- types is recognised and the treatment options tum CCL4 concentrations which suggest- are tailored according to those differences. ed this treatment might improve outcomes of T2-low asthma is still less well defined with URTI induced asthma exacerbations. different subtypes characterized by the low Imatinib inhibits tyrosine kinase of KIT, expression of T2 inflammatory markers and induces mast cell apoptosis and reduces bone normal to low eosinophils. marrow mast cell burden. It can reduce air- Several treatment options for T2-high way mast cell burden and improve AHR in asthma have been developed and some of severe asthma. those treatments like new anti-TSLP mon- 111 5‐lipoxygenase‐activating protein (FLAP) oclonal antibody tezepelumab are effective a inhibitors can reduce the sputum LTB4 levels also in T2-low asthma. The results of ongoing mh but there are no significant effects on sputum trials with sophisticated transcriptomic and st neutrophil counts. a proteomic characterisations of different T2- wo Modification of airway dysbiosis: Several low asthma patients will provide us tools to 2-l novel approaches beyond antibiotics that may t better characterise these patients and choose modify dysbiosis, including phage therapies, the precise therapeutic approaches. prebiotic nutrients, microbe-derived products (bacterial extracts, immune stimulants), and References specific live microbial species (probiotics) may 1. Kuruvil a ME, Lee FE, Lee GB. 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The role of antifungals in the man- Eosinophilic and Al ergic Asthma Phenotype and Therapeutic Possibilities 5.3 Ljiljana Bulat Kardum¹,² 1 Clinic of Internal Medicine, Abstract Clinical Hospital Centre Rijeka, Despite optimal treatment according to GINA guidelines, some patients with asthma have an Rijeka, Croatia uncontrolled, severe disease with significantly reduced lung function, an increased risk of ex-2 Faculty of Medicine, acerbations and disproportionate use of asthma-related health resources. The identification University of Rijeka, Rijeka, Croatia of specific phenotypes of asthma with unique pathophysiologic mechanisms such as T2-high and T2-low immunological pathways and clinical characteristics enabled the discovery of new and more effective treatments for severe asthma. The emergence of novel biologic treatments, including monoclonal antibodies as anti-IgE, anti IL-5/anti IL-5Rα and anti IL-4/IL-13 are has led to an enhanced understanding of the pathogenesis of asthma and highlighted the importance of patient-specific treatment dependent on phenotypic characteristics. Keywords: severe asthma, phenotypes, T2 asthma, non-T2 asthma, biologic treatment, an-ti-IgE, anti IL-5/anti IL-5Rα, anti IL-4/IL-13 More than 300 mil ion people worldwide with an increased risk of exacerbations and suffer from asthma and it is estimated that overuse of asthma-related health resourc-400 mil ion people will suffer from asth- es including frequent hospital care and sig- ma by 2025. It is present in all regions of the nificantly reduced lung function with a risk world regardless of their socioeconomic lev-of further deterioration over time.3 In this el, although its prevalence varies. In the Unit- group of patients, it is necessary to identi- ed States, the prevalence of asthma is 7.6% fy those who manifest uncontrol ed asthma and 8.4% for adults and children, respective-and in whom accurate diagnosis or adequate ly; in the European Union the prevalence is treatment will significantly improve the cur-about 8.2% and 9.4%, respectively.1,2,3 Most rent control of the disease (“difficult-to-treat patients can achieve good disease control asthma”). It is estimated that about 24% of and a satisfactory quality of life with conven-asthma patients have GINA treatment of 4th tional treatment according to international or 5th step, 17% of all asthma patients have guidelines such as the Global Asthma Initi- “difficult to treat asthma”, while 3.7% of ative (GINA)3. asthma patients have severe asthma.4. The systematic review of 195 articles reporting How Common is Severe Asthma? on severe asthma studies found the preva- Despite optimal treatment, some patients lence of severe uncontrolled asthma to be as with asthma have uncontrol ed severe asthma high as 87.4%.5 https://doi.org/10.26493/978-961-293-157-5.115-123 Evolving Concepts of Severe Asthma: mechanisms in asthma has advanced, which Personalized Asthma Management has further contributed to the differentiation Asthma is a complex respiratory disorder of certain phenotypes and endotypes of asth-characterized by pronounced heterogenei- ma.13 Two separate pathophysiological path- ty in disease triggers and individual respons- ways cause eosinophilic inflammation in asth- es to therapy. It is a heterogeneous disease ma: with different phenotypic characteristics that arise from the complex interrelationship of 1. In allergic asthma, dendritic cel s af-genotypic characteristics and environmen- ter a contact with the al ergen as well as tal factors. Therefore, a standard therapeutic alarmins IL-25, IL-33 and thymic stro- 116 approach is not as effective as unique patho- mal lymphopoietin (TSLP) from ex-physiological mechanisms underlying a par- posed epithelial cel s of the airway mu- ticular disease subtype which alter the re- cosa, present antigen to Th0-naive CD4 sponse to conventional therapy.8-10 + lymphocytes and induce their trans- Severe asthma is defined as an asthma formation into activated Th2 cel s, that requires treatment of level 4 or 5 according which produce IL-4, IL-5 and IL -13. In s to GINA guidelines (high doses of ICS/LABA w this process, B lymphocytes were also ac- ie and/or tiotropium, leukotrienes or theophyl- v tivated to produce IgE antibodies, air- la line) in the previous year or treatment with way eosinophilia, and hypersecretion of ic systemic corticosteroids (CS) 50% of the pre- in mucus.13-15 l c vious year to prevent the development of “un- 2. In d nonallergic eosinophilic asthma, air n control ed” disease or it remains uncontrol ed a despite this therapy. The next therapeutic step pol ution, microbes, and glycolipids in- sic duce the release of cytokines from epi- a is to consider the indication for biological ther- - b apy, while oral corticosteroids according to the thelial cel s, including alarmins IL-25, am latest GINA guidelines revision are a backup IL-33 and TSLP, which activate naive h st therapeutic option to consider.3,9 lymphoid cel s (ILC2) in an antigen-in- ae dependent manner. Activated ILC2 cel s r Treating asthma with biological agents ev is the first step towards personalized thera- produce high amounts of IL-5 and IL-13 py. Such approach is made possible by an in- causing eosinophilia, mucosal hyperse- 1: sem crease in the understanding of the pathophys- cretion and airway hyperreactivity. The ur iological pathways in asthma and paved the importance of Th2 lymphocytes in this foa way for new asthma treatments based mainly process was highlighted through the cy- mh on T2-high pathway cytokines and associated tokines IL-4, IL-5 and IL-13 involved in st a certain phenotypes of severe asthma. There- eosinophilic inflammation and IgE pro- er fore, with the help of better identification of e duction, in an asthma phenotype called v asthma phenotypes, we can select an effective se T2-asthma (T2-high asthma).15-17 targeted therapy (biological) that will al ow us to achieve disease control in patients with Th17 cel s with cytokines IL-17, IL-8 severe asthma, in whom standard therapy has and growth factor participate in neutrophilic not been effective.10-13 inflammation in non-T2 asthma (T2-low asthma).14 Two Different Pathways Lead to Eosinophilic Airway Inflammation Implications of T2-High and T2-Low in Asthma Pathway on Asthma Phenotypes In the same time as the recognition of pheno- Several strategies have been proposed for the types of severe asthma, new knowledge about identification of severe asthma phenotypes, the pathophysiological and inflammatory based on different clinical characteristics or in relation to the types of cel ular airway inpatients for targeted type 2 asthma treatment. filtration. Although the stratification of asth- Blood eosinophils due to its high predictive ma phenotypes by blood eosinophils is rela- value of ≥300/µL is used as an initial bio- tively easy, it does not al ow a deeper/more marker to predict treatment responses target-detailed identification of clinical phenotypes. ing IL-4, IL-5, and IL-13.15,23 Therefore, cluster analysis is used to identify Consistent with its central role in the de- groups of patients with asthma who share spe- velopment of al ergic asthma, serum value cific clinical characteristics, e.g., cluster anal- of IgE is a good biomarker of an atopic sta- ysis using clinical characteristics of patients tus. Serum IgE levels are positively correlated such as asthma onset age, lung function value, with the severity of asthma in adults and chil-bronchodilator reversibility and demograph- dren. Serum total IgE is used to predict re- ics. The Severe Asthma Research Program sponses to anti-IgE therapy, but is not useful (SARP) identified five clinical groups of asth-for monitoring responses.15,24 ma in adults, in which four groups showed eo- The role of periostin and FENO in tai- 117 sinophilia of varying degrees.18 loring the biologic therapy targeting type 2 In order to identify severe asthma phe- asthma is less clear. Periostin is an extracel u- sie notypes, ADEPT study19 was conducted lar matrix protein secreted from IL-4 and IL-it and identified four clusters of asthma, which 13-induced airway epithelial cel s, but has not been shown to be a good biomarker in routine ssibil were also present in the UBIOPRED study.20 use. Changes in FENO after dupilumab ther-po Three of these four asthma clusters were asso- ict ciated with eosinophilia. apy (anti IL-13/IL-4) correlate wel with im- peu In the evolution of knowledge of clinical provement in FEV1.25-27 are phenotypes, Saly Wenzel and her co-workers h t have made a definition as fol ows: early-on- Allergic and Eosinophilic Asthma dn set al ergic, late-onset eosinophilic and exer- Phenotype ape cise-induced phenotype, all identified by bio- The decision to choose biological therapy is yto markers of Th2 asthma; and three phenotypes preceded by a process of asthma phenotyping ne of non-Th2 asthma, obesity- related, neutro- based on the identification of clinical charac- pha philic and asthma in smokers. No biomarkers teristics and driving mechanisms of inflam-mh of non-Th2 asthma have been identified so far mation. Biomarkers help us in the rational st choice of biological and predict a positive re- a as a basis for new biologics and markers of a icg positive response to that treatment.21,15 This is sponse of patients to the selected treatment: rel due to the lack of knowledge of the non-T2- l 1. The “Early-onset al ergic asthma” phe- ad High (T2-Low) immune response associat- notype usual y begins before the age of n a ed with the activation of Th1 and/or Th17 12. Triggers are al ergens and other al- icil cel s and IL-17, IL-8 cytokines and the mech- lergic diseases, and/or a positive fam- ph anisms underlying the recruitment and main- o ily history is associated too. Specific sin tenance of neutrophilic inflammation.22 biomarkers are elevated total IgE, spe- oe cific IgE and cytokines of T2 inflamma- Biological Agents Targeting Airway tion.9,10,13, 21 Inflammation in Asthma: 2. In the “Late-onset persistent eosinophil- The Rational Choice ic asthma” phenotype, symptoms begin Biomarkers can warn of the severity of the dis- in adulthood, often are associated with ease and predict the response to a particular chronic sinusitis and nasal polyposis. Bi- treatment. Some of the biomarkers, alone or omarkers of this phenotype are elevat- in combination, will be useful in identifying ed eosinophils of peripheral blood and sputum. In some patients, “aspirin exac-and higher blood eosinophils may benefit erbated respiratory disease” is also pres- from delayed omalizumab therapy.33,36 ent.21,28,29 While IgE is involved early in the inflam- Mechanism of Action of Anti IL-5/Anti IL- matory cascade and can be considered a cause 5Rα and Anti IL-4/IL-13 Treatments of allergic asthma, eosinophilia can be con-in Eosinophilic Asthma Phenotype sidered a consequence of the whole process. IL-5 is a key factor in the eosinophil matura-Hence the different roles of the IgE pathway tion, mediates eosinophil mobilisation, acti-and the IL-5 eosinophil pathway in the path- vation and survival. It achieves its effects by binding to a specific subunit of the IL-5 re- 118 ogenic mechanisms of airway inflammation ceptor, which is IL-5Rα. The IL-5Rα subu-occurring in asthma, and thus the reason for nit binds only IL-5. Eosinophils express up to choosing anti-IgE monoclonal antibody or three times more IL-5Rα on their cell mem-anti-IL-5/IL-5Rα treatment.30 brane than basophils. Th2 cel s, mast cel s, innate lymphoid cel s (ILC 2), CD34 + pro- s Mechanisms of Action of Anti-IgE genitor cel s, natural kil er (NK) T cel s and wie Treatment in Allergic Asthma Phenotype eosinophils themselves are the main cel ular vla Omalizumab is an anti-IgE treatment. It source of IL-537 Therefore, targeting IL-5 or ic binds to free IgE and thus reduces the bind- in IL-5Rα is a logical approach to treat patients l c ing of IgE to mast cel s, basophils and eosin- with severe eosinophilic asthma. dn ophils. In addition, omalizumab reduces the Two different anti-IL-5 monoclonal anti- a bodies, mepolizumab and reslizumab, bind to sic expression of high-affinity FcεRI receptors a for IgE on these cel s, thereby further reduc- different epitopes of IL-5 by interfering with - ba ing IgE binding to them. This reduces the its binding to IL-5R expressed on the eosino-mh release of mediators from the cel s, reduces phil membrane by reducing the IL-5 signal-st a ing pathway that impairs eosinophil matura- e al ergic inflammation, prevents the exacer- re tion and survival. v bation of asthma and reduces symptoms.31,32 Omalizumab is indicated for adults and chil- Mepolizumab is a humanized monoclo- 1: se nal IgG4 antibody, administered subcuta- m dren over six years of age with uncontrol ed ur moderate to severe al ergic asthma with ele- neously at a dose of 100 mg every 4 weeks. fo Criteria for introducing mepolizumab into a vated total IgE antibodies, a positive skin al- mh lergy test, or specific IgE antibodies to peren- treatment are: forced expiratory volume in st a 1 second (FEV1) less than 80% of predict- e nial al ergens.33A r ed value, at least two exacerbations of asth- e Omalizumab statistical y significantly v ma in the previous year treated with systemic se reduced daily symptoms, reduced exacerba- glucocorticoids while the patient was treat- tions, and the dose of inhaled corticosteroids. ed with high doses of inhaled corticosteroids Omalizumab has improved asthma control with a long-acting beta2-agonist, and at least and reduced the need for other asthma med-with an additional control er and an eosino- ications. All these effects are visible after 12 phil count of at least 150 cel s per microliter in weeks of therapy.32,34,35 In the STELLAIR peripheral blood at screening or at least 300 study, the rate of exacerbation reduction was cel s per microliter at some point during the similar in patients with severe al ergic asth-previous year. Mepolizumab reduces the rate ma with high (≥ 300 cel s/µL) and low (< of exacerbations by 53% compared to place-300 cel s/µL) eosinophils. Patients with high- bo (P<0.001), reduces exacerbations requir- er serum IgE levels, shorter disease duration ing an emergency visit and hospitalization by 61%. It also improves the quality of life β-agonists, with baseline blood eosinophil and lung function, which is reflected in the av-counts ≥300 cel s/μL. erage increase in FEV1 compared to placebo Dupilumab is the only biologic that has (P=0.03).33,34,38 dual inhibitory activity; inhibits the signa- Reslizumab is also a humanized mono- ling pathways of IL-4 and IL-13 by block- clonal IgG4 antibody, administered intrave- ing the alpha chain of the IL-4 receptor, nously at a dose of 3 mg/kg body weight every thus acting on two separate pathophysiolog-four weeks. Reslizumab is indicated in pa- ical pathways cause eosinophilic inflamma- tients with uncontrol ed severe asthma despite tion in asthma:allergic and non-alergic eosin-treatment with high doses of inhaled corticos- ophilic patways. So, effects are not limited to teroids with a long-acting beta2-agonist, with those patients who have eosinophilia28. Dup-the addition of one or more control ers and/ ilumab improved lung function and reduced or with additional OCS therapy. The blood severe exacerbations in patients with an un-eosinophil counts of ≥150 cel s/μL at screen- control ed severe asthma, regardless of the in- 119 ing or ≥ 300 cel s/μL within 12 months pri- itial number of eosinophils and had a favora- or to treatment of ≥300 cel s/μl i had to be ble safety profile, and therefore with inhaled sie present. Reslizumab reduces the incidence of corticosteroids and long-term therapy with it asthma exacerbations compared to those re- β2-agonists could improve the life of patients ssibil ceiving placebo, In two studies of Castro et with uncontrolled asthma in standard treat-po al, patients receiving reslizumab had a signifi- ment.34,41,42 Therefore, dupilumab is indicated ict cant reduction in the frequency of asthma ex- in adults and adolescents 12 years and older peu acerbations - in study 1. exacerbation rate was with severe asthma characterised by blood eo-are reduced by 50%; in study 2 exacerbation rate sinophil count of >150 cel s/µL and/or raised h t reduced by 59%; both p<0·0001) compared fraction of exhaled nitric oxide (FeNO) >25 dn with those receiving placebo. Lung function ppb, inadequately control ed with high dose ape (FEV1) , asthma control (ACQ) and quality y ICS and one of more controlers. to of life (AQLQ) have been improved over pla- ne cebo.32-34,39 Looking into the Near Future: pha Benralizumab has a dual effect: it is a Anti-epithelial Cytokine Antibodies mh blocker of the IL-5Rα receptor on the eosin- The epithelial cytokines: thymic stromal lym- st a ophil membrane and thus prevents the bind- phopoietin (TSLP), IL-25 and IL-33 are re- icgr ing of activated IL-5, while binding NK cel s leased from the airway epithelium in response ell that cause accelerated eosinophil apoptosis. to al ergens, air pol ution, and viruses trig-ad This effect is associated with a rapid reduc- gering an inflammatory cascade in asthma. n a tion in eosinophilia in the blood. It is adminis- It has been hypothesized that the blockade icil tered subcutaneously at a dose of 30 mg every of these cytokines, compared with biological ph four weeks for the first three doses and then o agents aimed at T2-inflammation, could im- sin every eight weeks. Benralizumab significant- prove severe asthma outcomes in a much wid- oe ly reduced asthma exacerbations and conse- er patient population. The results of recent quently progressively reduced daily OCS in- RCTs have shown the efficiency of tezepelum- take, improved ACT questionnaire value and ab, a human monoclonal antibody which tar-an increase in lung function.33,34,40. Benral- gets TSLP; itepekimab, an anti IL-33 human izumab is indicated in patients 12 years or monoclonal antibody; and astegolimab, a hu-older and in adults with severe eosinophilic man monoclonal antibody with an IL-33 reasthma inadequately control ed despite high- ceptor blockade effect in patients with severe dose inhaled corticosteroids plus long-acting asthma.45-48 In phase 3, RCT tezepelumab as add-therapy in those patients with elevated eosin- one therapy in uncontrol ed severe asthma ophils while IgE is in the reference values. If at a dose of 230 mg administered subcutane-there is no effect of IL-5 therapy, bronchial ously every 4 weeks in adolescents and adults, thermoplasty should be considered as in those has reduced the annual exacerbation rate by patients with low IgE and low eosinophils.22 56%, and among patients with blood eosin- Patients who have an intermediate response to ophil counts less than 300 cel s/µL reduced therapy either need to continue treatment for exacerbation rate by 41%. In addition, teze-one year to assess response or consider switch- pelumab has improved lung function, asth- ing to alternative biologic therapy if a thera- ma control and the quality of life in the T2- peutic effect is absent. Clinical experience and 120 high asthma group, but also in the T2-low new research may identify a panel of new bi-asthma group. A rapid decline in blood eosin- omarkers that wil better predict a positive re- ophil counts, a decrease in FeNO, a gradual sponse to biological therapy and facilitate our reduction in serum total IgE and a reduction therapeutic option.43 in bronchial hyperreactivity were observed. Unfortunately, none of the biological s Safety profile of tezepelumab was similar to agents can meet the needs of patients whose wie placebo.45,46 asthma is not mediated by a T2 response (T2- vl Itepekimab (anti IL-33) in phase 2 RCT low asthma). Due to our limited understand-aic at a dose of 300 mg sc every 2 weeks has re- ing of the immune response of in T2 low asth- inl c duced exacerbations and improved lung func- ma, our therapeutic options are very limited dn tion in patients with moderate to severe un- and are a reflection of unmet needs in severe a control ed asthma45,47, while astegolimab (anti uncontrolled asthma.22,44 sica IL-33R) in phase 2 RCT was administered - ba subcutaneously every 4 weeks in patients with References mh severe asthma, including those with low pe- 1. Data, statistics, and surveil ance [Inter- st a ripheral blood eosinophils, reduced the rate of e net]. Atlanta, GA: Centers for Disease re exacerbations, but did not improve lung func- Control and Prevention; [updated 2021 v tion.45,48 Positive results of phase 3 RCTs of Sep 16]. Available from: https://www. 1: se monoclonal antibodies efficacy against epi- cdc.gov/asthma/asthmadata.htm. mur thelial cytokines are expected, especial y for 2. 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As in today’s approach to asthma management, we tend no more to “me too 3 School of Medicine, medicine”, but to individual therapy in personalised and precise medicine. This article is deal-University of Zagreb, ing with some controversies and dilemmas in the field. After introducing biological therapy in Zagreb, Croatia the early 2000s, systemic glucocorticoids became the second option for patients with severe asthma. Starting with the controversy about accurate asthma diagnosis, then the question of where patients with severe asthma are hiding, thirdly, are we treating those patients appropriately and comprehensively, and final y, are we emphasising enough the necessity of smoking cessation? After reviewing the facts, and considering the extensive discussion exposed in controversies, a similar analysis brought up a few dilemmas, i.e. how could we precisely define severe asthma phenotypes, how should we distinguish asthma from COPD in middle-aged smoking patients, and how to make the right personalized choice of biologicals. There is also the dilemma about age - how old (or young) should the patient be for the indication for biologicals, and lastly, the length of treatment which is appropriate to assess a patient’s response to biologicals (“responder” or “non-responders”). Keywords: asthma, diagnostics, precision medicine, smoking cessation, response to therapy assessment Introduction 2% of misdiagnosed patients were thought to Asthma is the most frequent chronic respira-have asthma, but instead, they had other se- tory disease1, with almost 1 in 8 children and rious diseases (like tracheal stenosis, and cor-1 in 12 adults affected2. Asthma has a great onary artery disease. .). A significant part of impact on the person, the health system and these patients was frequently diagnosed with society. Therefore, investigating asthma from asthma without sufficient evidence, which is different angles is important, as is dealing not beneficial for the patient (over-diagnosis)- with controversies and dilemmas in the field. around 33% of patients had innocent diseases (i.e. rhinitis, GERB, anxiety etc.)3. Some of The First Controversy in Asthma the patients also had a failure of recognising Always Starts with Asthma Diagnosis asthma ( underdiagnosis). In the general popu-There is a substantial number of patients with lation of younger subjects < 44 years who on a an incorrect diagnosis of asthma. Around questionnaire reported respiratory symptoms https://doi.org/10.26493/978-961-293-157-5.127-139 compatible with asthma, around 32% of the history should determine asthma immediate-asthma was confirmed by further examina- ly. Respiratory symptoms were present from tion i.e. methacholine chal enge testing, skin childhood, they had sensitisation to perenni-prick tests and serum IgE measurement (4). al al ergens, they were treated for asthma in Although in older patients >65 years, a low-youth, or have eosinophilia etc . “Lack of career percentage of underdiagnosed asthma was ful history taking is intel ectual y lazy, it is too found - in 15% of them. This fact is very im-expensive, so should be condemned.”7 portant, because, in older patients with typi- “Poor perceivers” are those patients with cal asthma symptoms, asthma is a rarely per- asthma who do not report symptoms when ceived physician-diagnosed disease, even in their FEV dropped by 20%8. In the group 128 those patients who had< 10 pack-years of 1 with an established asthma diagnosis in this smoking or no history of congestive heart fail- study of 1155 subjects, 6% were poor perceiv- ure5. Independent risk factors for asthma mis- ers of dyspnea, while in the group which did diagnosis are spirometry underutilization and not have physician-diagnosed asthma despite missing data on pack-years of smoking6. verified airways obstruction, 26% were poor An even bigger problem is the diagnosis s perceivers. Both under and overdiagnosis of w of severe asthma. There is a significant delay ie asthma lead to significant risks to patients, vl in some severe asthma patients until the right and every effort should be undertaken to es-aic diagnosis of severe asthma is established. The tablish a proper diagnosis9. inl most logical possible explanations are twofold: c It is usual y stated that 5-10% of all asth- d the appearance of disease with atypical pres- n ma patients have severe asthma10. Since 2016, a entations of asthma in persons with paral el the Global initiative for asthma (GINA) has sica conditions (like obesity), and secondly - some stated that asthma is a heterogeneous dis- - b patients are “poor perceivers” (although there a ease11. Asthma heterogeneity can be seen in m are also medical professionals failing to rec- h diverse clinical presentations, different re- st ognize the disease). There are asthma patients a sponses to treatment, and different patho- e that never have wheezing, some never cough, re physiological features and findings due to v but most of them have dyspnea. As dyspnea can be a manifestation of many diseases, the various pathogenic mechanisms, which lead 1: se to multiple asthma phenotypes. m most often from cardiac origin, it is not sur- ur prising that some patients for many years do fo Here Comes the Second Controversy: a not perform any pulmonary diagnostics. Of mh course, heart diseases are the most common Where are Those Patients With Severe st a pathology in the elderly, so they are often pres- Asthma Hiding? er There is an unmet need for standardisa- e ent as a comorbidity, but are not necessarily v tion of the referral pathway leading to early se the leading etiology. As many patients smoke and their obstructive disease is presented for identification of patients with severe or diffi-the first time during an exacerbation, they im- cult-to-treat asthma12. . A possible solution for mediately receive a COPD diagnosis, which better referral to asthma specialists is better has been going on for years. From person-communication with emergency departments al experience, a certain number of “COPD” (ER).Patients discharged from the emergency patients disclosed their asthma features af-departments after an acute asthma exacerba- ter usage of a single or dual bronchodilator tion episode should be referred to an asthma therapy in COPD became more regular, and specialist, either a pulmonologist, al ergist or somewhat earlier patients were advised to dis-pediatrician. Another possibility is also better continue ICS from their therapy. The fact is access to the general practitioner’s (GP’s) pool that in most of those patients careful medical of “problematic“ asthma patients. Patients are often put on a short course of OCS, without there should be at least 5% of severe asthmat-an individualised strategy for the patient dur- ics, which is 10,792 patients. Not all of them ing the high-risk period after an emergency are candidates for biological therapy; eligible room or hospital visit. Around 29% of asth-are only those asthma patients who are prone ma patients, who are using high doses of ICS, to exacerbations or who need oral steroids for also take harmfully high doses of oral steroids treatment. of more than 0.429 per year13. Oral steroids In the entire asthma population, have devastating effects on a person’s health – one-quarter of the patients are prone to ex-an annual cumulative dose of 2 grams of oral acerbations, not al of them, but 10% have se-steroids is associated with adverse side effects, vere asthma18. Prone to asthma exacerbations like diabetes, osteoporosis, arterial hyperten-means more than two or three (some authors sion, cataracts, depression, but also adrenal count four - still there is no consensus on the insufficiency - the side effect of which we are number of asthma exacerbations per year). A thinking the least14. patient is said to have suffered from a severe 129 There are also obstacles and barriers to exacerbation if any of the fol owing are pres-diagnosing severe asthma patients. Here I re- ent: either systemic steroids had been used to am fer to all kinds of medical doctors, GPs’ and treat the attack, the maintenance dose was re-h st all different specialists, including pulmonol- quired to be escalated for at least 3 days; or an ae emergency visit due to asthma had to be made r ogists. We have to ask ourselves: are we ap- ev propriately listening to our patients? Are we to a health-care facility, during which systemic se asking the right questions? Do we perform steroids were administered19. The same severe insa objective measurements, like questionnaires, asthma population revealed that more than a mm PEF or other lung function measurements, third of those patients do not have asthma ex-eil do we detect airflow variability, FeNO, blood acerbation at al . The most important risk fac-dd tors for asthma exacerbations were BMI, gas- n and sputum eosinophilia, skin prick tests etc. as Are we actively looking for other diseases sim- troesophageal reflux, rhinosinusitis and blood sie ilar to severe asthma from a differential diag- eosinophils. Expenses for the 5% of patients rev nosis (ANCA test, total and specific IgE to As- prone to exacerbation make up almost 50% ort pergil us fumigatus, computed tomography of the total exacerbation burden20. Until now, no different cohort analyses did not reveal a sin- c HRCT, nasal polyps, drug sensitivities etc)? There is a lot of room for improvement in this gle phenotype of patients prone to exacerba-area. tions21. It seems that patients became prone to Extrapolation of results from the data- exacerbations when having an increased un- base to the general Dutch population: there derlying biological risk, and when he or she is are about 6000 patients with severe asthma exposed to a certain environment with al er-who are candidates for biologic treatment gens, pol ution or stress22. – 1.5% of the entire asthma patient popula- There are 30% of patients with severe tion (13). If we try to estimate the situation for asthma who need oral steroids for their treat-Croatia, with 4,087,843 inhabitants (accord- ment to prevent their asthma from becoming ing to the mid-2018 estimate by the Croatian uncontrol ed, or for improvement in symp-Bureau of Statistics) the asthma prevalence is toms and prevention of exacerbations23. 5.28%, as it was shown to be a European prev- If we account for these facts, and if this alence15 (although there are epidemiological is a similar situation in Croatia (we do not data that the asthma prevalence in schoolchil-have solid statistical data about severe asth- dren in Croatia is higher - 6.02%–6.9%16,17), ma) there are around 3500 patients with se-there are 215,838 asthmatics; among them vere asthma who are prone to exacerbations or are permanently on oral steroid therapy. As (57.1%). Croatian pulmonologists also iden-half of them have type 2 inflammation24, then tified the problem of financial restrictions at it is reasonable to assume that there are 1780 the level of hospitals. When we examine the patients in Croatia eligible for some kind of bi-guidelines prescribed by CHIF, poor lung ological therapy. function (FEV1 <60% expected) is for all bio- If we consider a different count, paral- logics one of the key criteria that had to be ful- lel y, in Croatia as in the Netherlands, where fil ed. In international guidelines, poor lung 1.5% of all asthma patients are eligible for bi-function is not mentioned for indications for ologicals, we get similar numbers. In Croatia, biologicals or it is restricted to FEV1 ≤80%. 1.5% of all asthma patients consist of 3237 in- Therefore, negotiations with CHIF based on 130 dividuals. Half of those patients are 1618 pa- pharmaco-economic and health-related qual-tients with severe asthma who are al ergic or ity of life (HRQoL) criteria should be initiat-have eosinophilic asthma, or have asthma ed to implement less stringent criteria for the with type 2 inflammation - all of them are reimbursement of biologics according to ineligible for either anti-IgE, antiIL-5 or an- ternational y recommended guidelines25. ti-IL-4/IL-13 biological therapy. sw We investigated Croatian pulmonolo- ie Third controversy: Are we Emphasizing v gists’ attitudes toward the prescription of bi- l the Necessity of Smoking Cessation aic ologicals in severe asthma patients, to iden- Enough? inl tify reasons for the discrepancy between the Asthma is not considered a disease of high cd number of eligible severe asthma patients and n mortality. Stil , each day there are 3-6 deaths a proper biological treatment. Biologics can be from asthma, as reported in Brazil26. Investi-sica prescribed only by a pulmonologist fol owing gations have proven that decreasing the num- - b specific guidelines proclaimed by the Nation- a ber of smokers also decreases the prevalence m al Health Insurance (Croatian Health Insur- h of respiratory deaths27. st ance Fund, CHIF) and has to be approved by a Tobacco smoke from cigarettes has many e the Hospital Medicines Committee (HMC). re toxic compounds such as acrolein, acetalde- v We found that regular treatment with system- ic glucocorticoids and frequent acute exacer- hyde, and formaldehyde, which contribute to 1: se respiratory irritation28. Tobacco can increase m bations were the most frequent major indica- ur tions for biologics in severe asthma patients, the prevalence of al ergic diseases, like asth-fo ma, allergic rhinitis and atopic dermatitis. It a 91.7% and 82.1%, respectively, fol owed by m could precipitate al ergic sensitization directly h frequent ER visits or hospitalizations (53.6%). st – by affecting the IgE production on a cel u- a The average period from establishing the in- e lar level, or indirectly – by increasing the per- r dication for biologic therapy until the actual ev application was estimated to be 2 months, sig- meability of respiratory epithelium29. In the se nificantly shorter in university hospitals (58 research conducted on Croatian citizens, we vs. 105 days, z=2.255, p=0.024) but without have found a statistical y significant increased a difference between regions (p=0.561). A sig-prevalence of allergic diseases and increased nificant number of pulmonologists reported level of total IgE, both in active and passive that some of their patients did not receive bio-smokers as opposed to non-smokers30. Active logical treatment for their severe asthma dur- smoking increases the inflammatory process ing the last 12 months even though they need- with cell infiltrations, especial y eosinophils31. ed it: due to inappropriate diagnosis (64.3%), The clinical picture of asthma in smokers is strict administrative directions for the reim-more severe in terms of symptoms, with more bursement by the Croatian Health Insurance frequent exacerbations than in asthmatic Fund (70.2%), and limited hospital resources non-smokers,. Secondhand smoking leads to more severe airway obstruction and greater Dilemmas in Severe Asthma hyper-responsiveness32. First Dilemma: How Could we Precisely It is obvious that smoking negatively in- Define a Severe Asthma Phenotype? fluences asthma -it aggravates symptoms and The real-world situation in medical praxis is treatments for exacerbation, increases inflam-concerning. Around half (1/2) of the physi- mation and decreases the possibility of asth- cians in the world do not have an approach ma control. That is why physicians and al to diagnostic tools satisfying for establish-other health care professionals should ex- ing an accurate diagnosis. Around one third ert the greatest effort to bring the awareness (1/3) of the patients in the world receive in-about harmful effects of tobacco smoking to appropriate treatment, and around one quar-our patients. ter (¼) of patients have potential life-threat- It is important to build a national capac- ening side-effects because of inappropriate ity for smoking cessation policy, which the treatment. World Health Organization (WHO) summa- Today, defining severe asthma pheno- 131 rizes in a document33. There are enumerated types is a process based on a biomarker-driv-measures influencing the demand for tobac- a en approach35. Asthma phenotypes with un- mh co products (like taxation and legislation) and derlying mechanisms became the centre of st other interventions directly targeted to facili- asthma research as there are efficient pheno- aer tate the changes in tobacco user attitudes and type-driven therapies available. This thera-ev behaviour (like Quit and Win competition, py is usual y biological36, 37, but also includes se mass media communications campaign, tele- macrolides, which are a successful therapy insa phone help-line etc.). At the individual level m in uncontrolled asthma38 (although the im- me the most recommended is the 5A strategy34: munomodulatory effect of azithromycin was il d proven more than a decade ago in healthy d 1. Ask: Identify and document the tobac-n persons39) and other airways diseases such as a co-use status of every patient at every s chronic obstructive pulmonary disease, sie visit. re 2. Advis: In a clear, strong, and personal- Precisiondefinition of severe asthma phe- vo notype is crucial for applying personalized r ized manner, urge every tobacco user to tn medicine40. o quit. c 3. Assess: Is the tobacco user wil ing to For that purpose, we should combine make a quit attempt at this time? medical history, physical examination, bio- 4. Assist: For the patient wil ing to make a markers and imaging methods. In medical quit attempt, use counsel ing and phar-history the most important is the age when macotherapy to help him or her quit. an asthma diagnosis was established. Other 5. Arrange: Schedule follow-up contact, factors to take into consideration are: wheth-preferably within the first week after the er it is childhood or adulthood asthma (ear-quit date, in person or by telephone. ly-onset or late-onset asthma), if there are al ergies or any drug sensitivities, is there a It would take only a few minutes to speak family history of al ergies, is there a smoking to patients and learn about their tobacco use habit or obesity present, which comorbidities and habits. We should help the smoker to undoes the patient have, especial y nasal polyps, derstand the health risks of smoking. Tobac- and careful y monitoring of a steroid side ef- co is the single greatest preventable cause of fect, like arterial hypertension, diabetes mel-disease and premature death. Stop smoking litus, depression, adrenal insufficiency or catis the best thing one could do for his or her aracts. Among biomarkers for clinical praxis, health. the most important are total and specific immunoglobulin E (IgE), eosinophils in It is very difficult to distinguish whether blood and (induced) sputum, alsofraction- chronic airflow limitation is due to asthma or al exhaled nitric oxide (FeNO). It is impor- a CD, especial y in smokers and the older pop- tant to find fungi in sputum if they are pres- ulation. Prevalence of FAO is higher in more ent and to distinguish if it is just sensitisation severe degrees of asthma, in severe or diffi- (SAFS - severe asthma fungal sensitisation), cult-to-treat asthma there are 55% to 60% of or colonisation and/or invasion (like ABA – patients with FAO; of them fulfiling the crite-allergic bronchopulmonary aspergil osis). ria for COPD (42).When we compare asthma Imaging like radiography or computed to-patients with asthma with and without FAO, mography (CT scan) wil disclose bronchiec- those with FAO are more likely to be male and 132 tasis, eosinophilic infiltrates, also eosinophil- to have a longer asthma duration43 . Mannino ic granulomatosis with polyangi tis (EGPA), et al. found that up to 30% of subjects with as wel as signs of bronchiolitis or mucoid im-airflow obstruction have a history of asthma pactions. In some cases, it will be necessary rather than COPD, but reversibility was not to perform bronchoscopy for a differential assessed in this epidemiologic survey, which s diagnosis or to remove thick and sticky eosin- could make this number even higher44. wie v ophilic secretion in the airways. la Third Dilemma: How to Make the Right icin Second Dilemma: How Should Personalized Choice of Biologicals? l c we Distinguish Asthma From COPD As phenotype may or may not be associated dn a in Middle-aged Smoking Patients? with underlying disease mechanisms, clini- cal phenotypes alone are not precise enough sic The answer to this question at the beginning a to guide targeted immune-modulator thera- - b lies in detailed anamnesis, which no single a py without a “biologic” marker to reveal un- m diagnostic test could replace. A connection h derlying biologic heterogeneity45.This means st of symptoms to certain triggers, like al er- ae gen exposure worsening respiratory symp- that the mandatory choice of biologicals is bi- re omarkers, total and specific immunoglobulin v toms, or coexistence of respiratory symptoms E (IgE), eosinophils in blood and (induced) 1: se with comorbidities like eosinophilic lung in- sputum, as well as fractional exhaled nitric m filtrate, rhinosinusitis with or without nasal ur polyps, urticaria, atopic dermatitis, psoria- oxide (FeNO). When we take everything into fo account, clinical and laboratory aspects, to- a sis, fungi sensitisation, etc., should be asso- mh ciated to asthma. Also, an al ergy should al- gether with functional tests and imaging, we st a can make a responsible choice. e ways be looked for, or an aspirin sensitivity, r Stil , there are a few problems to be re- ev as well as multiple episodes of respiratory solved. We need to develop biomarkers, which se symptoms during childhood and family his- could lead us to a more precise choice of tory of al ergies, whether in predecessors or which biological therapy to start with, which descendants. will have a better predictive value for respon- Another important factor, after medi- siveness to biologics. Also, those biomarkers cal history data, is lung function variabili- should be predictive for effective monitoring, ty. The situation is not so clear when there is or to give a signal when to stop biologics. Not fixed airway obstruction (FAO) or persistent to mention how important it is to find new bi-airflow limitation (PAL). Asthma and COPD omarkers for the T2-low asthma phenotype are syndromes consisting of several endotypes (or non-T2 endotype), after which a search for and phenotypes, consequently comprising a an effective treatment could become a more spectrum of diseases41. realistic option for such patients. Fourth Dilemma: Age. How Old Fifth Dilemma: Length of Treatment (or Young) Should Our Patients Appropriate to Assess a Patient’s be for Indication for Biologicals? Response to Biologicals (“Responder” Allergic asthma is usual y an early-on- or “Non-responders”) set (during childhood, before the age of 12 We do not have a universal y accepted defini-years), but not necessarily, while eosinophil- tion of response to biologicals in severe asth- ic asthma is usual y a late-onset, but also not ma. There is no one parameter most impor-necessarily. In children, after the age of 6 tant in an evaluation. Most experts agree that years, omalizumab showed good tolerability it is necessary to assess different asthma el-and safety, while anti-IL-5 treatment mepoli- ements during fol ow-up, from the clinical zumab and benralizumab are recommended point (frequency of exacerbations, symptom after the age of 12 years (reslizumab after the score), lung function, therapy dosages that age of 18), as well as dupilumab with the inpatients need to control asthma symptoms, dication for severe asthma46. Registries of se- as well as inflammatory biomarkers values49. 133 vere asthma patients show that the average In the present-day perspective, it is also essential to have shared decision making. The im- a age of severe asthma patients receiving bio- m portance of a conversation should be empha- h logicals is older than 50 years, with a median st of 56 years (with the oldest patient at the age sized, which will define the patient’s goals in aer biological treatment–that together,the patient e of 83 years)47. In the group of late-onset se- v vere asthma, there is also a group of patients and his physician should decide what the asth-se matic person would like to improve with his in with a “Non-T2 high” phenotype. They have sa asthma48. m neutrophils in induced sputum and are ster- m Responses to biological drugs in severe e oid-resistant. At this moment of medical sci- il asthma are defined as super responders, par- d ence development, this group will not bene- dn fit from any of today’s known biologicals45. tial y responders and non-responders50. In this as Once again, the most important factor is group of 114 Dutch patients with severe asth-sier ma treated with antiIL-5 therapy, it was es- e to distinguish and properly define the asth- vo tablished that 14% of super responders, after r ma phenotype, to identify all comorbidities, t two years of fol ow-up had no residual man- no the level of symptoms with the quality of life c achieved with standard asthma treatment ifestation of asthma. The majority consisted and good adherence, and to assess the poten-of partial responders, 69%, who have some tial benefit of biologic therapy. This should be asthma symptoms occasional y, while the done in a precise medical manner, personal-smal est group were non-responders, 11% of ly in just that patient, with defined goals in patients whose asthma showed clinical worsening. Amongthe experienced residual man- asthma treatment by the patient himself48, ifestations of the disease most often were un-while chronological age is the least important control ed asthma symptoms, impaired lung factor. function, and uncontrolled sinonasal symp- Of course, our goal is also to find young- toms. er patients, able to work, or to improve their A reasonable period for assessment of bi- education, to ensure them a full life, by pre- ological treatment response in severe asthma venting exacerbations and airway remodel- patients is one (the first) year of treatment (12 ling with the least damage and side effects of months), enough to count the number of ex-medical treatment of their asthma. acerbations, oral steroid dosage, asthma con- trol, eosinophilia, and estimate trends in lung function. Different health care providers and inpatients’ therapy. It is of utter importance to surance companies have different indications assess the duration of therapy seriously, with as well as rules for assessing the efficacy of bi-all sides and on a multidisciplinary basis, i.e. ological therapy in severe asthma, sometimes clinical y, functional measurements, and lab-even medical y and scientifical y non-log- oratory biomarkers, as well as to discuss with ical and not correct. An example is that in the patient, and only then the proper decision some countries if a patient during omalizum-should be made. ab treatment for the first 4 months could not stop oral steroids, he or she is considered a Sixth Dilemma: Should we Treat non-responder, which is wrong. Many stud- a Patient With Severe Asthma 134 ies conducted with any biological treatment and Another Significant Disease, have revealed that more than a third of pa- Like Allergic Broncho-pulmonary tients with severe asthma could not stop their Aspergillosis (ABPA), or Eosinophilic steroid treatment (51), despite step 5 GINA Granulomatosis with Polyangiitis treatment, good adherence and proper inhal- (EGPA)? s er technique applied, with administered bio- Biologics have been used in recent years to wie logicals in concordance with asthma pheno- treat ABPA and EGPA in patients with severe vl type and type 2 inflammation (although 80% asthma. However, robust clinical evidence of aic of patients significantly reduce steroid dos- biological therapy efficacy in severe asthma inl c age52). Although patients could not stop ster- with allergic broncho-pulmonary aspergil o- dn oids, they experience other benefits from bi- sis (ABPA) is lacking and stil out of the label55. a ologicals, like less frequent exacerbations and ABPA develops in susceptible patients whose sica overall quality of life, so it is an injustice to airways are colonized with Aspergil us fumig- - ba withdraw omalizumab after such a short peri- atus. ABPA develops in 1-5% of asthmatic pa- mh od of treatment. GINA strategy suggests that tients or 2-15% of patients with cystic fibrosis. st a 4 months should be adequate for assessment Biologics are used in patients with severe ere of mepolizumab response, but NICE guide- asthma and ABPA who have frequent acute v lines indicated 12 months of treatment of me- exacerbations, who did not have a response 1: se polizumab53. to antifungal medication and in patients with mu stage IV ABPA (steroid-dependent asthma). r The next question is about the dura- fo tion of biological treatment when a person All biologicals available for severe asthma am has at least a partial response. Some coun- have been applied, anti-IgE (omalizumab), h st tries have the rule to quit biologicals after 2 anti-IL-5 (mepolizumab and benralizum-ae ab), and anti IL4/13(dupilumab). In al treat- r years of treatment, despite good response, ev which is considered too short in the asthma ed groups an improvement has been shown, se scientific community. There are not many with fewer exacerbations and symptoms with studies published on the length of biological a steroid-sparing effect. The best improve-treatment, as well as what happens after the ment was found in lung function measured by discontinuation of biological therapy. Results FEV in the vast majority of patients, where 1 from the Spanish severe asthma registry have an improvement of more than 10% has been shown that the effects of 6 years of omalizum-considered clinical y relevant based on patient ab may persist after discontinuation of ther- perception56. With the purpose to avoid hy- apy in 60% of patients for at least 4 years54. per-eosinophilia, dupilumabwas introduced There are no published data with results for simultaneously with oral steroids57. other biologicals because they are of a short- EGPA became an indication for target- er time in real life praxis with severe asthma ed biological anti-IL-5 treatment, with the first FDA approval in 2017 for mepolizum-including clinical and laboratory aspects, to- ab, but in a higher dose of 300 mg subcuta- gether with functional tests and imaging, we neously (sc.), while in Europe it is stil not ap- can make a personalized choice of treatment, proved for this indication of EGPA, and not in with a reasonable chance for significant im-this higher dose (just in a dose of 100 mg for provement for our severe asthma patients. severe asthma58). EGPA is always connected Stil , there are many controversies and dilem-with asthma, hyper-eosinophilic syndrome, mas in the field. often rhinosinusitis with nasal polyps, as wel as damage to two or more organs due to ne- References crotising vasculitis of small vessels (heart, 1. Soriano JB, Abajobir AA, Abate KH, lung, skin, kidneys, gastrointestinal or nerv-et al. Global, regional, and national ous system). With the purpose of induction deaths, prevalence, disability-adjusted or maintenance of remission or preventing re- life years, and years lived with disabil- lapse or refractory EGPA, higher dosages of ity for chronic obstructive pulmonary disease and asthma, 1990-2015: a sys- 135 mepolizumab were applied. Further studies of EGPA treatment with “asthma-tailored” tematic analysis for the Global Burden am dosages (100 mg sc. every 4 weeks (q4 w) in- of Disease Study 2015. 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Mepolizumab in a population with izumab in a patient with eosinophil- severe eosinophilic asthma and corti- ic granulomatosis with polyangi tis re- fractory to mepolizumab. Multidiscip Respir Med. 2021 Jun 24;16(1):779. doi: 10.4081/mrm.2021.779. 60. Manka LA, Guntur VP, Denson JL, et al. Efficacy and Safety of Reslizum- ab in the Treatment of Eosinophil- ic Granulomatosis with Polyangi tis. Ann Al ergy Asthma Immunol. 2021 Jun;126(6):696-701.e1. 139 amh st aerev se insammeil ddn as sierevortnoc Contributors Assoc. Prof. Ljiljana Bulat Kardum MD, piratory physiology section at ERS. Cer- PhD tified European project manager, received Ljiljana Bulat Kardum is a specialist in in- a certificate in 2010. Project manager co-ternal medicine and pulmonology. Since ordinator in the 6th and 7th Framework EU 2008 she has been the head of the Depart- Programs and Interreg projects for Slove-ment of Pulmonology of the Clinical Hos- nia. pital Center Rijeka, with focus on COPD He is a member of many European advi-and asthma , and an associate professor sory boards in development of new drugs at Medical School, University of Rijeka, for asthma and COPD. Croatia. She has published several profes- sional and scientific articles, participated Prof. Irena Hočevar Boltežar MD, PhD at domestic and international congress- Irena Hočevar Boltežar has finished study es and is the author of several chapters in of medicine at University of Ljubljana books." (UL). She obtained her MSc, and PhD degree at the same university. Since 1987 Assist. Prof. Matjaž Fležar MD, PhD she has been employed at the University Specialist in Pulmonology and Internal Medical Centre Ljubljana, Department of medicine and former Director of the Uni- ORL & HNS in Ljubljana. In 1993 she versity Clinic of Respiratory and Al er- finished her training in otorhinolaryngol-gic Diseases Golnik, Slovenia. He is spe- ogy and started working also at Faculty cialized in lung function testing and sleeps of Medicine, UL. She has expanded her medicine, senior consultant in the field of knowledge at Harvard Medical School, obstructive lung diseases, principal inves- Boston, USA, and HNO-Universitätsk-tigator in a number of clinical trials in linik Graz, Austria. asthma and COPD. Currently, he is the At the moment she has a position of ful head of the Respiratory function labora- professor, is the head of the Department tory at University Clinic Golnik. of Otorhinolaryngology at Faculty of He is a Member of EBAP at ERS, Na- Medicine, and also a lecturer for students tional delegate at ERS for Slovenia in of speech pathology at University of Lju-years 2005-2008, member of the Res- bljana. She is the head of Center for Voice, Speech and Swal owing Disorders at the he spent one year in Clinic for Rheuma-university hospital. She is the author of tology and Clinical Immunology / Al-two university textbooks, and more than lergology, Inselspital, University of Bern, 350 published papers. She was the su- Switzerland and where he was involved pervisor or co-supervisor of 6 MSc, and in clinical and research work. In 2012 he 7 PhD dissertations at the University of passed EAACI/UEMS Knowledge Ex-Ljubljana. She is a reviewer for 10 inter- amination in Al ergology and Clinical national journals with IF. Immunology. His main clinical and research interests 142 Assoc. Prof. Tomaž Kocjan MD, PhD. are in atopic diseases such as asthma and Tomaž Kocjan is Associate Professor al ergies, particularly immunotherapy of Internal Medicine and Endocrinolo- and severe asthma. He is very pleased to gy at the Faculty of Medicine, Universi- be part of the international y renowned research team at the Golnik Clinic, where ty of Ljubljana and head of the Endocrine s experts in basic immunology and clini- w Unit, Department of Endocrinology, Di- ie cal medicine are closely linked and work v abetes and Metabolic Diseases, Univer- l very wel together. He is active member of aic sity Medical Centre Ljubljana, Slovenia. EAACI, ENDA group and GA2LEN Ur-inl He received his MD and PhD from the c ticaria network. d University of Ljubljana. His expertise in n a clinical endocrinology was further devel- sic Assoc. Prof. Dr. Ramesh Kurukulaaratchy a oped at Royal Free Hospital and Univer- BM DM FRCP - ba sity Col ege Hospital in London, UK. His mh special clinical and research interests are Ramesh Kurukulaaratchy BM DM st a adrenal diseases, especial y endocrine hy- FRCP is Associate Professor at the Uni-er versity of Southampton and Honor- e pertension, pituitary, and metabolic bone v diseases. He is the principal author of the ary Consultant in Respiratory & Gen-1: se eral Medicine plus Al ergy at University m national guidelines on postmenopausal ur osteoporosis, the national position state- Hospital Southampton, United Kingdom fo (UK). After graduating from the Univer- a ment on glucocorticoid osteoporosis and mh the on-going national screening program sity of Southampton and completing jun-st a ior training posts, Ramesh undertook a e for osteoporosis endorsed by the Ministry re Research Fel owship at the David Hide v of Health of Slovenia. He published more se than 50 articles in international peer-re- Asthma & Al ergy Research Centre, Isle viewed medical journals. He authored of Wight, UK. That fuel ed a clinical and and edited chapters in Slovenian text- research interest in Asthma and Al ergy. books of Internal Medicine and Endocri- Ramesh developed and led the Regional nology. Difficult Asthma Clinic as a Multidiscipli- nary team at Southampton for 11-years. His research interests include asthma ep- Assist. Peter Kopač MD, PhD idemiology across the life course and pre- Dr. Kopač graduated from the Faculty vention strategies in asthma and al ergy. of Medicine at the University of Ljublja- He also leads the WATCH study of dif-na in 2005. Already during his residency ficult asthma at Southampton, studying difficult asthma phenotypes, endotypes a specialist in pulmonology and al ergolo-and the role of multimorbidity. He holds gy. He earned a Ph.D. degree in 1998. In grants with NIH, Asthma-UK and Indus- 2012 he was nominated as a ful professor try, has an H-index of 36 and has pub- of internal medicine. He is a medical doc-lished 93 scientific papers. tor and a head of the Department of Clin- ical Research at the University Clinic of Prof. Peter Korošec MD, PhD Respiratory and Al ergic Diseases Golnik Peter Korosec is Professor of Immunolo- and a head of the Chair of Internal medi-gy and Microbiology at University Clin- cine at the Medical Faculty, University of ic Golnik. He was awarded M.Sc. (1998) Ljubljana. His research interests are ana-and Ph.D. (2001) at Medical Faculty in phylaxis, venom and drug al ergy. He is Ljubljana. His professional training con- a project manager of a national research project P3 – 0360: Slovenian network of sisted successive appointment as Special- 143 al ergy and asthma: from epidemiology to ist in Clinical Laboratory Genetic (2015). genetics. He was a mentor of 8 Ph. D. stu-sr He serves as the Associate Editor of Clini- o dents. He is a president of Slovenian As- t cal & Experimental Al ergy. sociation of Al ergology and Clinical Im- ibur Prof Korosec has worked tirelessly to t munology and od Slovenian Respiratory no build the scientific basis of al ergy and c Society, a member of State expert body pulmonology (https://scholar.google.si/ of internal medicine and a member of Peter Korosec). His research has focused UEMS, section al ergology. He published upon the anaphylaxis, recombinant al- over 150 articles in journals with impact lergens, basophils, asthma genetics, he- factor, his H-index is 42 and has 10.000 reditary angioedema and interstitial lung pure citations. diseases. His studies of using Basophil Ac- tivation Test (BAT) and recombinant al- Marina Lampalo MD, PhD lergens substantial y impacted clinical practice in insect sting al ergy. Marina Lampalo graduated from Uni- His current research programme com- versity of Zagreb, Medical school in 2001. bines recent developments within the field Since March 2008 she has been working of immunology and genetics. This ef- as internal medicine physician, and since fort enabled the discovery of novel patho- 2010 as subspecialist pulmonologist, at genesis pathways in anaphylaxis and the Clinic for Lung Diseases Jordanovac - severe asthma, and helped identify phe- Department for Obstructive and Al ergic notype-specific immunological and ge- Diseases. In March 2019, she acquired the netic risk factors. He has supervised 13 title of primarius. PhD students to completion. Marina Lampalo, MD, PhD, became a doctor of science in the field of natural sciences, scientific field of biology, 2017. at Prof. Mitja Košnik MD, PhD the Faculty of Science, University of Za- He graduated at the Medical Faculty, greb, defending her dissertation entitled University of Ljubljana in 1987. In 1992 “The effect of ABO blood genotypes and he finished a specialisation of the inter- tissue plasminogen activator inhibitor on nal medicine, latter he was nominated as lung ventilation in asthma”. She is an active member of the Croatian Prof. Sanja Popović-Grle MD, PhD Thoracic Society, the Croatian Respira- Sanja Popović-Grle is a Professor of Res-tory Society, the European Respiratory piratory Medicine at University of Za-Society, the Croatian Medical Associa- greb, Croatia, and Chief of Clinical De-tion and the Croatian Medical Chamber. partment for al ergic and obstructive She has actively participated in numerous pulmonary diseases at University Hospi-domestic and international scientific and tal Centre Zagreb. professional conferences. After qualifying in medicine and obtain- In 2018, she participated in the ERS ing her Doctor of Medicine degree from 144 spirometry training programme, and obtained a European license for an educator the University of Zagreb in 1983., prof. in the field of respiratory function. Grle started her professional career in the So far, she has published several scientif- central state Pulmonary hospital Jordano-ic and professional papers, 4 indexed in vac in Zagreb, as an employee from the Medical faculty, after obligatory praxis s Current Contents, 9 in international in- w for 2 years as a general practitioner. ie dexed publications and 7 in other publi- v Prof. Grle main research interest is in the la cations. She has participated in numerous ic field of asthma, al ergy, and COPD, espe- in domestic and international scientific and l cial y in clinical diagnostic methods and c professional conferences, especially in the d management. She has published papers n a field of pulmonology and al ergology. So in peer-reviewed journals and book chap-sic far, she has actively participated in con- a ters for students, residents, specialists or - b gresses and gatherings organized by the a patients. In addition to the clinical duties, m Croatian Thoracic Society (2014, 2016, h prof. Grle has lectured extensively on top- st 2017, 2018, 2019), International Con- a ics. She is a reviewer of various interna- er gress of the European Respiratory Socie- e tional journals. She has been Member of v ty (2018, 2019) European Academy of Al- Organizing and Scientific Committees. 1: se lergy and Clinical Immunology Congress mu (2019). r Assist. Prof. Matija Rijavec PhD fo She has 24 conference papers published am in proceedings. She is the winner of After graduating from the Biotechnical h st Faculty, University of Ljubljana (2004), a “Toraks” Award for Best Scientific Pa- er per in 2016. Since 2019 she has been a re- he earned his PhD degree in the field of ev Biomedicine at the University of Ljublja- se search associate at the School of medicine, University of Zagreb, and since October na (2010). Since 2015 Matija is also As-2020 she has been elected as a senior lec- sistant Professor in the field of Immunolo-turer at the Faculty of Medicine, Univer- gy at the Biotechnical Faculty, University sity of Rijeka. The narrower area she has of Ljubljana. Matija is involved in dif-been dealing with for many years are ob- ferent fields of clinical research, main-structive lung diseases - primarily asthma, ly studying immunology and genetics of chronic obstructive pulmonary disease complex diseases, al ergy/anaphylaxis, and lung function and al ergic diseases. hereditary angioedema, asthma, COPD, atopic dermatitis, sarcoidosis, cystic fibro- sis, and alpha-1-antitrypsin deficiency. A great proportion of his research activities Heterogenous Asthma Research Col abo-represent the use of different techniques ration) National lead. in molecular biology to study DNA (se- Dr. Škrgat is a member of Slovenian Res-quencing, PCR, qPCR, MLPA, NGS, piratory Society steering committee and ddPCR), expression profiles of mRNA, a member of SHARP steering committee miRNA (RT-qPCR, NGS), proteins (flow since 2021. cytometry, ELISA) in various disease en- She launched the first Severe asthma fo-tities, in an attempt to decipher disease rum-joint meeting of South East Europe mechanisms and finding novel biomark- which was held in Bled, Slovenia in 2018. ers for diagnosis and prognosis/predic- tion. Currently, his research is focused Stylianos Vittorakis MD, PhD on hereditary angioedema, asthma, and anaphylaxis mechanisms, genetics and Stylianos K. Vittorakis MD, PhD, received his medical education and his PhD 145 pharmacogenetics, as evident from the summary of our latest publications in this from National and Kapodistrial Universi-sr ty of Athens. He completed his residency o field. He published 51 original scientific t papers, and 6 review scientific papers, and in Pulmonary Medicine at “Sotiria” Ath-ibur ens Chest Hospital, Greece and obtained t has an H-index of 17. no the European Diploma in Adult Respira- c Assist. Prof. Sabina Škrgat MD, PhD tory Medicine E.R.S – H.E.R.M.E.S in 2011. He has conducted research in Cel- Sabina Škrgat, MD, graduated from the lular Immunology and Asthma at Bio-Faculty of Medicine at the University of medical Research Foundation (Academy Ljubljana (1996). She is a specialist of in- of Athens) and Asthma Research Center-ternal medicine (2004) and pneumonolo- 7th Respiratory Medicine Department gy (2011). She got her PhD degree at the (Sotiria Hospital). His research is mainly University of Ljubljana (2009) with the focused on asthma as an active member topic of investigation, related to angiogen- of Hel enic Thoracic Society Asthma and esis and complement activation in asthma COPD working groups. Currently he is a and chronic obstructive pulmonary dis- private consultant Pulmonologist in Cha-ease. nia/Greece, and he is Coordinator in Hel- Her main clinical work consists of man- agement of patients with severe asthma lenic Thoracic Society Primary Health and other obstructive lung diseases. She is Care Group. an Assistant professor at Medical Faculty of Ljubljana and she curently has a lead- Prim. Žarko Vrbica MD, MS ing position in Slovenian National recom- Dr. Žarko Vrbica graduated from the Fac-mendations for asthma management. She ulty of Medicine at the University of Belis the clinical lead of Severe asthma Clin- grade (1988). He is a specialist in interic at University Medical Centre Ljubljana, nal medicine (1999 – UHC Zagreb) and Slovenia. pneumonology (2003 – UHC Zagreb). Beside clinical work, she is active in re- Dr. Vrbica earned his MS degree at the search of severe asthma by PhD mentor- University of Zagreb (2003) with the top-ing. She is also the ERS SHARP (Severe ic of psycho-neuro-immunology of lung cancer. He is a head of the Ward for pneumology and immunology in Dubrovnik County Hospital. His main clinical in- terest are obstructive lung diseases and is an active member of the Croatian GOLD and GINA initiative. He is a senior lectur- er at the University of Dubrovnik. Assist. Prof. Mihaela Zidarn MD, PhD 146 Mihaela Zidarn graduated from the Fac- ulty of Medicine at the University of Lju- bljana (1997). She is a specialist in inter- nal medicine (2005), pneumology (2012) and al ergy (2013). She got her PhD de- s gree at the University of Ljubljana (2014) wie v on the topic of al ergen immunotherapy. la Her main clinical work consists of the icin management of patients with al ergic dis- l cd eases and asthma. She is an Assistant pro- n a fessor at the Medical Faculty of Ljubljana. sica Besides clinical work, she is active in re- - b search on al ergic rhinitis, anaphylaxis am and hereditary angioedema. She is an au- h st a thor/co-author of 58 papers with an H-in- er dex of 24. ev 1: semur foamh st aerevse Index A D adrenal insufficiency 37, 39, 40, 129, 131 diagnostics 67, 70, 127, 128 allergy 51, 58, 67, 69, 70, 77, 95, 96, 99, difficult asthma 45, 46, 47, 48, 49, 50, 51, 118, 132 52, 53, 54, 55, 56, 57, 58, 59 anti-IgE 38, 115, 117, 118, 130, 134 drug hypersensitivity 93, 97, 98 anti IL-4/IL-13 115 dyspnea 67, 68, 69, 70, 77, 95, 128 anti IL-5/anti IL-5Rα 115 aspirin 48, 93, 94, 95, 96, 97, 98, 99, 118, E 132 asthma 11, 13, 14, 17, 18, 19, 20, 21, 22, endotype 17, 18, 20, 23, 51, 87, 107, 108, 23, 27, 28, 29, 30, 31, 32, 37, 38, 39, 132 40, 41, 45, 46, 47, 48, 49, 50, 51, 52, eosinophils 17, 19, 20, 21, 22, 27, 70, 83, 53, 54, 55, 56, 57, 58, 59, 67, 68, 69, 85, 86, 87, 96, 105, 107, 108, 111, 117, 70, 71, 77, 78, 79, 80, 83, 84, 85, 86, 118, 119, 120, 129, 132, 135 87, 93, 94, 95, 96, 97, 98, 99, 105, 106, 107, 108, 109, 110, 111, 115, 116, 117, G 118, 119, 120, 127, 128, 129, 130, 131, glucocorticoids 13, 30, 31, 37, 39 132, 133, 134, 135 asthma phenotype 77, 117, 118, 131 I asthma treatment 13, 22, 27, 28, 29, 31, 32, 46, 67, 68, 71, 83, 84, 86, 117, 133 ICS 27, 29, 30, 31, 32, 46, 55, 107, 108, 109, 116, 119, 128, 129 B immune cells 17, 23 innate lymphoid cells 21 basophils 17, 19, 22, 96, 98, 118 biologic treatment 38, 50, 115, 120, 129 L biomarkers 83, 84, 86, 87, 105, 106, 117, 120, 131, 132, 133, 134, 135 LABA 27, 31, 32, 46, 107, 109, 110, 116 laryngitis 67, 68, 71 C lung function tests 77, 80 clusters 83, 117 120, 127, 128, 129, 130, 131, 132, 133, M 134, 135 mast cells 17, 19, 22, 27, 96, 98, 118 multi-disciplinary team 49 W multimorbidity 45, 47, 48, 49 work related asthma 77 N neutrophylic asthma 105 nonsteroidal antiinflamatory drugs 93, 94, 148 95, 96, 99 O OCS 27, 29, 53, 55, 58, 107, 119, 129 s P wie v paucigranulocytic asthma 84, 86, 105 la phenotype 17, 18, 32, 39, 51, 77, 83, 84, icin 86, 87, 93, 94, 108, 116, 117, 129, 131, l c 132, 133, 134 dn a precision medicine 127 sica - b R amh response to therapy 87, 120, 127 st a rhinitis 48, 51, 67, 68, 71, 111, 127, 130 erev S 1: sem severe asthma 11, 17, 18, 46, 83, 105, 116, ur 135 foa side effects 13, 14, 29, 37, 39, 41, 129, 133 mh smoking 49, 50, 52, 83, 105, 106, 108, 127, st a 128, 130, 131 ere smoking cessation 52, 108, 127, 131 vse T T2 asthma 17, 115, 116 T2-low asthma 105, 106, 107, 109, 111, 116, 120, 132 treatable traits 45, 48, 49, 58 treatment 13, 14, 17, 22, 27, 28, 29, 30, 31, 32, 37, 38, 39, 41, 45, 46, 47, 48, 49, 50, 51, 53, 55, 57, 67, 68, 71, 78, 80, 83, 84, 85, 86, 94, 96, 97, 99, 105, 106, 107, 109, 111, 115, 116, 117, 118, 119, Severe Asthma - Basic and Clinical Views Edited by Sabina Škrgat Reviewers Mitja Košnik, Sanja Popović-Grle, S abina Škrgat Severe Asthma Forum, 1 E-ISSN 2738-4128 https://zalozba.upr.si/issn/2738-4128/ Managing Editor, Design and Typesetting Jonatan Vinkler Cover Image Patrick Guenette, Alamy Stock Vector Založba Univerze na Primorskem/University of Primorska Press For publisher: Klavdija Kutnar, rector Titov trg 4, SI-6000 Koper Editor-in-chief Jonatan Vinkler Managing editor Alen Ježovnik Koper, 2022 © Authors ISBN 978-961-293-157-5 (pdf) http://www.hippocampus.si/ISBN/978-961-293-157-5.pdf ISBN 978-961-293-158-2 (html) http://www.hippocampus.si/ISBN/978-961-293-158-2/index.html DOI: https://doi.org/10.26493/978-961-293-157-5 Conflict of Interest Authors have no relevant conflicts of interest to declare in relation to the content of this monograph. Kataložni zapis o publikaciji (CIP) pripravili v Narodni in univerzitetni knjižnici v Ljubljani COBISS.SI-ID 109560835 ISBN 978-961-293-157-5 (PDF) ISBN 978-961-293-158-2 (HTML) Assist. Prof. Sabina Škrgat, MD, PhD university medical centre ljubljana faculty of medicine, university of ljubljana Sabina Škrgat, MD, graduated from the Faculty of Medicine at the University of Ljubljana (1996). She is a specialist of internal medicine (2004) and pneumonology (2011). She got her PhD degree at the Uni- versity of Ljubljana (2009) with the topic of inves- tigation, related to angiogenesis and complement activation in asthma and chronic obstructive pulmo- nary disease. Her main clinical work consists of management of patients with severe asthma and other ob- structive lung diseases. She is an Assistant professor at Medical Faculty of Ljubljana and she curently has a leading position in Slovenian National recommenda- tions for asthma management. She is the clinical lead of Severe asthma Clinic at University Medical Centre Ljubljana, Slovenia. Beside clinical work, she is active in research of severe asthma by PhD mentoring. She is also the ERS SHARP (Severe Heterogenous Asthma Research Col aboration) National lead. Dr. Škrgat is a member of Slovenian Respiratory Society steering committee and a member of SHARP steer- ing committee since 2021. She launched the first Se- vere asthma forum-joint meeting of South East Eu- rope which was held in Bled, Slovenia in 2018. Založba Univerze na Primorskem University of Primorska Press Titov trg 4, SI-6000 Koper Document Outline Škrgat, Sabina, ed. 2022. Severe Asthma - Basic and Clinical Views. Koper: University of Primorska Press. Severe Asthma Forum, 1 Contents Sabina Škrgat • Prvi monografiji o hudi astmi na pot: predgovor Sabina Škrgat • Preface 1.0 • Basic Principles in Severe Asthma 1.1 • Matija Rijavec and Peter Korošec • Endotypes and Immune Cells in Severe Asthma Abstract Introduction Phenotypes and Endotypes in Severe Asthma Immune Cells Drivers of Severe Asthma Eosinophils Innate Lymphoid Cells Mast Cells and Basophils Conclusion References 2.0 • Long Journey of Corticosteroids 2.1 • Stylianos Vittorakis, Chrysa Kontogianni, Anastasia Levounets, Eleftherios Zervas and Mina Gaga • The Story of Corticosteroids in Asthma Abstract Introduction: Historical Overview Early Therapeutic Interventions The Introduction of Corticosteroids on Asthma Management The Break-through of ICS in Asthma Treatment Pilot Studies on Asthma Pathophysiology: The Role of Inflammation Enhancing Efficacy of ICS with LABA: Past and Present Summary References 2.2 • Sabina Škrgat, Peter Kopač, Natalija Edelbaher and Tomaž Kocjan • Challenges of Systemic Glucocorticoids Taper in the Treatment of Severe Asthma Abstract Introduction Evidence from European Registries Approaches to Systemic GC Taper After Introduction of Monoclonal Antibodies Conclusions References 3.0 • Multidisciplinary Approach in Severe Asthma 3.1 • Ramesh J Kurukulaaratchy and Chellan Eames • The Multi-Disciplinary Team Approach to Specialist Adult Difficult Asthma Care Abstract Introduction – Burden, Disease Mechanisms, and Definitions of Difficult-to-Treat Asthma Difficult Asthma as a Multimorbidity Difficult Breathing Syndrome – The Concept of Treatable Traits Structured Multi-Disciplinary Team Approaches to Difficult Asthma Care The MDT Components of Specialist Difficult Asthma Care in a Specialist Clinic The Asthma Specialist Physician The Asthma Nurse Specialist The Asthma Specialist Pharmacist The Asthma Physiotherapist Speech & Language Therapist The Asthma Psychologist The Asthma Dietitian Impact of Combined Difficult Asthma MDT Approaches Conclusions References 3.2 • Irena Hočevar Boltežar • The Characteristics of Upper Respiratory Tract in the Patients with Asthma and the Patients with Episodic Laryngeal Obstruction Abstract Upper Respiratory Tract Problems in the Patients with Asthma Nasal Disorders Laryngeal Disorders Episodic Laryngeal Obstruction Etiology Classification Epidemiology Symptoms and Signs Diagnostic Procedures Treatment Conclusions References 4.0 • Diagnostic and Therapeutic Chalenges in Severe Asthma 4.1 • Matjaž Fležar • Lung Function Tests to be Used in Severe Asthma: Spirometry and Bronchodilator Test, Diffusion Capacity for CO, Induced Sputum, Body Plethysmography, Electronic PEF Measurements Abstract Introduction Clinically used Tests and Physiological Background Smooth Muscle Hyperresponsiveness Bronchial Hyper Responsiveness vs. Bronchial Reversibility Structural Changes in Airways Linked to BHR Airway Smooth Muscle (ASM) Epithelial Damage and Inflammation Techniques to Measure Bronchial Hyper Responsiveness Direct and Indirect Bronchial Challenge Tests Conclusions References 4.2 • Marina Lampalo • Biomarkers in Severe Asthma Abstract Introduction Biomarker: Type 2 Inflammation Blood Eosinophils Markers of Eosinophil Activation Periostin Dipeptidyl Peptidase-4 - DPP4 Immunoglobulin E Fractional Exhaled Nitric Oxide Concentration (FeNO) Induced Sputum and Airway Inflammation Conclusion References 5.0 • Asthma Phenotypes and Therapeutic Possibilities 5.1 • Peter Kopač and Mihaela Zidarn • Asthma and Aspirin Exacerbated Respiratory Disease Abstract Introduction NSAID Hypersensitivity Clinical Characteristics of AERD Epidemiology Pathophysiology Diagnostics Management of AERD Aspirin Desensitization in AERD Summary References 5.2 • Žarko Vrbica • T2-low Asthma Abstract Introduction Clinical Characteristics Pathophysiology Neutrophylic Asthma Impact of Corticosteroids on Sputum Neutrophilia Paucigranulocytic Asthma Management of T2-low Asthma Non-pharmacological Treatment Pharmacological Treatment Investigational Products Treating Comorbidities Conclusion References 5.3 • Ljiljana Bulat Kardum • Eosinophilic and Allergic Asthma Phenotype and Therapeutic Possibilities Abstract How Common is Severe Asthma? Evolving Concepts of Severe Asthma: Personalized Asthma Management Two Different Pathways Lead to Eosinophilic Airway Inflammation in Asthma Implications of T2-High and T2-Low Pathway on Asthma Phenotypes Biological Agents Targeting Airway Inflammation in Asthma: The Rational Choice Allergic and Eosinophilic Asthma Phenotype Mechanisms of Action of Anti-IgE Treatment in Allergic Asthma Phenotype Mechanism of Action of Anti IL-5/Anti IL-5Rα and Anti IL-4/IL-13 Treatments in Eosinophilic Asthma Phenotype Looking into the Near Future: Anti-epithelial Cytokine Antibodies References 6.0 • A View Toward Controversies and Dilemmas 6.1 • Sanja Popović-Grle • Abstract Introduction The First Controversy in Asthma Always Starts with Asthma Diagnosis Here Comes the Second Controversy: Where are Those Patients With Severe Asthma Hiding? Third controversy: Are we Emphasizing the Necessity of Smoking Cessation Enough? Dilemmas in Severe Asthma First Dilemma: How Could we Precisely Define a Severe Asthma Phenotype? Second Dilemma: How Should we Distinguish Asthma From COPD in Middle-aged Smoking Patients? Third Dilemma: How to Make the Right Personalized Choice of Biologicals? Fourth Dilemma: Age. How Old (or Young) Should Our Patientsbe for Indication for Biologicals? Fifth Dilemma: Length of Treatment Appropriate to Assess a Patient’s Response to Biologicals (“Responder”or “Non-responders”) Sixth Dilemma: Should we Treat a Patient With Severe Asthma and Another Significant Disease, Like Allergic Broncho-pulmonary Aspergillosis (ABPA), or Eosinophilic Granulomatosis with Polyangiitis(EGPA)? Conclusion References Contributors Index A B C D E G I L M N O P R S T W Colophone