SEVERE ASTHMA F O R U M 2 Monitoring and Treatable Traits in Severe Asthma 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 Prof. Zorica Lazić MD, PhD University Clinical Centre Kragujevac; Faculty of Medical Sciences, University of Kragujevac; Kragujevac, Serbia 2.0severeasthmaforum SEVERE ASTHMA F O R U M 2 Monitoring and Treatable Traits in Severe Asthma Edited by Sabina Škrgat 2 0 2 3 Contents Sabina Škrgat 9 Predgovor ⁞ Preface 1.0 Dysfunctional Breathing Maja Šereg Bahar 13 Dysfunctional Breathing – View of Otorhinolaryngologist Ivan Kopitović and Milica Mirić 23 Dysfunctional Breathing – View of Pulmonologist 2.0 Asthma Phenotypes and Comorbidities Sabina Škrgat and Katarina Pelicon Slabanja 41 Aspergil us Sensitisation and Severe Asthma Clinical Outcomes Ivan Čekerevac and Bojan Djokić 47 OSA in Patients with Severe Asthma-Alternative Overlap Syndrome 3.0 Asthma Monitoring and Evaluation Sanja Popović-Grle, Gordana Pavliša, Marina Lampalo, Anamarija Štajduhar, Branko Pevec, Mira Pevec, Dina Rnjak, Valentina Fiket, Ivana Rubil and Silvana Smojver-Ježek 55 Induced Sputum Role in Severe Asthma Phenotyping Sanda Škrinjarić Cincar 63 Monitoring and Evaluation of Therapeutic Response in Patients with Severe Asthma on Biologics 77 Contributors 83 Index 85 Benefactors Predgovor ︲ Preface Sabina Škrgat1,2 Pričujoča monografija je nastajala samoza- Our first monograph already confident- 1 University Medical Centre vestno. Ker je bila pred njo že naša prva, ki ly found a place in the hands of pneumolo-Ljubljana, Ljubljana, Slovenia je orala ledino. In je našla mesto v rokah spe- gy residents and doctors, who saw an oppor- 2 Faculty of Medicine, University of Ljubljana, cializantov pnevmologije in zdravnikov, ki so tunity to upgrade and test their severe asthma Ljubljana, Slovenia v njej videli priložnost za nadgradnjo in pre- knowledge. And that made me incredibly verjanje svojega znanja. In to me je neznan- happy. I was delighted to see monographs in sko veselilo. Veselile so me malo pomečkane hands of young doctors with an underlined mono grafije v rokah mladih zdravnikov s and colour-coded text of some chapters in the podčrtanim in barvno označenim tekstom process of learning. nekaterih poglavij. Severe Asthma Forums (SAFs), which Astma forumi (SAF), ki so sledili s svo- fol owed with their topics, are also the cor- jimi temami, so tudi temelj za nastanek sedaj nerstone for now the second Monograph. At druge monografije. Na tem mestu se posebej this point, I would especial y like to thank zahvaljujem profesorjem Sanji Popović-Grle, professors Sanja Popović-Grle, Mitja Košnik Mitji Košniku in Zorici Lazić za opravljeno and Zorica Lazić for their role of peer re-recenzentsko vlogo. Besedila smo povezali v view. Chapters have been linked to the sto-zgodbo Monitoring and Treatable Traits in ry of Monitoring and Treatable Traits in Se-Severe Asthma in si tako dopustili opredel- vere Asthma and thus al owed us to define itev do disfunkcionalnega dihanja, fenotipov dysfunctional breathing, asthma phenotypes, astme in nekaterih astmi pridruženih bolezni some asthma comorbidities and monitoring ter spremljanja bolnikov z astmo. Nekatera of patients with severe asthma. Some chap-poglavja so zastavljena tako, kot v klinični ters are written according to our clinical work praksi v dobrih centrih za hudo astmo tudi v in good severe asthma centres- with typical resnici postopamo – multidisciplinarno. multidisciplinary approach. Ker obravnava bolnika s hudo astmo ni Because treating a patient with severe zgolj zdravljenje, je kanček umetnosti. asthma is not just a therapy, it is also a bit of art. Srečno. Good luck! https://doi.org/10.26493/978-961-293-297-8.9 1 Dysfunctional Breathing Dysfunctional Breathing – View of Otorhinolaryngologist 1.1 Maja Šereg Bahar 1, 2 1 University Medical Centre Abstract Ljubljana, Ljubljana, Slovenia Background. Dysfunctional breathing – vocal cord dysfunction (VCD) or paradoxical vocal 2 Faculty of Medicine, fold movement (PVFM) is inappropriate vocal fold movement. Adduction of the vocal folds University of Ljubljana, appears during inspiration, resulting in dyspnea and inspiratory and sometimes expiratory Ljubljana, Slovenia stridor, and acute upper airway obstruction. It is a functional disorder, an important mimicker of asthma, leading to unnecessary morbidity and high medical utilization, unnecessary drug use, and high-dose corticosteroid use. The gold standard test for diagnosis of VCD is direct visualization of the vocal folds by laryngoscopy while a patient has symptoms or is combined with special maneuvers that trigger symptoms. Methods. The recent papers on vocal cord dysfunction were reviewed. Results. VCD is an important differential diagnosis of refractory asthma, that is widely unrecognized. But concomitant vocal cord dysfunction and asthma are seen in a high degree of patients, up to 50%. VCD is a benign and self-limiting disorder and there are no long-term sequelae. Correct diagnosis is important due to proper treatment. The cornerstone of the VCD treatment is speech therapy like respiratory retraining, learning breathing techniques, and different maneuvers that enable quick release of symptoms. Psychotherapy and hypnosis are important modes of treatment as wel . Medications and botulinum toxin are used rarely. Conclusions. We should suspect VCD in patients with asthma-like symptoms that do not respond to conventional asthma therapy or are induced by stress and exercise. A team of different specialists is necessary to find the correct diagnosis and proper treatment. Keywords: dyspnea, vocal cords dysfunction, speech, and language therapy, maneuvers Introduction presenting mainly during inspiration leading More than 70 terms have been used to de- to dyspnea of varying intensity21. scribe the abnormal movement of the true vo- cal cords. The two most encountered terms in Epidemiology medical literature are paradoxical vocal fold The overall incidence of VCD in the gener-motion (PVFM) and vocal cord dysfunction al population is not well defined, because of (VCD)9. PVFM/VCD is a condition charac-the lack of uniformity in definitions and di- terized by abnormal adduction of the vocal agnostic criteria for VCD. The incidence is folds during inspiration, leading to episodic underappreciated in clinical practice. Preva-dyspnea, wheezing, and stridor23. VCD is an lence has been reported to range from 2.5% intermittent extrathoracic airway obstruction of patients presenting to an asthma clinic to https://doi.org/10.26493/978-961-293-297-8.13-22 up to 22% of patients with recurrent emer-Pathogenesis of VCD gency department visits for dyspnea8. Patients The etiology of VCD is complex and multi-with exertional dyspnea are reported to have factorial. VCD is a functional disorder. In the VCD in 12%, and patients with exercise-in-pathogenesis of VCD, there are several patho- duced asthma in 9%. Patients with “refracto- genetic mechanisms. The essential patho- ry asthma” have VCD in 10% alone, 30% of physiology is that of a hyper-functional la-them have both VCD and asthma36. VCD af- ryngeal reflex to protect the lower airways 21. fects mainly children, young adults, and ath- The sensitivity of the laryngeal sensory recep- letes, with female predominance (65%: 35%). tors is increased and the response of the glottic closure and cough reflex to several triggers 14 Family history was not proven18. is heightened. It is analogous to bronchial or nasal hyper-responsiveness. Direct stimula- Vocal cord anatomy and function tion of the sensory nerve endings in the up- The larynx is a valve separating the trachea per or lower respiratory tract and hyperventi-from the upper aero-digestive tract. The glot- lation may also lead to glottic narrowing due tis consists of the true and false vocal cords a to underlying laryngeal hyper-responsive- m and an opening between them, the rima glot- h ness. Another possible etiology of VCD is neu- st tidis. The principal muscle for vocal cord ab- a rological, where autonomic neurophysiologic e duction is the posterior cricoarytenoid (PCA). r balance is altered. Central brain regions such ev Adduction is performed mainly by the lateral as the medul a, midbrain, and prefrontal cor-se cricoarytenoid muscle (LCA). During normal in tex are polysynaptic linked with the larynx s inspiration, the glottic opening is control ed it and the balance can be altered37. The hypoth- ar through the medul ary respiratory center, via t esis is, that there is an initial inflammatory in- e the vagus nerve, which leads to contraction of sult, which causes laryngeal hyper-respon-bla the PCA muscle and therefore to vocal cord t siveness and/or altered autonomic balance, ae abduction. During normal expiration there r which may be short or persistent. Subsequent t is a decrease in the tonic activity of the PCA d stimuli (psychological stresses or cold air and n a muscle and contraction of the LCA muscle, irritants) induce local presynaptic reflexes gin resulting in a 10-40% narrowing of the rima causing airway narrowing18. While the etiol-ro glottides, al owing air movement to and out ogy of this disease is still unclear, many sup-itno of the lungs18. The larynx has the function of port the theory that VCD has a psychiatric - m protection the lower airway, which is strictly basis6,9,25,36. am reflective. The other functions of the larynx h st are respiration and phonation, which are reg- a Specific triggers of VCD e ulated partial y by involuntary brainstem re- r Specific triggers are not always identified, be- ev flexes and may be initiated voluntarily. Pul- cause VCD episodes quickly begin and end. monary protection is mediated by the glottic 2: se VCD triggers are classified into three groups: m closure and cough reflexes, to protect the low- u irritants, psychological and emotional, and r er airway from noxious inhaled stimuli and fo exertional6. Initial y, one patient has a single a aspiration of foreign material during respira- m trigger, then develop multiple triggers, that h tion. The cough reflex is initiated by an ad- st were previously benign. Self-reported triggers a verse stimulus triggering one of the many sen- e are upper respiratory tract infection, occupa- re sory receptors of the larynx1,9. In VCD there v tional exposures, talking, laughing, singing, se is a brief inappropriate adduction of the vo- acid reflux, cough, different foods, physi- cal folds during inspiration. This may mani- cal exertion, exercise, postnasal drip, weath- fest with audible inspiratory sounds32. er changes, emotional stressors, odors, strong scents and other airborne triggers, chlorine in ryngeal irritation associated with GORD swimmers and others9. may also contribute to bronchial constriction. It is a vagal y mediated reflex18. The role of psychogenic factors – triggers Exercise as a trigger Initial reports of VCD emphasized the dom- EILO – exercise-induced laryngeal obstruc- inant underlying psychological disorders. tion is caused by maximal exercise or ath-It is still thought that psychological stimu- letic competitions, it can be also seen during li can trigger VCD, including anxiety disor- routine exercise, but is related to exercise in- der, stress, somatoform disorders, depression, tensity. EILO symptoms resolve quickly on psychiatric il ness, social stress in competitive exercise cessation16. Most patients are high-sports, prior history of sexual abuse, conver- ly competitive, elite athletes and military per- sional profile, and others. Psychological stim- sonnel, who are required to exercise regularly. uli can trigger VCD and are considered major EILO is common, affecting 5-7% of adoles-15 precipitating factors for VCD18. Not all pa- cents and up to a quarter of athletes present- tients have an underlying psychiatric il ness. ing with “exertional asthma-type”. EILO has ist And anxiety can be also the result of chronic g a female preponderance and a peak age of on- ol respiratory il ness, not the cause9,17,22. set in the teenage years. It has been speculat- ogn ed that the laryngeal growth difference be- yra Irritant triggers tween genders seen in the peri-pubertal age lo Irritant triggers can be extrinsic including group might explain this observation38. Pa-inhr chemical, olfactory, and even visual. Irritants tients develop wheezing during exercise. The ot are environmental and occupational irritant differential diagnosis is asthma, but metha-of exposure to smoke, gasses, vapors, dust, air- choline chal enge testing is negative, as is the ow borne pol utants, and odors. Triggers can be bronchoprovocation testing9. Some patients ie intrinsic such as gastroesophageal reflux, si- can have both asthma and VCD. 35 – 56% – vg nusitis, postnasal drip, pharyngitis, and lar- of patients with VCD have coexistent asth- inh yngitis. They lead to chronic inflammation t ma. EILO represents a maladaptive response ae and hyper-responsiveness. Reflex adduction to exercise. Increased work breathing might br of vocal cords might be protective and is re- l contribute to exercise limitation. Endurance an sponsible for the development of VCD1,9,18. training induces large and significant adap- iotc tations within the cardiovascular, musculo- n The role of gastroesophageal reflux skeletal, and hematological systems. But the sfuy disease – GORD structural and functional properties of lungs d There is much speculation in different studies. and airways do not change in response to re-In some, there is a high proportion of GORD petitive physical activity. In elite athletes, the in patients with VCD (95%), and in others pulmonary system may become a limiting low proportion of patients with GORD. In a factor to exercise. As a consequence, of this re-group of elite athletes with exercise-induced spiratory paradox, the highly trained athlete laryngeal obstruction (EILO), only 2.3% had may develop intrathoracic and extrathoracic GORD38. VCD is triggered by acid reflux in obstruction, expiratory flow limitation, respi-some patients. Laryngospasm is induced by ratory muscle fatigue, and exercise-induced hydrochloric acid in the esophagus by sensi-hypoxemia. All of these maladaptations may tization of subglottic chemoreceptors through influence performance29. Increased and ab-a vagal y mediated mechanism. Reflux events normal ventilation through the narrowest part cause vocal cord adduction and apneas. La-of the airway causes the col apse of laryngeal structures. In pediatric patients, it is hypoth-of VCD is greater than 4 years8. Patients with esized that increased laryngeal diameter due asthma may also have comorbidities, such as to growth might spontaneously improve their VCD, which are associated with worse asth-exercise capacity26. Asthma is common in en- ma outcomes, increased symptoms, more ex- durance sports athletes, likewise the preva- acerbations, and poorer quality of life24. Im- lence of EILO is high. Cross-country skiers proved VCD control can reduce asthma and biathletes have a very high prevalence medication use18,23. of asthma and EILO. Coexisting EILO and asthma seem to be common in skiers, espe- Important differential diagnosis od VCD cial y females. It is mainly believed to be due Patients with VCD are often misdiagnosed 16 to repeated and prolonged inhalation of cold as having refractory asthma, which can lead dry air, therefore, leading to osmotic chang-to unnecessary morbidity and high medical es and epithelial damage in the airways19. La- utilization, unnecessary drug use and high ryngopharyngeal reflux, al ergy, infections, dose corticosteroid use, emergency room vis-irritants, temperature, the humidity of the air its, hospitalizations, and even intubation. a in the surroundings, and psychological aspect They found that 42% of all VCD subjects mh are also the etiological factors of EILO15. had been previously misdiagnosed with asth- st a ma for an average of 9 years9,34. The differ- ere Other possible etiologies for VCD ential list for suspected VCD is broad and in- v se There are some other factors as extubation af- cludes any disorder with episodic dyspnea, in ter general anesthesia. Central neurological cough, and wheezing. There are many mim-sit disorders like Arnold Chiari malformation, ickers of VCD, with asthma at the top of the ar t Parkinson’s syndromes, ALS (amyotrophic list. Other conditions are psychogenic disore ders, anaphylaxis, aspiration of foreign body, bl lateral sclerosis), and others may be associat- at angioedema, chronic obstructive pulmonary a ed with VCD18. er disease, croup, epiglottitis, extrinsic airway td compression, laryngomalacia, laryngospasm, n Clinical features of VCD a laryngeal tumor, laryngeal dystonia, exer- g Clinical presentation can be very variable, in cise-induced bronchospasm, vocal cord pare- r ranging from no symptoms to mild dyspnea, o sis, laryngeal and tracheal stenosis, and oth- it and acute onset respiratory distress, which can no mimic an asthma attack9. VCD episodes fre- ers9,18,35. - ma quently begin and end abruptly. Patients are mh not hypoxic and have a normal level of con- Diagnosis of VCD st Diagnosis is made by careful history, physical a sciousness. If the patient is with altered men- er tal status or hypoxemia, more serious causes examination – laryngoscopy, and spirometry ev should be considered. Symptoms are period- or pulmonary function testing9. Imaging has 2: se ic: shortness of breath, asthma-like symptoms no role in the evaluation of VCD32. A careful mu during exercise, and intense emotion, which history is very important. We should be sus-r fo does not respond to asthma drugs. Other picious in a patient with asthma-like symp-am symptoms are air hunger, dyspnea, choking toms unresponsive to bronchodilators or cor-h st sensation, chest pain, stridor, voice changes, ticosteroids, absence of nocturnal symptoms, ae difficulty in speaking and swal owing, globus and more difficulty with inspiration than ex-rev sensation, intermittent aphonia, dysphonia, piration. Asthma inhalers can even trigger or se chronic cough, throat clearing, panic, and exacerbate symptoms1. Symptoms in VCD anxiety which worsen respiratory symptoms9. patients are precipitated by stress, emotion-The period from symptom onset to diagnosis al factors, or anxiety. The patient has no spu- tum18. We should be suspicious in a patient tion, and exercise7,21. Patients with VCD of-with exercise-induced asthma-like symptoms, ten show inappropriate vocal fold movement or an athlete with choking sensation during during inspiration or expiration when laryn-exercise and irritant-induced asthma-like goscopy is performed immediately fol owing symptoms. But we must be aware that VCD a bronchoprovocation chal enge with metha-with asthma is possible, and we should be also choline. Therefore, laryngoscopy should be aware of exercise-induced bronchospasm32. ideal y performed after a bronchoprovoca- tion chal enge with methacholine. We should Assessment of symptoms avoid benzodiazepines and lidocaine before Relevant issues should be discussed with pa- the examination. Negative laryngoscopy in tients. We can use standardized question- an asymptomatic patient does not rule out naires, for example, 12-item VCDQ (vocal VCD5,18. cord dysfunction questionnaire), which is a valid tool for symptom monitoring and track- Continuous laryngoscopy during 17 ing improvement in scores after speech thera- exercise – CLE test py. It also gives insight into which symptoms Video recorded trans nasal flexible laryngos-ist are important to patients and could guide fu- copy and larynx examination are performed gol ture therapy refinements11. Another one is the during exercise from the rest to the peak ex-og ercise – continuous laryngoscopy exercise test n Pittsburgh VCD index, which helps distin- yr (CLE test). Any form of physical exercise can a guish VCD from asthma. This scoring sys- lo tem correctly diagnosed VCD in 77.8% of pa- be used, running, or cycling on stationary bi- inh tients. Since many patients have coexistent cycles, which provoke symptoms15. A flexible rot VCD and asthma, further diagnostic tests laryngoscope is attached to the head via a hel-of should be performed, if a strong suspicion of met. The tip of the scope is introduced through ow asthma exists33. the nose into the larynx, al owing visualiza- ie tion of the supraglottic and glottic structures in – vg Physical examination real time throughout the exercise. During test- inh ing cardiopulmonary data is col ected, as the t The physical examination in patients with a patient exercise to peak in an attempt to repro- e VCD is normal when they are not experienc- br duce EILO symptoms. EILO-related findings l ing an acute attack. During symptoms, we an can identify high-pitched wheezing, stridor, on laryngoscopy include vocal fold narrow-iot ing, supraglottis narrowing, obstruction, and/ c tachypnea, hoarseness, dysphonia, cough, n and respiratory distress. Arterial hypoxemia or col apse of supraglottic structures. CLE is sfuy is usual y lacking. The patient has a normal the test of choice for EILO32. d oxygen saturation. Only in a few patients with VCD, we can identify the presence of hypox- Other tests emia. Laryngoscopy is the gold standard for Pulmonary function tests, methacholine chal-the diagnosis of VCD. Direct visualization lenge testing, spirometry, and flow volume of the vocal folds via flexible, trans-nasal fi-loops are also done in VCD and EILO pa- ber-optic laryngoscopy should be done while tients1. a patient has symptoms. Complete adduc- tion of the vocal folds during inspiration and Treatment a formation of a small posterior glottal chink Correct diagnosis is essential for proper treat-during exhalation is seen18. In asymptomat- ment. The patient should be reassured that ic patients, we can provoke symptoms by deep the condition is benign and self-limited. The breathing, cold air, phonation, forced expira-treatment approach is multidisciplinary. Pri- mary care physician, pulmonologist, al er-to repeat them often, to ensure that a pa- gist, ENT doctor, gastroenterologist, neurol- tient can respond automatical y when acute- ogist, psychiatrist and psychologist, speech ly symptomatic (5 repetitions 20 times per pathologist and athletic trainer participate in day). Phonation of soft “s” sound while ex-the treatment. Effective long-term therapy re- haling, is successful to divert attention from quires psychosocial support, speech therapy, inhalation, and give auditory feedback on and biofeedback9. air movement. Another maneuver is panting, which activates the PCA muscle, a laryngeal Speech therapy abductor. Coughing and sniffing are also re- Speech therapy is the cornerstone of the treat- leasing maneuvers. Sniffing reduces air tur- 18 ment18. It is the most common long-term treat- bulence and shifts the narrowest part of the ment of VCD. Patients are educated about the breath from the larynx to the nose. Common pathophysiology of VCD and are educated breathing techniques include jaw trust, nasal about the suppression of laryngeal abusive be-inspiration with pursed-lip exhalation, and haviors (cough and throat clearing). Patients breathing through a large-diameter straw or a are trained on how to control the laryngeal cut endotracheal tube. These techniques are mh area and maintain an adequately open air- designed to interrupt the irregular respirato- st a way during respiration. Patient are al owed ry pattern or spasm and al ow familiar neu-ere to view their laryngoscopy, to understand and rologic signals to reengage and relax the vo-v se accept the disease. Visual feedback al ows the cal folds8,18,30. in patient to modify their breathing, visual feed- sit back enables a reduction in symptoms and the a EILOBI breathing techniques r t use of medication. Breathing techniques are e In EILO adduction of the vocal folds and/or bl learned by the speech and language therapist a inspiratory prolapse of the supraglottic struc- t (SLT), and VCD symptoms, and triggers are ae tures during high-intensity exercise appears. r assessed. Patient education is a crucial com- t Although respiratory retraining is a prima- d ponent of the treatment. The therapist offers n a supportive counseling. Respiratory retrain- ry therapy of EILO, many patients report gin ing is practiced by the SLT. Desensitization symptom persistence despite the adequate ro performance of traditional techniques. EI- it is attempted to be achieved for specific irri-n LOBI (EILO biphasic) inspiratory breathing o tants. Voice therapy and different breathing - m techniques are practiced – quick release tech- techniques are novel breathing techniques am niques and different maneuvers. Studies have for EILO therapy20. Patients are encouraged h st shown that speech therapy can achieve symp- to train in biphasic inspiratory breathing: ae tom control and eliminate emergency depart- from high inspiratory resistance then rapid- rev ment visits in 90% of patients with VCD8,14,23. ly changed to low resistance breathing. High resistance inspiratory phase (tongue vari-2: se Non-pulmonary-related shortness of breath m treated with respiratory retraining can effec- ant - inhaling through the nose, tooth vari- ur tively eliminate dyspnea. The patient should ant - inhaling through the teeth placed firm-foa perform respiratory retraining exercises three ly against the lower lip, lip variant - inhaling mh to four times daily for four weeks, and daily through the pursed lips) is fol owed by low st ae exercises for two additional months13. resistance inspiratory phase – inhalation re through a wide-open mouth. Thus, optimiz- vse Treatment of VCD – maneuvers ing the glottic aperture with maneuvers that Different maneuvers can be used to achieve can be performed during high-intensity exer-a quick release of symptoms. It is necessary cise is achieved8,30. Inspiratory muscle training devices and effective option for individuals with mod- Treatment of EILO in athletes and other pa- erate to severe supraglottic-type EILO who tients with VCD with inspiratory muscle have failed initial conservative treatment10. training devices is possible. It is a conservative treatment tool to achieve better control of the Botulinum toxin vocal folds. Patients can use resistive flow-de- pendent devices. The inspiratory valve in- Botulinum toxin laryngeal injection is rarely creases resistance to inspiration and decreases used in VCD treatment. Chemical denerva-the inspiratory rate of airflow, consequently, tion is achieved and paralysis, the vocal folds there is less turbulence and less stimulation are in the open position. It is useful in laryn-of the vocal folds4. Another one is the use of geal dystonia. It is used only in severe cases of continuous positive airway pressure – CPAP refractory VCD, that do not respond to con-to relieve acute symptoms of VCD. CPAP re- ventional therapy, and in patients with re- lieves dyspnea by slowing the expiratory flow, fractory dyspnea symptoms fol owing appropriate medical therapy and respiratory 19 thereby increasing lung volume, which in turn results in a more open glottis. CPAP is retraining protocols28,36. ist also reducing the effort needed for inspiration go Treatment of VCD with medications l by establishing a favorable pressure gradient og for inhalation18. – pharmacotherapy nyr In persistently symptomatic patients, mild alo Psychotherapy sedatives may facilitate VCD management. inh Psychotherapy remains an important mode Benzodiazepines are effective in terminating rot of treatment in patients with VCD. There are acute symptoms and relieving anxiety. Before of many forms of psychotherapy used in VCD, giving this medication, we should confirm ow which include relaxation therapy to al eviate normal oxygen saturation and exclude hy-ie the distress associated with symptoms, identi- percapnia18. When breathing techniques are – vg fication of stressors, development of new cop- unsuccessful, helium-oxygen inhalation and inh ing strategies for dealing with stressors, family t noninvasive positive-pressure ventilation may ae therapy, and behavioral cognitive therapy18. be successful in resolving VCD. Heliox is the br Hypnosis and self-hypnosis induce relax- l mixture of oxygen (20%) and helium (80%), an ation. Biofeedback may be used in conjunc- it is less dense than air and reduces the work of iot tion with psychotherapy for treating patients c breathing. Inhalation of Heliox reduces tur- n with VCD2,3,12,17,25. bulence in the airway and eliminates respira- sfuyd tory noise7,18. In some centers, they use inhala- Surgical treatment tion of anticholinergic drugs. Neuromuscular Surgical treatment – supraglottoplasty is used treatment such as Gabapentin is successful in only in refractory cases. It gives good results some patients. GORD treatment is reasonable in selected patients. The most commonly used method is to cut the aryepiglottic folds clos- if GORD is proven, the success of such treat- er to the epiglottis and to remove the muco- ment is very good in those patients in whom sa and cuneiform cartilage from the aryepi- reflux has been demonstrated21,31. glottic fold with the help of a laser. The use of a suture that pul s the epiglottis towards Prognosis the root of the tongue and lateralization of VCD is a benign and self-limiting disorder. one vocal fold with the suture are also de- The majority of patients respond to speech scribed27,39. EILO surgery appears to be a safe therapy. There are no long sequelae18,32. Conclusions 7. Christopher KL, Wood RP, Eckert VCD is an important differential diagnosis of C, et al. Vocal cord dysfunction pre- asthma, that is widely unrecognized. If mis- senting as asthma. N Eng J Med. 1983 diagnosed as asthma, VCD can lead to high Jun;308(26):1566-70. medical utilization, unnecessary high-dose 8. Denipah N, Dominguez CM, Kraai steroid use, and other dangerous consequenc-EP, et al. Acute Management of Para- es. We should suspect VCD in patients with doxical Vocal Fold Motion (Vocal Cord asthma-like symptoms that do not respond Dysfunction). Ann Emerg Med. 2017 to conventional asthma therapy or are in- Jan;69(1):18-23. duced by stress and exercise. The gold stand- 9. Dunn NM, Katial RK, Hoyte FCL. 20 ard test for VCD is direct visualization of the Vocal cord dysfunction: a review. Asth-vocal cords by laryngoscopy. The cornerstone ma Res Pract. 2015 Sep 22:1:9. doi: of VCD treatment is speech therapy. VCD 10.1186/s40733-015-0009-z. should be included in the differential diagno- 10. Famokunwa B, Sandhu G, Hull JH. sis for patients reporting episodic dyspnea or Surgical intervention for exercise-in- duced laryngeal obstruction: A UK a respiratory distress. Patients with asthma may m perspective. Laryngoscope. 2020 h also have comorbidities such as VCD. Identi- st Nov;130(11):E667-E673. a fying and treating VCD should be included in e 11. Fowler SJ, Thurston A, Chesworth B,, r the management of patients with asthma. ev et al. The VCDQ--a Questionnaire se for symptom monitoring in vocal cord in References s dysfunction. Clin Exp Al ergy. 2015 it 1. Altman KW, Simpson CB, Amin MR, ar Sep;45(9):1406-11. t et al. Cough and paradoxical vocal fold e 12. Guglani L, Atkinson S, Hosanagar A, bl motion. Otolaryngol Head Neck Surg. a et al. A systematic review of psycholog- ta 2002 Dec;127(6):501-11. e ical interventions for adult and pediat- r t 2. Anbar RD. Hypnosis in pediatrics: ap- ric patients with vocal cord dysfunction. dn plication at a pediatric pulmonary cen- a Front Pediatr. 2014 Aug 8;2:82. doi: g ter. BMC Pediatr. 2002 Dec 3;2:11. doi: 10.3389/fped.2014.00082. inr 10.1186/1471-2431-2-11 o 13. Hatzelis V, Murry T. Paradoxical vo- it 3. Anbar RD, Hehir DA. Hypnosis as a di- n cal fold motion: respiratory retraining o agnostic modality for vocal fold dys- to manage long-term symptoms. J Soc - m function. Pediatrics. 2001 Dec;106(6): a Bras Fonoaudiol. 2012;24(1):80-5. mh E81. doi: 10.1542/peds.106.6.e81. 14. Hicks M, Brugman SM, Katial R. Vo- st a 4. Archer GJ, Hoyle JL, McCluskey A, et cal cord dysfunction/paradoxical vo- er al. Inspiratory vocal cord dysfunction, a e cal fold motion. Prim Care. 2008 v new approach in treatment. Eur Respir Mar;35(1):81-103. 2: se J. 2000 Mar;15(3):617-8. 15. Hočevar Boltežar I. The Characteris- mu 5. Balkissoon R. Occupational upper air- tics of Upper Respiratory Tract in the r fo way disease. Clin Chest Med. 2002 Patients with Asthma and the Patients am Dec;23(4):717-25. with Episodic Laryngeal Obstruction. h st 6. Christopher KL, Morris MJ. Vocal cord In: Škrgat S, editor. Severe asthma - ba- ae dysfunction, paradoxic vocal fold mo- sic and clinical views. Koper, Slove- rev tion, or laryngomalacia? Our under- nia: Založba Univerze na Primorskem, se standing requires an interdisciplinary 2022. p. 67-74. approach. Otolaryngol Clin North Am. 16. Hull JH, Godbout K, Boulet LP. Ex- 2010 Feb;43(1):43-66. ercise-Associated Dyspnea and Stri- dor: Thinking Beyond Asthma. J Al- 26. Liyanagedera S, McLeod R, Elhas- lergy Clin Immunol Pract. 2020 Jul- san HA. Exercise induced laryngeal ob- Aug;8(7):2202-8. struction: a review of diagnosis and 17. Husein OF, Husein TN, Gardner management. Eur Arch Otorhinolaryn- R, et al. Formal psychological test- gol. 2017 Apr;274(4):1781-9. ing in patients with paradoxical vocal 27. Maat RC, Roksund OD, Olofson fold dysfunction. Laryngoscope. 2008 J, et al. Surgical treatment of exer- Apr;118(4):740-7. cise-induced laryngeal dysfunction. 18. Ibrahim WH, Gheriani HA, Almo- Eur Arch Otorhinolaryngol. 2007 hamed AA, et al. Paradoxical vo- Apr;264(4):401-7. cal cord motion disorder: past, pres- 28. Malaty J, Wu V. Vocal Cord Dysfunc- ent, and future. Postgrad Med J. 2007 tion: Rapid Evidence Review. Am Fam Mar;83(977):164-72. Physician. 2021 Nov 1;104(5):471-475. 19. Irewall T, Bäcklund C, Nordang L, et 29. McKenzie CD. Respiratory physiology: al. High Prevalence of Exercise-induced adaptations to high-level exercise. Br J 21 Laryngeal Obstruction in a Cohort of Sports Med. 2012 May;46(6):381-4. Elite Cross-country Skiers. Med Sci 30. Patel RR, Venediktov R, School- istgo Sports Exerc. 2021 Jun 1;53(6):1134-41. ing T, et al. Evidence-Based System- log 20. Johnston KL, Bradford H, Hodges H. atic Review: Effects of Speech-Lan- ny The Olin EILOBI Breathing Tech- guage Pathology Treatment for Individ- ral niques: Description and Initial Case Se- uals With Paradoxical Vocal Fold Mo- oin ries of Novel Respiratory Retraining tion. Am J Speech Lang Pathol. 2015 hro Strategies for Athletes with Exercise-In- Aug;24(3):566-84. t duced Laryngeal Obstruction. J Voice. 31. Poelmans J, Tack J, Peterson J, et al. of o 2018 Nov;32(6):698-704. Paroxysmal laryngospasm: a typical but wie 21. Kenn K, Balkissoon R. Vocal cord dys- underrecognized supraesophageal man- function: what do we know? Eur Respir ifestation of gastroesophageal reflux? – vgin J. 2011 Jan;37(1):194-200. Dig Dis Sci. 2004 Nov-Dec;49(11-12): ht 22. Lacy TJ, McManis SE. Psychogen- 1868-74. ae ic stridor. Gen Hosp Psychiatry. 1994 32. Sayad E, Das S. Exercise Induced La- brl May;16(3):213-23. ryngeal Obstruction. In: StatPearls [In- an 23. Le Blanc RA, Aalto D, Jeffery CC. ternet]. Treasure Island, FL: StatPearls iotc Visual biofeedback for paradoxical vo- Publishing; 2022 Jan. n cal fold motion. J Otolaryngol Head 33. Traister RS, Fajt ML, Landsittel D, et sfuyd Neck Surg. 2021 Feb 18;50(1):13. doi: al. A novel scoring system to distinguish 10.1186/s40463-021-00495-0. vocal cord dysfunction from asthma. J 24. Lee J, Denton E, Hoy R, et al. Para- Al ergy Clin Immunol Pract. 2014 Jan- doxical Vocal Fold Motion in Difficult Feb;2(1):65-9. Asthma Is Associated with Dysfunction- 34. Traister RS, Fajt ML, Petrov AA. al Breathing and Preserved Lung Func- The morbidity and cost of vocal cord tion. J Al ergi Clin Immunol Pract. Jul- dysfunction misdiagnosed as asth- Aug 2020;8(7): 2256-62. ma. Al ergy Asthma Proc. 2016 Mar- 25. Liao KS, Kwak PE, Hewitt H, et al. Apr;37(2):25-31. Measuring Quality of Life in Pediatric 35. Traister RS, Fajt ML, Whitman-Purves Paradoxical Vocal Fold Motion Using E, et al. A retrospective analysis com- the SF-36v2. J Voice. 2017 Jul;31(4):518. paring subjects with isolated and coex- e1-518.e5. istent vocal cord dysfunction and asth- ma. Al ergy Asthma Proc. 2013 Jul- Aug;34(4):349-55. 36. Vance D, Heyd C, Pier M, et al. Para- doxical Vocal Fold Movement: A Ret- rospective Analysis. J Voice. 2021 Nov;35(6):927-9. 37. Walsted ES, Faisal A, Jol ey CJ. In- creased respiratory neural drive and work of breathing in exercise-induced laryngeal obstruction. J Appl Physiol 22 (1985). 2018 Feb 1;124(2):356-63. 38. Walsted ES, Famokunwa B, Andersen L, et al. Characteristics and impact of exercise-induced laryngeal obstruction: an international perspective. ERJ Open Res. 2021 Jun 28;7(2):00195-2021. doi: am 10.1183/23120541.00195-2021. h st 39. Young O, Russel JR. Suture later- ae alization of vocal cord treating vo- rev cal cord movement: a case report. se Eur Arch Otorhinolaryngol. 2008 ins Apr;265(4):485-7. itar te blataer tdn aginroitno - mamh st aerev 2: semur foamh st aerevse Dysfunctional Breathing – View of Pulmonologist 1.2 Ivan Kopitović1,2, Milica Mirić1 1 Institute for Pulmonary Abstract Diseases of Vojvodina, Dysfunctional breathing (DB) is a respiratory disorder defined by non-regular breathing pat-Sremska Kamenica, Serbia terns. It is a breathing condition where long term changes in breathing pattern result in symp-2 Univeristy of Novi Sad, toms (main is dyspnoea) but also non-respiratory symptoms, with no prominent cardio-res-Faculty of Medicine, Serbia piratory or neuro-psychiatric disease (sometimes secondary to them). It has been identified in different age groups and also among asthma patients. Although DB has been investigated for long time, it is poorly understood because of lack in clinical trials and validated outcome measures specific to this population. DB irregularity is often missed, because of the similarity of its associated symptoms (dyspnoea, tachycardia, and dizziness) to those of other common car-diorespiratory diseases such as heart failure, asthma and chronic obstructive pulmonary disease (COPD). The high rates of misdiagnosis of DB suggest that health care professionals do not ful y understand this condition and may therefore fail to provide patients with an appropriate treatment. A holistic assessment is the most appropriate way to improve understanding and diagnostic accuracy. Keywords: dysfunctional breathing, hyperventilation, pulmonary function tests Abbreviations ACQ - Asthma Control Questionnaire AQLQ - Asthma Quality of Life Questionnaire BMI - Body Mass Index BHT - Breath Holding Time BPAT - Brompton Breathing Pattern Assessment Tool CART - capnography-assisted respiratory therapy COPD - Chronic Obstructive Pulmonary Disease CPET - Cardiopulmonary Exercise Testing DB - Dysfunctional breathing ET-CO2 - end-tidal carbon dioxide measurement HVPT - Hyperventilation Provocation Test HVS - Hyperventilation syndrome MARM - Manual Assessment of Respiratory Motion NQ - Nijmegen Questionnaire SEBQ - Self-Evaluation of Breathing Questionnaire https://doi.org/10.26493/978-961-293-297-8.23-38 Introduction of breathing that results in intermittent or Dysfunctional breathing (DB) is a chronic chronic symptoms which may be respirato-or recurrent alteration of normal breathing ry and/or non-respiratory”.9 Various terms pattern, recognized as an important differ-have been used: earlier it was mainly de- ential diagnosis for individuals with “unex- scribed as a hyperventilation syndrome, while plained” dyspnoea.1 Hidden in the complex nowadays it is more often cal ed dysfunction-management of many respiratory diseases, al breathing, functional breathing disorder, such as asthma, COPD and “long-COVID”, breathing pattern disorder and behavioural DB may exacerbate these diseases/disorders, or psychogenic breathlessness, etc. The later reduce symptom control and increase medi-terminology results from better understand- 24 cation and healthcare service use.2–6 Recent- ing of pathophysiological processes underly-ly, more evidence-based classification, diag- ing the abnormal pattern of breathing which nostic criteria and treatment modalities of DB itself does not necessarily include hyperventi-have been developed.2 lation. In this narrative review we will prefer the term “dysfunctional breathing”. a Dysfunctional breathing in the modern mh era? Aetiology and pathophysiology st a Eighty-five years ago a group of authors re- Efficient breathing results from balanced ere marked: “Patients presenting well known pat- motion between the upper rib cage and the v se tern of symptoms haunt the offices of physi- lower rib cage and the abdomen. It requires in cians and specialists in every field of medical synchronized movement of diaphragm, ab-sit practice. They are often shunted from one dominal and rib cage muscles.10 Discoordi-ar t physician to another, and the sins of commis- nation of muscle contractions results in sen- e bl sion inflicted upon them fil many black pages sations of dyspnoea and is often present in ata in our book of achievement.”7 DB, especial y in apical, thoracic dominant er t In 1975, in the respiratory physiology de- breathing.11 dn partment of Papworth Hospital, Cambridge, A simplified physiological process en- ag England, the specialists dubbed this phenom- countered in hyperventilation may help part- inr enon simply as the “multiple doctor” or the ly understand relationships between causes of oit “fat folder syndrome”.8 In the late 1960’s, one DB and its consequences (Figure 1). Hyper-no of the newly reported major side effects of re- ventilation is an increase in ventilation that is - m greater than that required by metabolic needs a cently introduced oral contraceptives was ve- mh nous thromboembolism. Since then, as many or arterial blood gas tensions. It may be acute, st episodic, and chronic. Furthermore, it has a physicians encountered young ladies taking er birth-control pil s that reported syncopal at- been wel -described that stressful events, es- ev tacks and other possible manifestations of pecial y emotional upset, can elicit a habitual 2: se pulmonary embolism, dysfunctional breath- change in breathing pattern.12 Indeed, chang- mu ing (most known as “ hyperventilation syn- es in breathing depend on a variety of exter- r fo drome” (HVS) has become more and more nal and internal factors (i.e. cold, heat, hypox-am recognized in different clinical settings. ia, pain and panic).13 DB can be described as a h st habit in breathing and in some cases includes ae Definition over-breathing (increase in both tidal volume rev There is no formal definition of DB. Bark- and respiratory rate). Thus, it may result in se er and Everard reviewed the literature and decrease in carbon dioxide. Consequently, hy-suggested a new definition of DB: “an alter- pocapnia directly induces cerebral vasocon- ation in the normal biomechanical patterns striction and cerebral hypoxia, while kidneys excrete the excess bicarbonate ion. Hydrogen tex) and involuntary (neural, emotional, en-ion deficiency suppresses hydrochloric acid docrine, and metabolic) control mechanisms. formation by the stomach as wel . Further on, Numbers of hormones participate in ventila-in the state of alkalosis, smooth muscles of the tory regulation. For example, hyperventila-digestive tract also constrict, while haemo- tion with resultant hypocapnia may be pres- globin slowly delivers smal er amount of oxy- ent during the luteal phase of the menstrual gen (Bohr effect). Hypocalcaemia, secondary to calciuria induced by alkalemia, results in cycle as well as in pregnancy.14 However, res-poor muscle and nerve function, e.g. hyper- piratory complaints appear to have a strong- excitability of skeletal and visceral muscles. er relationship to breathing pattern.15 Thus, As in the vicious circle, all potential resultant pathophysiological mechanisms underlying symptoms (Table 1) exaggerate previously ex-DB require further research on the levels of isting anxiety, which in its turn, aggravate dis- neural ventilatory control and skeletal muscle ordered pattern of breathing. The regulation metabolic function, which would include proof breathing involves both voluntary (cor- cesses in the normocapnic settings as wel .16 25 istgolonoml puf owie – vginhtae brlaniotcn sfuyd Figure 1.Pathophysiologic process in hyperventilation Epidemiology Presentation The prevalence of DB in general population The key respiratory symptom in dysfunction-is estimated to be approximately 8%.8 As the al breathing is breathlessness (“air hunger”). disordered is il -defined without standardized Non-respiratory associated symptoms may diagnostic tools, it is hard to estimate its true be attributable to hyperventilation (increased prevalence. Dysfunctional breathing may af-minute ventilation) and respiratory alkalosis such as paraesthesia (i.e. tingling), numbness, fect individuals across all age groups and is dizziness, palpitations and, rarely, tetany. more often found in asthmatics who are fe- Also, frequently reported are chest tightness, male, with poor asthma control, frequent ex- chest pain, deep sighing, exercise-induced acerbations and comorbid anxiety states.17–19 dyspnoea and frequent yawning. However, none of the symptoms are specific to dysfunc- “I get breathless even when I am resting” tional breathing.20 “My breath feels like it does not go in all the way” “My breath feels like it does not go out all the way” Table 1. Symptoms and signs of disfunctional “My breathing is heavy” breathing “I feel that I am breathing more” “My breathing requires work” “My breathing requires effort” System Most probably caused by hypocapnia “I find myself breathing through my mouth during the day” in hyperventilation “I breathe through my mouth at night while I sleep” Cardiovascular Palpitations, tachycardia, precordial pain, cold hands or feet Classification 26 Respiratory Shortness of breath, chest pain, chest tightness More than 45 years ago Lum and col eagues8 Gastrointestinal Globus, dysphagia, epigastric pain, proposed classification related to dominant aerophagy, bloated feeling in the stomach pattern in breathing: Neurological Central: dizziness, disturbance of consciousness, blurred vision, 1. Rapid breathing. Peripheral: paresthesia (tingling 2. Irregular amplitude of breaths. a fingers), tetany (rarely) m 3. Irregular rhythm. h Musculoskeletal Muscle pains, tremors, tetany st 4. Frequent sighs and yawns. a Psychic Feeling tense, anxiety e 5. Habitual sniffing and coughing. re General Fatigability, weakness, exhaustion, v 6. Fast breathless talking. sleep disturbance, nightmares se 7. General tension in the whole body insit In order to better il ustrate respiratory com- Researchers have suggested a few alter- ar t plains that may be evaluated, we quote in Ta- native classifications for other patterns of DB. e Boulding and col eagues found that bl ble 2 the questions included in a preliminary at version of Self Evaluation of Breathing Ques- “tracking of respiratory flow, frequency and aer tionnaire, revised by Courtney R and Green- volumes during quiet tidal breathing, of- td ten performed before and after exercise, can n wood KM.21 a give useful information to the clinician and be gin used for providing feedback to the patient.” r Table 2. The Self-Evaluation of Breathing o Further, they used those data to guide them in it Questionnaire (SEBQ), revised version (21). no defining and classifying various dysfunction- - m al breathing patterns.2 a “I get easily breathless out of proportion to my fitness” m Classification of DB, by Boulding and h “I notice myself breathing shal owly” st “I get short of breath reading and talking” colleagues: ae “I notice myself sighing” re 1. Hyperventilation syndrome is associat- v “I notice myself yawning” “I feel I cannot get a deep or satisfying breath” ed with symptoms both related to res- 2: se “I notice that I am breathing irregularly” piratory alkalosis and independent of mu hypocapnia. r “My breathing feels stuck or restricted” fo “My rib cage feels tight and can’t expand” 2. Periodic deep sighing represents fre- am “I notice that I am breathing quickly” quent sighing with an irregular breath- h “I get breathless when I am anxious” st ing pattern. a “I find myself holding my breath” e 3. Thoracic dominant breathing is charac- re “I feel breathless in association with other physical symptoms” v terized by an absence of costal expan- se “I have trouble coordinating my breathing when I am speaking” sion and an increased reliance on upper “I can’t catch my breath” thoracic muscles during inspiration. As “I feel that the air is stuffy, as if not enough air in the room” a consequence, this type of breathing results in high operating lung volumes 5. Thoraco-abdominal asynchrony is seen and reduced inspiratory capacity, as in when there is delay between rib cage HVS. Also, it can frequently manifest and abdominal contraction resulting in in organic disease, but in the absence of ineffective breathing mechanics.2 disease it may be considered dysfunc- tional and results in dyspnoea. The most recognized model of DB is HVS, 4. Forced abdominal expiration: these characterized by acute or chronic hyperventi-patients utilize inappropriate and ex- lation (increased minute ventilation) at rest or cessive abdominal muscle contraction during exercise/stress. HVS may be part of so-to aid expiration. This type of DB re- matic/physiological conditions, stil it common- sults in very low lung volumes, and ly develops secondary to psychological/behav-therefore a reduced functional residu- ioural factors (particularly anxiety, depression, al capacity. perfectionism, and feelings of inferiority).22–24 27 istgolonoml puf owie – vginhtae brlaniotcn sfuyd Figure 2. Differential diagnosis between DB and difficult-to-treat asthma and the detrimental effect of DB on asthma and asthma-related outcomes.30,31 Modified from: Denton E, Bondarenko J, Tay T, et al. Factors Associated with Dysfunctional Breathing in Patients with DifficulttoTreat Asthma. J Al ergy Clin Immunol Pract. 2019;7(5):1471-1476. Connett GJ, Thomas M. Dysfunctional Breathing in Children and Adults With Asthma. Front Pediatr. 2018;6:406. Associated conditions ity of 95%. The questionnaire consists of 16 DB can occur either in the absence of organic items of which seven are linked with respira-diseases (i.e., due to psychogenic causes such tory symptoms, four assess excessive ventila-as anxiety) or it may be coexisting with res- tion and five relate to central nervous system piratory diseases (asthma, COPD, interstitial symptoms. Questions are answered in a few lung diseases), cardiovascular disease, tho-minutes on a five-point scale ranging from racic wall abnormalities, hyperventilation in ‘never’ (0 points) to ‘very often’ (4 points).34 anxiety related disorders and panic disorder. The score ranges from 0 to 64, with cut-off Symptoms of DB can mimic asthma, which value of 23 and more points that best indi-may influence the level of disease control and cates HVS. However, elevated score is not di-28 potentialy lead to overtreatment, especialy agnostic of a specific syndrome. The ques-in difficult-to-treat and severe asthma pheno- tionnaire has been increasingly used as an type, as il ustrated in Figure 2.17,25,26 The ex-outcome measure in various clinical and re- pected treatment success with bronchodila- search settings for physiotherapists and other tors and anti-inflammatory medicines may specialists. The cut-off value to detect DB and be substantial y reduced due to the presence a distinguish it from other abnormalities de- mh of disorder in breathing pattern. Among in- pends on the context in which the NQ is used, st a dividuals with asthma, a positive diagnosis of i.e. in poorly managed asthma, COPD, panic er DB is found in a third of women and a fifth disorder and anxiety, where its specificity may ev of men.27 Also, DB may exacerbate myofas- se be lower.6 Actual y, the score measures “func- in cial pain syndromes, such as temporomandib- tional respiratory complaints” meaning that sit ular joint disease 28, and other common condi- it refers to ventilation, dyspnoea and breath- ar t tions such as headaches and migraines.29 DB ing movement in relationship with stress and e bl is present in the so-cal ed ‘long COVID’ syn- anxiety. Van Dixhoon and group of authors34 at drome as part of a long-lasting dyspnoea asso- a that developed the questionnaire comment er ciated with previous SARS-CoV-2 infection that “it detects transdiagnostic and probably td persisting for months after acute infection. nonmedical abnormality”, “reflects a subjec- n ag tive aspect of DB” and that “early detection inr Diagnostic methods of these tension related complaints would pre- oit Diagnosis of DB may be established only af- vent unnecessary visits to medical specialists no ter assessment, exclusion or adequate treat- and treatment”. The NQ is not copyrighted - m ment of other possible conditions. A gold (free to use) but depends heavily on patients’ am understanding of questions and adequate h standard diagnostic method is yet to be es- st self-assessment. a tablished. Several questionnaires and func- er tional tests have been used with less or more The Self-Evaluation of Breathing Ques- ev success. Tools should help multidimensional tionnaire (SEBQ) includes 25 questions 2: se evaluation of breathing as it comprises three of which 23 refer to breathing or forms of m breath. Thus, it is complementary to NQ as u main functions: gas exchange (lung func- r tion), change in posture and movement of the it evaluates more respiratory symptoms relat-foam trunk (biomechanical function)9 and a “sense ed to the manual assessment measure.35 In a h study by Courtney R and Greenwood KM, st of self” (mental function).32,33 We offer a brief ae algorithm in assessment of DB ( Figure 3). SEBQ demonstrated both very high test–re- rev The Nijmegen Questionnaire (NQ) was test reliability and internal consistency in a se introduced and validated in individuals with group of adults from the general population.21 exercise induced hyperventilation syndrome, However, as they concluded, “whilst SEBQ where it shows sensitivity of 91% and specific- may bring a greater sensitivity than alterna- •anamnesis DB •physical exam suspected •chest X-ray, lung function tests, arterial blood gasses, ECG, blood glucose, CBC, kidney and liver function tests, consult otorhinolaryngologist and psychologist Dg and •most common differential dg: asthma, COPD, respiratory failure, heart failure, treat other neuromuscular diseases, panic disorder, anxiety, upper airway disorder causes •assess functional respiratory complaints with observation-based tools and Persistent questionnaires, i.e. NQ, BPAT, MARM etc. symptoms of DB •erratic ventilation; hyperventilation with frequent sighing present at rest/during exercise; hypocapnia 29 CPET •normal PaO2, alveolar-arterial pressure gradient of oxygen, dead space volume/tidal volume and arterial-ETCO2 pressure gradient at end-exercise istgol •asthma or exercise-induced bronchoconstriction on •deconditioned - abnormal or normal physiological limit o exercise- m •exercise-induced arrhythmia, intracardiac shunting, exercise-induced anaphylaxis, l induced dyspnea etc. puf owie •dyspnea independent from bronchospasm and unresponsive to beta-agonists •functional (disordered breathing pattern or paradoxal vocal fold motion disorder) – v or structural (phrenic nerve palsy, repaired diaphragmatic hernia, g DB bronchomalacia, laryngomalacia, subglotic stenosis, etc.) inhtae brlaniot Figure 3. An example of diagnostic algorithm for DB cn sfuyd tives to the assessment of DB-related symp- ent aspects of breathing (i.e. rate, regularity). toms because it is not oriented around the di- The most important part is to assess breath- rect effects of hyperventilation, the trade-off ing pattern and the relative distribution of may be reduced specificity, particularly for breathing motion between upper rib cage and people with respiratory medical conditions lower rib cage and abdomen. The MARM is such as asthma, for whom similar symptoms a practical and reliable tool for the breathing might arise from pathological changes in air-pattern assessment with good agreement be- ways rather than from disturbed biomechani- tween examiners. Moreover, one study com- cal breathing patterns”. paring MARM with respiratory induction The Manual Assessment of Respira- pletizmography found that it can better dis- tory Motion (MARM) is a palpation tech- tinguish thoracic from abdominal breath- nique based on the examiner’s interpretation ing.36 and estimate of motion identified by hands at The Brompton Breathing Pattern As- the posterior and lateral lower rib cage. The sessment Tool (BPAT) is, like MARM, a tool MARM enables examiner to measure differ-used by the observer (i.e. physiotherapist). The BPAT includes assessment of abdominal latory response) and prolong BHT to 40 or or apical breathing, inspiratory and expira-50s.42 A short BHT (<30s) after normal ex- tory flow, inspiration and expiration through piration at functional residual capacity is con-mouth or nose, air hunger, breathing rate and sidered to be related to DB. A physician Kon-rhythm.17 Recently, it appeared to be a useful stantin Buteyko, M.D., Ph.D., that developed screening tool for identifying DB in patients breathing technics to reduce HVS claimed with difficult-to-treat and severe asthma (with that BHT can detect chronic hyperventila-score ≥4 as a cut-off for diagnosing DB was tion and that BHT predicts alveolar CO2 confirmed with sensitivity 95% and specifici- (PaCO2) according to his patented mathe- ty 78%).37 Similarly, it is useful in evaluating matical formula.41,43 30 DB in long COVID (12 weeks after confirmed Finaly, to objectively evaluate breath-or presumed pneumonia caused by SARS- ing patterns in various clinical and outpa- CoV2 virus). Using the established cut-off, it tient settings, an ideal system should tend to showed a sensitivity of 89.5% and specificity fulfill the fol owing characteristics: (1) Accu-of 78.3%.3 rate calculation of volume changes without a The Hyperventilation Provocation Test using a mouthpiece that may alter the normal mh (HVPT) requires voluntary hyperventilation breathing pattern; (2) Need of a simple, sta-st a for several minutes and is considered positive ble and repeatable calibration; (3) Possibility ere if symptoms of HVS are recognized by the of use in non-col aborating subjects (during v se examinee. Earlier, the test was a gold stand- sleep, or in unconscious patients); (4) Per- in ard for diagnosing HVS and the symptoms mitting the analysis in different postures; (5) sit of HVS were largely attributable to hypocap- Permitting the analysis under dynamic con- ar t nia (low end-tidal carbon dioxide). Howev- ditions such as walking or cycling; (6) Al ow- e ing high frequency response in order to accu- bl er, a high percentage of false-positive results at during the HVPT has been found in stud- rately describe rapid phenomena (i.e. electric aer ies with a control condition of stressful men- or magnetic stimulation of phrenic nerves); td (6) Al owing the analysis of movements and n tal load.38,39 What is more, when limiting a volume changing of the upper thorax, low- g symptoms to hypocapnia, a study in the Lan- in er thorax, and abdomen; (7) Al owing the r cet found a high rate of false positives (66%) o analysis of movements and volume chang- it in patients where end-tidal pCO2 was main- no tained at baseline value by manual titration of ing of the hemi thoraces; (8) Being non-inva- - m carbon dioxide from the cylinder into the in- sive and safe for the patient.44 Different tech-am niques with various limitations are available h spired air.40 st for measuring natural breathing at rest - tid- a The end-tidal carbon dioxide measure- er ment (ET-CO2) is measured using capnogra- al breathing patterns, as well as exercise-in- ev phy with an expected low ET-CO2 in hyper- duced changes in breathing. A less frequently 2: se ventilation.41 used techniques include pneumotachography, m respiratory induction plethysmography opto- u The Breath Hold Test or Breath Hold- r electronic plethysmography and structured fo ing Time (BHT) is an indicator of a person’s a light plethysmography . These vary in the m ventilatory response to biochemical (sensitivi- h source of the signal and the type of param- st ty to hypoxia and hypercapnia), biomechani- ae cal (lung volumes), non-chemical factors, and eters that are generated, such as thoraco-ab-rev psychologic factors, as well as training, exer- dominal asynchrony.45–47 Only structured se cise and altitude, etc. For example, divers may light plethysmography does not necessitate accommodate to the absence of respiratory direct contact with patient’s body and is less movements (non-chemical factors for venti-dependent on patient’s cooperation.47 How- 31 istgolonoml puf owie – vginh Figure 4. Ventilation slopes and Wasserman panel (VT/V’E). (A) Normal subject. (B) Respiratory limitation tae showing a regular, but limited increase of tidal volume with high breathing frequency. (C) Dysfunctional br breathing with an erratic pattern. Plots of tidal volume (VT on the right y-axis) and breathing frequency la (BF on the left y-axis) against minute ventilation (V’E on the x-axis) during incremental exercise testing. nio Data are not filtered in the ventilation slopes. Geratherm Respiratory combined filter is used in the tc Wasserman panel (VT/V’E). BF, breathing frequency; VT, tidal volume; V’E, minute ventilation.51 n sfuyd ever, these techniques are resource- and ev- respiratory panels of CPET can bring up to idence-limited and need further clinical and a diagnosis of DB. Furthermore, CPET may experimental research.48 unravel the mechanisms of breathlessness Cardiopulmonary Exercise Testing by simultaneously evaluating cardiovascu- (CPET) is the most detailed diagnostic tool lar adaptation, ventilation, and gas exchange to objectify breathing patterns during exer-through exercise. CPET permits recognition cise and it represents “an ideal candidate” of any pathophysiological cause of exertion-for gold standard among proposed diagnostic al dyspnoea which would not manifest during methods for DB.12 A major benefit of CPET tests performed at rest.49–51 Precisely, patients is that, in contrast to the questionnaires and with DB usual y present with high frequency observation-based approaches, it offers objec-of breathing at rest which rises swiftly at the tive measurements and plots data which can begging of exercise, while tidal volume may be directly analysed. Erratic ventilation, hy-remain stable. This can increase dead space perventilation with frequent sighing present ventilation and change the kinetics of multiple at rest or during exercise and recorded in the CPET variables. Also, decreasing PaCO2 set point in rapid shal ow breathing, as seen in hy-PaO2, alveolar-arterial pressure gradient of perventilation type of DB, typical y induces oxygen, dead space volume/tidal volume and ventilatory inefficiency characterized by high arterial-ETCO2 pressure gradient at end-ex-minute ventilation/CO2 output (VE/VCO2 ercise. These findings can help differentiate slope), with general y a normal dead volume/ from other conditions in which chronic hy- tidal volume ratio. Important to notice is that perventilation occurs, as in patients with in-increase in end-inspiratory and end-expira- creased dead space ventilation, such as those tory lung volumes, as seen in hyperinflation, with heart failure or pulmonary hyperten-therefore reduces inspiratory capacity and sion. Similarly, an identified marker of disease possibly contributes to the troublesome dysp-severity in patients with heart failure due to 32 noea sensation regardless of the existence of left ventricular systolic dysfunction is period-true hypocapnia.2 However, other types of ic breathing. As happens in DB, it may devel-DB with normal PaCO2 and VE/VCO2 have op at rest or during exercise and last through-been described, in particular, erratic ventila- out the entire period of incremental workload tion with wide and irregular variations of tid- or disappear facing the end of exercise. How- ever, the characteristic periodicity of waxing a al volumes and breathing frequency over the m and waning of tidal volumes (minute venti- h progression of effort during CPET.52 Bould- st lation, as wel ) present in periodic breathing a ing and col eagues suggested a classification of e is in sharp contrast to the unpredictable and re DB patterns according to incremental CPET v irregular breathing pattern of DB. Further, se data, as well as change in breathing frequen- thoracic-dominant patterns may be present in cy, tidal volumes, and respiratory muscle me- s in morbidly obese patients in response to their it chanics before and after exercise.2 Analysis of a low abdominal compliance. At last, one must r t ventilation patterns on CPET may contrib- e consider asthma and COPD, where patients bl ute in differentiating types of breathing dys- a may develop thoracic-dominant and forced ta regulation in people with dyspnoea present e expiratory breathing patterns as a physio- r in the absence of deconditioning as a post– t logical adaptive response to pulmonary hy- d acute-phase sequelae of mild infection with n perinflation, in which case they should not be ag SARS-CoV2 virus. Nonetheless, one should regarded as dysfunctional.12 Ionescu and col-inr consider its highly demanding resources and o leagues proposed a diagnostic and therapeu- it setups in the context of the high prevalence of n tic algorithm for patients with unexplained o post-COVID-19, as well as the fact that “ex- dyspnoea. Starting with high clinical suspi- - m ercising at physiological limits may exacer- a cion of DB, electrocardiography, chest radi- m bate symptoms in these patients, also referred h ography and spirometry test should be one st a to as postexercise malaise”.12,53 An example of the first tools to exclude or prove possi-er of CPET in a normal subject compared with e ble cardiopulmonary etiologies of dyspnoea. v a person with limited tidal volume and high If symptoms persist after adequate manage-2: se breathing frequency and a person with dys- ment, the next step is CPET. If there is good mu functional breathing is showed in Figure 4.51 fitness on CPET with no evidence of DB, reas- r fo Differential diagnosis should always and sure the patient and discharge. If there are ab-am firstly include all diseases that can be the cause normalities present in terms of cardiac, venti-h st of dyspnoea in the first place, and also, may latory, gas exchange or metabolic parameters ae be associated with DB. The finding of erratic on CPET, proceed to targeted management. rev breathing on CPET cannot exclude accompa- If there are, in addition or alone, one or more se nying disease, nor can it precisely confirm DB features of DB identified on CPET, refer the diagnosis. Most frequently patients with DB patient to a chest physiotherapist, with target-present with resting hypocapnia and normal ed therapeutic intervention.12 Combining different tools possibly could costeroids or that requires such treatment to be the best choice as it may increase diagnostic maintain good symptom control and reduce accuracy. For example, in the recent studies the risk of exacerbations.26 The aforemen-the NQ was used to evaluate symptoms relat- tioned findings reinforce the idea to routinely ed to DB, and supplemented with the BPAT to search for DB in the patients referred for spe-objectively assess breathing pattern in patients cialist management of asthma.25,54 Further in-with difficult-to-treat asthma.17,25 Identify- vestigations are necessary to determine a pos- ing DB as a co-morbidity in difficult-to-treat sible benefit of physiotherapeutic treatment in asthma is of a special interest, to avoid poten-reduction of inhaled corticosteroids use in pa- tial y harmful or costly overtreatments such tients with concomitant asthma and DB. as oral steroids, or biological treatments. One group of researchers found that almost quar- Treatment ter of patients referred to severe asthma clin- ic had only DB.17 In comparison, Sedeh and Patient education about the condition, reassurance 33 colleagues25 firstly comprehensively and sys- Abdominal breathing retraining tematically verified asthma diagnosis in al Breathing rate and depth control ist Breathing retraining in progressively taxing postures such as g participants, then assessed disease severity ac- o walking lo cording to international recommendations26 Recognition of triggers no and, at last, applied the NQ, BPAT, as wel Control of symptoms during an episode of DB and manual ml as Asthma Control Questionnaire (ACQ) therapy puf and Asthma Quality of Life Questionnaire ow (AQLQ). The researchers found that patients Various modes of breathing retraining pro-ie with uncontrol ed asthma and DB were most- grams guided by a qualified professional (e.g. – v physiotherapist) are recommended, such as g ly female (74%), had higher body mass index in breathing control, diaphragmatic breath- h (BMI), had significantly poorer asthma con- ta ing, yoga breathing, Buteyko breathing, bio- e trol and lower quality of life compared to pa- feedback-guided breathing modification, and br tients without DB. After adjusting for BMI lan the relationship between DB and poor asthma yawn/sigh suppression.55,56 iot control, did not change, meaning that symp- Educating patients about DB is the key cn toms of DB were not induced by obesity. Also, and the first step in the program. Helping pa-sfuy DB alone, the NQ score as well as the BPAT tients differentiate symptoms of DB from the d were an independent determinants of ACQ- associated conditions, such as asthma, is an score meaning that the adverse impact of DB important goal. For instance, DB would not on asthma control could not be explained respond to targeted treatments for asthma. by other factors such as more bronchial hy- One randomized control ed trial by per-responsiveness or lower lung function in Lindeboom and col eagues compared re-patients with DB. Moreover, patients with a laxation therapy versus relaxation thera-low NQ, but high BPAT (objective signs of py and breathing exercises.57 According to a DB), had a significantly poorer asthma con-Cochrane review58, the results of this study trol, compared to patients with both low NQ “describe a significant reduction in frequen-and low BPAT. Similar results were found in cy and severity of hyperventilation attacks in one study on asthma patients using the NQ the breathing exercise group compared with and ACQ-score.54 Difficult-to-treat asthma is the control group, which demonstrated an asthma that is uncontrol ed despite medium/ increase in the frequency and severity of at- high dose inhaled corticosteroids with a sec- tacks. In addition, a significant difference in ond control er, or on maintenance oral corti- frequency and severity of hyperventilation at- tacks between the breathing and relaxation tions as they perceive the practitioner wish-group was reported.” es them to, lowering the scores given to de- Diaphragmatic (abdominal) breath- scribe the presence of their symptoms in order ing represents breathing in slowly and deep- to demonstrate the treatment is working. Sim- ly through the nose using the diaphragm with ilarly, the practitioner knows that the patient the least possible movement of the chest in has received therapy and so will be search-a supine position with one hand laid on the ing for proof that therapy has been success-chest and the other on the umbilical region. ful. In reality, it has been noticed that patient Lately, a systematic review has reported that symptoms and quality of life improve, as as-mind–body exercises, such as yoga or tai chi, sessed in one study with Asthma Quality of 34 which incorporate diaphragmatic breath- Life Questionnaire, even though the NQ/ ing can lower effect of intense stress or unfa- SEBQ/BPAT scores do not substantial y in- vourable emotions by balancing the sympa- crease from the baseline.61 CPET may be ef- thetic and vagal tone.59 Even through many fective in the objective guidance of the breath-trials have found that breathing exercises are ing retraining process and in the monitoring a helpful in treating COPD, asthma, and post- m of therapeutic effect.12 h operative pulmonary function, the efficacy of st a diaphragmatic breathing in managing other e Conclusion re diseases/disorders, i.e. cancer, heart failure, v Taking into account the heterogeneity, psy- se and anxiety, still needs to be studied further. chological and physiological aspects of DB, a in To stress out, diaphragmatic breathing may s multidimensional, holistic assessment would it worsen dyspnoea in severe COPD patients.55 ar appear the most correct approach to improve t A novel mind-body breathing therapy e understanding and diagnostic efficiency. bl intervention adjunct is a capnography-assist- a The current narrative review was composed ta ed respiratory therapy (CART) has found ap- e in a manner of brief summary of the avail- r plication in COPD-related DB management. td CART consists of patient-centered biofeed- able data considering DB, in order to pro- n a mote understanding of the disorder by health g back, tailored breathing exercises, a home ex- in care professionals. Upgrading knowledge of r ercise program and motivational interviewing o the etiologic and pathophysiologic factors, di- it counselling.60 no Primary therapeutic outcome should be agnostic tools and treatment options in DB - m management enables practitioners to improve a improvement in quality of life. Secondary m health-related quality of life in people experi- h outcomes mainly include the Nijmegen ques- st encing breathing pattern abnormalities. a tionnaire score, minute volume, tidal volume, er respiratory frequency, ET-CO2 or transcuta- ev neous CO2 measurement, and functional ex- References 2: se ercise capacity. However, over the course of 1. Siewers K, Walsted E, Manivannan mu the therapy, evolution from the first assess- B, et al. Heightened ventilatory re- r sponse during stair climbing in individ- fo ment to consecutive fol ow-ups is frequently am recorded using NQ, SEBQ, or BPAT scores. uals with dysfunctional breathing. ERJ h Open Res. 2022 Oct 10;8(4):00285- st As aforementioned, these tools subjective- ae ly differentiate symptoms and breathing pat- 2022. doi: 10.1183/23120541.00285- rev tern. What is more, there is risk of bias in pro- 2022. se cess monitoring. After initiating therapy, a 2. Boulding R, Stacey R, Niven R, et al. patient fil ing out a questionnaire may, either Dysfunctional breathing: a review of the intuitively or intentionally, answer the ques- literature and proposal for classification. Eur Respir Rev. 2016 Sep;25(141):287-stress: rate or depth? J Physiol. 2017 Sep 94. 1;595(17):5729-52. 3. Hylton H, Long A, Francis C, et al. 14. Saaresranta T, Polo O. Hor- Real-world use of the Breathing Pat- mones and breathing. Chest. 2002 tern Assessment Tool in assessment of Dec;122(6):2165-82. breathlessness post-COVID-19. Clin 15. Han J, Schepers R, Stegen K, et al. Med (Lond). 2022 Jun 27;22(4):376-9. Psychosomatic symptoms and breath- 4. Morgan MD. Dysfunctional breath- ing pattern. J Psychosom Res. 2000 ing in asthma: is it common, identifiable Nov;49(5):319-33. and correctable? Thorax. 2002 Oct;57 16. Van Voorthuizen EL, van Helvoort (Suppl 2):II31-II35. HAC, Peters JB, et al. Persistent Ex- 5. Taverne J, Salvator H, Leboulch C, et ertional Dyspnea and Perceived Ex- al. High incidence of hyperventilation ercise Intolerance After Mild COV- syndrome after COVID-19. J Thorac ID-19: A Critical Role for Breathing Dis. 2021 Jun;13(6):3918-22. Dysregulation? Phys Ther. 2022 Oct 35 6. Grammatopoulou EP, Skordilis EK, 6;102(10):pzac105. doi: 10.1093/ptj/ Georgoudis G, et al. Hyperventilation pzac105. istgo in asthma: a validation study of the Ni- 17. Todd S, Walsted ES, Gril o L, et al. lon jmegen Questionnaire – NQ. J Asthma. Novel assessment tool to detect breath- om 2014 Oct;51:839-846. ing pattern disorder in patients with re- l 7. Kerr WJ, Dalton JW, Gliebe PA. Some fractory asthma. Respirology. 2018 puf physical phenomena associated with Mar;23(3):284-90. owie the anxiety states and their relation to 18. Agache I, Ciobanu C, Paul G, et al. hyperventilation. Ann Int Med. 1938 Dysfunctional breathing phenotype in – vg Jan;11:962-92. adults with asthma – incidence and risk inht 8. Lum LC. Hyperventilation: the tip factors. Clin Transl Al ergy. 2012 Sep ae and the iceberg. J Psychosom Res. 19;2(1):18. doi: 10.1186/2045-7022-2- brl 1975;19(5-6):375-83. 18. an 9. Barker N, Everard ML. Getting to grips 19. Veidal S, Jeppegaard M, Sverrild A, et iotc with ‘dysfunctional breathing’. Paediatr al. The impact of dysfunctional breath- n Respir Rev. 2015 Jan;16(1):53-61. ing on the assessment of asthma control. sfuyd 10. De Troyer A, Estenne M. Function- Respir Med. 2017 Feb;123:42-7. al anatomy of the respiratory muscles. 20. Hornsveld H, Garssen B. The low spec- Clin Chest Med. 1988 Jun;9(2):175-93. ificity of the Hyperventilation Prov- 11. Simon PM, Schwartzstein RM, Weiss ocation Test. J Psychosom Res. 1996 JW, et al. Distinguishable types of Nov;41(5):435-49. dyspnea in patients with shortness 21. Courtney R, Greenwood KM. Prelimi- of breath. Am Rev Respir Dis. 1990 nary investigation of a measure of dys- Nov;142(5):1009-14. functional breathing symptoms: The 12. Ionescu MF, Mani-Babu S, De- Self Evaluation of Breathing Question- gani-Costa LH, et al. Cardiopulmonary naire (SEBQ). Int J Osteopath Med. exercise testing in the assessment of dys- 2009;12(4):121‐7. functional breathing. Front Physiol. 22. Gardner WN. The pathophysiology of 2020 Jan 27;11:620955. doi: 10.3389/ hyperventilation disorders. Chest. 1996 fphys.2020.620955. Feb;109(2):516-34. 13. Tipton MJ, Harper A, Paton JFR, et 23. Courtney R, Greenwood KM, Cohen al. The human ventilatory response to M. Relationships between measures of dysfunctional breathing in a population 33. Leupoldt AV, Sommer T, Kegat S, et al. with concerns about their breathing. J The unpleasantness of perceived dysp- Bodyw Mov Ther. 2011 Jan;15(1):24- nea is processed in the anterior insu- 34. la and amygdala. Am J Crit Care Med. 24. Jack S, Rossiter HB, Pearson MG, et al. 2008 May 1;177(9):1026-32. Ventilatory responses to inhaled carbon 34. van Dixhoorn J, Duivenvoorden dioxide, hypoxia, and exercise in idio- HJ. Efficacy of Nijmegen Question- pathic hyperventilation. Am J Respir naire in recognition of the hyperven- Crit Care Med. 2004 Jul 15;170(2):118- tilation syndrome. J Psychosom Res. 25. 1985;29(2):199-206. 36 25. Sedeh FB, Von Bülow A, Backer V, 35. Mitchell AJ, Bacon CJ, Moran RW. Re-et al. The impact of dysfunctional liability and Determinants of Self-Eval- breathing on the level of asthma con- uation of Breathing Questionnaire trol in difficult asthma. Respir Med. (SEBQ) Score: A Symptoms-Based 2020 Mar:163:105894. doi: 10.1016/j. Measure of Dysfunctional Breathing. rmed.2020.105894. a Appl Psychophysiol Biofeedback. 2016 m 26. Chung KF, Wenzel SE, Brozek JL, et al. h Mar;41(1):111-20. st International ERS/ATS Guidelines on a 36. Courtney R, van Dixhoorn J, Cohen M. e Definition, Evaluation and Treatment re Evaluation of breathing pattern: com- v of Severe Asthma. Eur Resp J. 2014 se parison of a Manual Assessment of Res- Feb;43(2):343-73. in piratory Motion (MARM) and res- s 27. Thomas M, McKinley RK, Freeman it piratory induction plethysmography. ar E, et al. The prevalence of dysfunction- t Appl Psychophysiol Biofeedback. 2008 e al breathing in adults in the communi- bl Jun;33(2):91-100. a ty with and without asthma. Prim Care t 37. Hylton H, Long A, Quantrill S, et al. ae Respir J. 2005 Apr;14(2):78-82. r P156 Use of the breathing pattern as- t 28. Bartley J. Breathing and temporoman- d sessment tool within the difficult asth- n a dibular joint disease. J Bodyw Mov g Ther. 2011 Jul;15(3):291-7. ma service. Thorax. 2019;74(Suppl inr 2):A175. o 29. Whittaker D. Multidisciplinary ap- it 38. Roll M, Zetterquist S. Acute chest pain n proaches to breathing pattern disorders. o Australas Chiropr Osteopathy. 2002 without obvious organic cause before - m the age of 40 years: response to forced a Nov;10(2):111. mh 30. Denton E, Bondarenko J, Tay T, et al. hyperventilation. J Intern Med. 1990 st a Factors Associated with Dysfunction- Sep;228(3):223-8. er 39. Hornsveld H, Garssen B, Fiedeldij Dop e al Breathing in Patients with Difficult to v Treat Asthma. J Al ergy Clin Immunol M, et al. Symptom reporting during 2: se Pract. 2019 May-Jun;7(5):1471-6. voluntary hyperventilation and mental mu 31. Connett GJ, Thomas M. Dysfunc- load: implications for diagnosing hyper- r fo tional Breathing in Children and ventilation syndrome. J Psychosom Res. am Adults With Asthma. Front Pedi- 1990;34(6):687-97. h st atr. 2018 Dec 20:6:406. doi: 10.3389/ 40. Hornsveld HK, Garssen B, Dop MJ, ae fped.2018.00406. et al. Double-blind placebo-control ed rev 32. Rosenkranz MA, Davidson RJ. Affec- study of the hyperventilation provoca- se tive neural circuitry and mind-body in- tion test and the validity of the hyper- fluences in asthma. Neuroimage. 2009 ventilation syndrome. Lancet. 1996 Jul Sep;47(3):972-80. 20;348(9021):154-8. 41. Courtney R, Cohen M. Investigating Crit Care Med. 2004 Jul 15;170(2):118-the claims of Konstantin Buteyko M.D., 25. PhD: the relationship of breath holding 50. Jack S, Rossiter HB, Warburton CJ, et time to end tidal CO2 and other pro- al. Behavioral influences and physiolog- posed measures of dysfunctional breath- ical indices of ventilatory control in sub- ing. J Altern Complement Med. 2008 jects with idiopathic hyperventilation. Mar;14(2):115-23. Behav Modif. 2003 Oct;27(5):637-52. 42. Delapil e P, Verin E, Tourney-Chol et, 51. Frésard I, Genecand L, Altarel i M, et Pasquis P. Breath-holding time: Ef- al. Dysfunctional breathing diagnosed fects of non-chemical factors in di- by cardiopulmonary exercise testing in vers and nondivers. Eur Respir J. 2001 ‘long COVID’ patients with persistent Jul;442(4):588-94. dyspnea. BMJ Open Respir Res. 2022 43. Stalmatski A. Freedom from Asthma: Mar;9(1):e001126. doi: 10.1136/bm- Buteyko’s Revolutionary Treatment. jresp-2021-001126. 37 2nd Revised ed. London: Kyle Cathie; 52. Neder J, Berton D AR. Abnormal pat- 1999. 176 p. terns of response to incremental CPET. ist 44. Romagnoli I, Lanini B, Binazzi B, et al. In: Palange P, Laveneziana P, Neder JA, gol Optoelectronic Plethysmography has editors. 2018 clinical exercise testing ono Improved our Knowledge of Respira- European respiratory monograph. Shef- ml tory Physiology and Pathophysiology. field, UK: European Respiratory Socie- puf Sensors (Basel). 2008 Dec 5;8(12):7951- ty, 2018. p. 34-58. ow 72. 53. van Voorthuizen EL, van Helvoort ie 45. Zhang Z, Zheng J, Wu H, et al. Devel- HAC, Peters JB, et al. Persistent Exer- – vg opment of a Respiratory Inductive Ple- tional Dyspnea and Perceived Exercise inh thysmography Module Supporting Mul- Intolerance After Mild COVID-19: A tae tiple Sensors for Wearable Systems. Sen- Critical Role for Breathing Dysregula- br sors. 2012 Sep 27;12(10):13167-84. tion? Phys Ther. 2022 Oct;102(10):p- lan 46. Parreira VF, Vieira DS, Myrrha MA, et zac105. doi: 10.1093/ptj/pzac105. iot al. Optoelectronic plethysmography: a 54. Veidal S, Jeppegaard M, Sverrild A, et cn review of the literature. Rev Bras Fisiot- al. The impact of dysfunctional breath- sfuy er. 2012 Nov-Dec;16(6):439-53. ing on the assessment of asthma control. d 47. Motamedi-Fakhr S, Wilson RC, Iles R. Respir Med. 2017 Feb:123:42-47. Tidal breathing patterns derived from 55. Hamasaki H. Effects of Diaphrag- structured light plethysmography in matic Breathing on Health: A Narra- COPD patients compared with healthy tive Review. Medicines (Basel). 2020 subjects. Med Devices (Auckl). 2016 Oct 15;7(10):65. doi: 10.3390/medi- Dec 29:10:1-9. cines7100065. 48. Levai IK, Massaroni C, Hull JH, et al. 56. Rama S, Bal entine R, Hymes A. Sci- Optoelectronic plethysmography (OEP) ence of Breath: A Practical Guide. in the assessment of dysfunctional Honesdale, PA: Himalayan Institute breathing (DB) in athletes. Eur Respir J Press; 1998. 119 p. Confer. 2016;48(Suppl. 60):A2248. 57. Lindeboom I, Vlaander–van der Gies- 49. Jack S, Rossiter HB, Pearson MG, et al. sen G. Hyperventilation and thera- Ventilatory responses to inhaled carbon py Hyperventilatie en therapie. Ned- dioxide, hypoxia, and exercise in idio- erlands Tijdschrift Voor Fysiothera- pathic hyperventilation. Am J Respir pie.1980;90(1):18-21. 58. Jones M, Harvey A, Marston L, et al. Breathing exercises for dysfunctional breathing/hyperventilation syndrome in adults. Cochrane Database Syst Rev. 2013 May 31:(5):CD009041. doi: 10.1002/14651858.CD009041.pub2. 59. Zou L, Sasaki JE, Wei GX, et al. Ef- fects of Mind-Body Exercises (Tai Chi/ Yoga) on Heart Rate Variability Param- eters and Perceived Stress: A Systemat- 38 ic Review with Meta-Analysis of Ran- domized Control ed Trials. J Clin Med. 2018 Oct 31;7(11):404. doi: 10.3390/ jcm7110404. 60. Norweg AM, Skamai A, Kwon SC, et al. Acceptability of capnography-as- am sisted respiratory therapy: a new mind- h st body intervention for COPD. ERJ Open ae Res. 2021 Oct;7(4):00256-2021. doi: rev 10.1183/23120541.00256-2021 se 61. Bruton A, Lee A, Yardley L, et al. Phys- ins iotherapy breathing retraining for asth- ita ma: a randomised control ed trial. Lan- r te cet Respir Med. 2018 Jan;6(1):19-28. blataer tdn aginroitno - mamh st aerev 2: semur foamh st aerevse 2 Asthma Phenotypes and Comorbidities Aspergil us Sensitisation and Severe Asthma Clinical Outcomes 2.1 Sabina Škrgat,1,2 Katarina Pelicon Slabanja3 1 Department for pulmonary Abstract and allergic diseases, University Fungal lung diseases represent a heterogenous group of conditions and the differing definitions Medical Centre Ljubljana, Slovenija are used to describe these relationships. Historical y there has been the nomenclature evolution on the spectrum of lung diseases linked to sensitisation to A. Fumigatus including SAFS ( se-2 Medical Faculty, University of Ljubljana vere asthma with fungal sensitisation) and ABPA/M (al ergic bronchopulmonary aspergillosis/mycosis). It seems that AFAD (airway fungal airway disease) therefore represents an open 3 Pulmonary Department, General Hospital dr. Franc definition of IgE sensitisation to thermotolerant fungi. It covers not only the most severe forms Derganc, Šempeter, Slovenija of the disease as SAFS and ABPA, but also milder forms of airway disease. It might represent a treatable trait which has to be seen, longitudinal y observed, and treated and consequently preventing lung damage. Keywords: al ergic fungal airway disease, severe asthma, IgE sensibilisation Introduction tal fungi such as non-thermotolerant Alter- Fungal lung disease represents a heterogene- naria and Cladosporium which act as season-ous group of conditions1. They can be divid- al aeroal ergens, the symptoms of which are ed into infective, toxic, or al ergic in nature, directly related to airborne concentrations although there is a degree of overlap. Some of of fungal material, and which can include them are connected and interact in patients acute severe exacerbations. The second type with asthma and particularly in severe asth-involves an al ergic response to thermotoler- ma. Its behaviour in interaction with fungi re- ant filamentous fungi such as species from the sults in different clinical asthma outcomes, Aspergil us and Penicillium which can act as which are under recognised and represents a aeroal ergens, and they have the additional clinical and diagnostical challenge. property of being able to germinate in the air- The differing nomenclatures are used ways. Consequently, they are colonising the to describe these relationships. A recent pro-lungs and causing a persistent al ergenic stim- posal of various clinical outcomes of airway ulus that can lead to lung damage2–4. colonisation with thermotolerant filamentous Historically the clinical and immunolog- fungi e.g. A. Fumigatus (table 1) includes al-ical variability in presentation of fungal al er- lergic group. This al ergic group can again be gy to thermotolerant fungi has developed into broadly divided into two, both of which can a separate differentiation/definition of two be associated with severe asthma. The first conditions: al ergic bronchopulmonary asper-type is an al ergenic response to environmen- gil osis/mycosis (ABPA/M) and severe asth- https://doi.org/10.26493/978-961-293-297-8.41- 46 Table 1. Clinical outcomes of airway colonisation graded with the criteria proposed by the In- with thermotolerant filamentous fungi e.g., A. ternational Fumigatus (adapted from 1) Society for Human & Animal Mycolo- gy (ISHAM)7 which are more relaxed mak- Basic Clinical manifestaton Further subclasification ing them more relevant to clinical practice5. Upper Proposed ABPA criteria includes: airway Al ergic fungal sinusitis Lower 1. the presence of asthma or cystic fibrosis, airway Cavitating lung disease Aspergilloma 2. evidence of specific IgE to A. fumigatus Fungal allergy Chronic pulmonary and total IgE above 1000 IU/ml 42 Chronic Lung disease aspergil osis Ekstrinsic allergy 3. at least two of raised IgG antibodies to alveolitis A. fumigatus, abnormal radiology con- Fungal bronchitis sistent with ABPA and an eosinophil Immunocompromised count (steroid-naive patients of greater host Invasive aspergil osis than 0.5X109/l) a ma with fungal sensitisation (SAFS). Recent In an accompanying diagnostic algo- mh publications1 support the idea that these pre- rithm, total IgE was central in distinguishing st a sentations should not be strictly seen as a com- between ABPA and IgE sensitization without ere pletely different entities since there is limited ABPA v se evidence that there are distinct mechanisms This structure has been very recently in involved in the spectrum of thermotolerant further upgraded8 with the work of the Japan sit fungal lung al ergy. Consequently, recently ABPM research program, supported by the ar t an inclusive set of criteria which includes al Japan Medical Research and Development e bl presentations of the disease under the umbrel- Organization. They developed new ten-com- ata la term al ergic fungal airway disease (AFAD) ponent diagnostic criteria for ABPA/ABPM er in non-cystic fibrosis patients (table 2 ) where t is preferred1,5. dn they compared the sensitivity and specificity ag Evolution of terminology toward AFAD of the new and conventional criteria to dis- inr criminate pathological and physician-diag- o The fungi that play a role in asthma can be it nosed ABPA/ABPM from related diseases, n divided into two groups: those that can grow o at body temperature, referred to as thermo- including fungus-negative mucoid impaction - m in bronchi, chronic eosinophilic pneumonia, a tolerant, which are capable of both infection mh and al ergy, and those that cannot but can stil fungus-sensitized severe asthma, and chron-st a ic pulmonary aspergil osis. The new diagnos- e act as al ergens in IgE sensitised individuals. r tic criteria, compared with existing criteria, e It is the thermotolerant group of filamentous v showed better sensitivity and specificity for fungi that cause AFAD1,5. The pathophysiol- 2: se diagnosing ABPA/ABPM; The sensitivity for m ogy behind different clinical outcomes is the u pathological ABPM with Rosenberg-Patter- r host response to airway colonising, al ergenic, fo son criteria, ISHAM criteria, and these new a thermotolerant, filamentous fungi, with A. fu- m criteria were 25.3%, 77.2%, and 96.2%, re- h migatus as the major culprit5. spectively. The sensitivity for physician di- st ae Sensitisation ot A. Fumigatus has been agnosed ABPA/ABPM were 49.2%, 82.7%, re associated with a spectrum of states includ- v and 94.4%, respectively. The areas under the se ing SAFS and ABPA/M. The descriptions of curve for the receiver operating characteris-ABPA criteria have developed over time and tic curves were 0.85, 0.90, and 0.98, respec-the Petterson s criteria6 were later further up- tively7. Table 2. Clinical diagnostic criteria for al ergic including lung damage and that »watch and bronchopulmonary mycosis in patients without see« strategy might be not enough. cystic fibrosis (adapted from 7) Pathophysiological abnormalities 1. Current or previous history of asthma or asthmatic symptoms and clinical outcomes related to airway 2. Peripheral blood eosinophilia (≥ 500 cel s/mm3) fungal allergy 3. Elevated total serum immunoglobulin E levels (IgE ≥ 417 IU/mL) Basic immunology 4. Immediate cutaneous hypersensitivity or specific IgE for Fungal sensitisation occurs in about 3–10% filamentous fungi 5. Presence of precipitins or specific IgG for filamentous fungi of the general population9 and 7–20% of 6. Filamentous fungal growth in sputum cultures or bronchial asthmatics. The prevalence is higher in pa-lavage fluid tients with severe asthma (rates between 35– 7. Presence of fungal hyphae in bronchial mucus plugs 75%)10. The hal mark of AFAD is exaggerat-8. Central bronchiectasis on computed tomography (CT) 9. Presence of mucus plugs in central bronchi, based on CT/ ed T2 immunity causing IgE sensitisation to bronchoscopy or mucus plug expectoration history filamentous fungi and eosinophilic inflamma- 43 10. High attenuation mucus in the bronchi on CT tion7. Airway epithelium is exposed to prote- se olytic enzymes from fungi fol owing deposi- m Filamentous fungi in 4-6 should be identical. oc Patients that meet 6 or more of these criteria are dition of the spores/hyphae or smal er particles tu agnosed with ABPM. on the surface. Those enzymes augment the ola permeability of the epithelial layer by digest- ic Many fungal sensitised individuals with in ing the proteins of tight junctions, destroying l severe asthma do not fulfil the criteria for c the integrity of epithelial cel s and by digest- a ABPA, so in 2006 the term SAFS was intro- m ing the structural proteins of the basement h duced. Denning and col eagues thus proposed st membrane. Selective production of TSLP, a the term severe asthma with fungal sensitisa- er IL-25, and IL-23 by epithelial cel s and inhi- e tion (SAFS) to describe this aspect of trouble- v some asthma and used criteria in opposition bition of IL-12 production by dendritic cel s sed (DCs) may be responsible for the shift toward n to the ABPA criteria by including an IgE of a Th2 responses11. In the study of Balenga and n 1000 IU/L8. However, SAFS includes asth- io co-workers they have shown that a major A. t matics with sensitisation to any fungus. isa It seems that AFAD therefore represent fumigatus al ergen, Asp f13, which is a serine sit protease, alkaline protease 1 (Alp1), promotes n an open definition of IgE sensitisation to ther- se airway hyper-responsiveness by infiltrating s motolerant fungi, therefore a treatable trait lu which has to be seen, longitudinal y observed the bronchial submucosa and disrupting air-ilg way smooth muscle (ASM) cel -extracel u- r and treated as appropriate. It covers not only spe the most severe forms of the disease as SAFS lar matrix (ECM) interactions12. The group a and ABPA, but also milder forms of airway later demonstrated that Alp1 quantities were disease. It is important to stress that many pa-significantly higher in sputum from patients tients with clinical y significant fungal al ergy with Af sensitivity than those without, re-do not have severe asthma. Nevertheless, al gardless of clinical severity of the disease. But patients with IgE sensitisation to thermotoler-the amount of Alp1 in the lower airways of ant fungi in the context of asthma and other asthmatics correlated with severity of disease airway disease are at risk of progressive lung and interestingly with sputum neutrophil, but damage, and as such should be monitored not eosinophil counts. They suggested that it closely irrespective of a diagnosis of ABPM7. is proteolytic destruction of lung tissue, which The terminus AFAD reminds a clinician, could promote influx of neutrophils into the that the disease might progress in other forms airway lumen13. Mucus impaction ease and as a result almost twice the dura- Mucus impaction in AFAD is most striking- tion of asthma. Those with AFAD had over- ly evident in those patients who present with al about a 10% deficit in FEV1 which was not lobar col apse due to inspissated mucus but is related to atopy and not seen in patients sen-also seen in the smal er airways on CT scans7. sitised to non- thermotolerant or non-filamen-The precise pathway by which IgE sensitisa- tous fungi. Significant differences in radio- tion to thermotolerant filamentous fungi may logical appearances between those sensitised cause production of viscid mucus is not clear and non-sensitised to fungi included bronchi-but could be related to excess production of ectasis (50% versus 29%), tree-in-bud (17% MUC5AC by goblet cel s because of vigor- vs 4%) and col apse/ consolidation (35% vs 44 ous T2 hyperimmune stimulation7,14. Evolu- 21%). Authors suggested that IgE sensitisation tion of mucin synthesis is complex and include to thermotolerant filamentous fungi, in par-activated eosinophils as well since there is ev- ticular A. fumigatus but not total IgE, is asso-idence that they induce mucin synthesis in ciated with fixed airflow obstruction and sev-human airway epithelial cel s via EGFR (epi- eral radiological abnormalities in moderate to severe asthma. a dermal growth factor receptor)15. mh The group of Kurukulaaratchy18 re- st a Immaging, functional impairment ported that A. fumigatus sensitisation in pa-er tients with difficult asthma identifies a more e and comorbidities v severe form of disease associated with older se Aspergil us fumigatus sensitization defined by in a specific IgE of 0.35 kU/L or greater was as- age, male sex, longer duration of disease, lung sit function impairment, bronchiectasis, higher a sociated with functional and radiological ab- r t normalities: 83.4% had an abnormal HRCT inflammatory parameters, greater treatment e needs but less psychophysiologic comorbidi- bl with bronchial wal thickening (41.3%), bron- at ties. a chiectasis (35.3%), air trapping (20.3%) and er bronchial dilatation (16.5%). Radiological td evidence of airway disease was also associat- Fungal bronchitis n ag ed with more obstructive spirometry. A. fumi- Fungal bronchitis describes chronic purulent inr gatus sensitization was associated with a 2.01 sputum production due to non-invasive in-oit increased hazard ratio of bronchiectasis and fection with thermotolerant fungi in the con-no more obstructive spirometry. They suggested text of a relatively immunocompetent host. It - m that patients with A. fumigatus sensitization is not widely used in the medical literature. am had variable clinical and radiological A positive sputum culture for thermotoler-h st characteristics that frequently did not ant fungi is critical for the diagnosis of fun-aer conform to the conventional diagnostic gal bronchitis. In a recent report19 the group ev criteria for ABPA16. of Wardlaw and co-workers have recognised 2: se All patients with IgE sensitisation to A. a clinical presentations of often chronic exac-mu fumigatus are at risk of lung damage irre- erbations of airway disease which were un- r spective of whether they meet the criteria for fo responsive to standard treatment with broad am ABPA17. A large cohort (n = 431) of asthmat- spectrum antibiotics or high dose oral corti- h costeroids, in which sputum culture was pos- st ics enriched for IgE sensitisation to fungi were ae recruited in a cross-sectional study to deter- itive for either A. fumigatus or Candida spp. rev mine the relationship between immunological Usual y the sputum was white/creamy or se biomarkers of fungal al ergy and evidence of brown rather than the green associated with lung damage in asthma17. The patients with bacterial infection, and was very mucoid or AFAD had higher rates of early-onset dis-rubbery in consistency19. Management of AFAD ommendation from the group of Wardlav1 To a large extent management of AFAD is recommends that three months is necessary similar to the management of the underlying and usual y sufficient. Repeated courses are airway disease with personalised approach. sometimes necessary. An approach toward treatment of T2 treat- able trait (eosinophilic pattern of disease) in- Conclusions cludes inhaled corticosteroids. They are a cor- The term AFAD has a liberal definition, based nerstone of therapy. There exist a theoretical on the presence of IgE sensitisation to thermo-risk of augmentation od fungal colonisation, tolerant fungi and evidence of fungal-relat-but with the approach toward using the low- ed lung damage23. As such it is more inclusive est dose of inhaled corticosteroids to achieve than ABPA or SAFS, not being focused on to-a control of disease this might not be serious tal IgE and not restricted to severe asthmatics problem in clinical practice. In severe cases only. The recommendation supports close pa-low dose continuous or intermittent oral cor- ticosteroids (OCS) are necessary to achieve tient s fol ow up due to detecting and prevent-45 control. ing long term lung damage17. s Furthermore, unlike SAFS, AFAD dis- e Since OCS are seen as a last resort in m tinguishes between sensitisation to thermotol- o asthma therapeutic algorithms, anti-T2 bio- ct erant and non-thermotolerant fungi5. u logical therapy is a possible option in AFAD ol treatment. Evidence on omalizumab, but also aic mepolizumab, benralizumab and dupilumab Literature inl are based mostly on case series and reports. 1. Wardlaw AJ, Rick EM, Ozyigit LP, et ca Favourable reported responses include signif- al. New Perspectives in the Diagno- mh icant reduction in OCS burden, reduction sis and Management of Al ergic Fungal st a in acute exacerbations, improvement in lung Airway Disease, J Asthma Al ergy. 2021 ere function and improvement in patients out- May 25:14:557-73. v 2. Denning DW, O’Driscoll BR, Hogabo- se comes120–23. dn The place of antifungal therapy in AFAD am CM, et al. The link between fun- an remains uncertain. Whilst open studies have gi and severe asthma: a summa- iot often reported a benefit, placebo control ed, ry of the evidence. Eur Respir J. 2006 isa blinded studies have shown either no benefit Mar;27(3):615-26. sitn or a modest improvement at best compared 3. Denning DW, Pashley C, Hartl D, et al. ses to standard of care, which these days proba- Fungal al ergy in asthma-state of the art lu bly includes biological therapy. Clinical prac- and research needs. Clin Transl Al erg. ilgr tice would suggest that in the majority of pa- 2014 Apr 15:4:14. doi: 10.1186/2045- spe tients with AFAD the benefits of azole therapy 7022-4-14. a are not outweighed by side effects. However, 4. Knutsen AP, Bush RK, Demain JG, et where fungal bronchitis is present, particular-al. Fungi and al ergic lower respiratory ly in the context of difficult to treat exacerba- tract diseases. J Al ergy Clin Immunol. tions, they are an important adjunct to thera- 2012 Feb;129(2):280-3. py and can lead to a dramatic improvement 5. Pashley CH, Wardlaw AJ. Al ergic fun-in symptoms in relatively short time. Positive gal airways disease (AFAD): an under- sputum fungal culture seems to be a useful bi- recognized asthma endotype. Myco- omarker of a response to antifungal therapy pathologia. 2021 Oct;186(5):609-22. even in the case of Candida species if it is per-6. Agarwal R, Chakrabarti A, Shah A, sistent5. There are no definitive guidelines on e. Allergic bronchopulmonary asper- how long a course should be, but clinical rec- gil osis: review of literature and pro- posal of new diagnostic and classifica-chiectasis in severe asthma. Al ergy. tion criteria. Clin Exp Al ergy. 2013 2011 May;66(5):679-85. Aug;43(8):850-73. 17. Woolnough KF, Richardson M, New- 7. Asano K, MD, Hebisawa A, Takashi by C, et al. The relationship between Ishiguro T et al. New clinical diagnos- biomarkers of fungal al ergy and lung tic criteria for al ergic bronchopulmo- damage in asthma. Clin Exp Al ergy. nary aspergil osis/mycosis and its val- 2017 Jan;47(1):48-56. idation. J Al ergy Clin Immunol. 2021 18. Mistry H, Ajsivinac Soberanis HM, Apr;147:1261-68.e5. Kyyaly MA, et al. The Clinical Implica- 8. Denning DW, O’Driscoll BR, et al. The tions of Aspergil us Fumigatus Sensiti- 46 link between fungi and severe asthma: zation in Difficult-To-Treat Asthma Pa-A summary of the evidence. Eur Respir tients. J Al ergy Clin Immunol Pract. J. 2006 Mar;27(3):615-26. 2021 Dec;9(12):4254-67.e10. 9. Horner WE, Helbling A, Salvaggio JE, 19. Ozyigit LP, Monteiro W, Rick E-M, et et al. Fungal al ergens. Clin Microbiol al. Fungal bronchitis is a distinct clin- Rev. 1995 Apr;8(2):161-79. ical entity which is responsive to anti- am 10. Del Giacco SR, Bakirtas A, Bel E, et al. fungal therapy. Chron Respir Dis. 2021 h st Al ergy in Severe Asthma. Al ergy. 2017 Jan-Dec;18:1479973120964448. doi: ae Feb;72(2):207-20. 10.1177/1479973120964448. rev 11. Yike I. Fungal Proteases and Their 20. Eraso IC, Sangiovanni S, Morales se Pathophysiological Effects. Mycopatho- EI, et al. Use of monoclonal anti- ins logia. 2011 May;171(5):299-323. bodies for al ergic bronchopulmona- itar 12. Balenga NA, Klichinsky M, Xie Z, et ry aspergil osis in patients with asth- te al. A fungal protease al ergen provokes ma and cystic fibrosis: literature re- bla airway hyper-responsiveness in asthma. view. Ther Adv Respir Dis. 2020 tae Nat Commun. 2015 Apr 13:6:6763. doi: Jan-Dec;14:1753466620961648. doi: r t 10.1038/ncomms7763. 10.1177/1753466620961648. dn 21. Dhariwal J, Hearn AP, Kavanagh JE, a 13. Basu T, Seyedmousavi S, Sugui JA, et g al. Aspergillus fumigatus alkaline pro- et al. Real-World Effectiveness of Anti- inro tease 1 (Alp1/Asp f13) in the airways IL-5/5R Therapy in Severe Atopic Eo- itn correlates with asthma severity. J Al er- sinophilic Asthma with Fungal Sensiti- o gy Clin Immunol. 2018 Jan;141(1):423- zation. J Al ergy Clin Immunol Pract. - ma 5.e7. 2021 Jun;9(6):2315-20.e1. mh 14. Bonser LR, Erle DJ. Airway mu- 22. Eldaabossi SAM, Awad A, Anshasi N. st a cus and asthma: the role of MU- Mepolizumab and dupilumab as a re- ere C5AC and MUC5B. J Clin Med. placement to systemic glucocorticoids v 2017 Dec;6(12):112. doi: 10.3390/ for the treatment of Chronic Eosino- 2: se jcm612011269. philic Pneumonia and Al ergic Bron- mu 15. Burgel PR, Lazarus SC, Tam DC, et al. chopulmonary Aspergil osis - Case se- r fo Human eosinophils induce mucin pro- ries, Almoosa specialist hospital. Respir am duction in airway epithelial cel s via Med Case Rep. 2021 Oct 1;34:101520. h st epidermal growth factor receptor ac- doi: 10.1016/j.rmcr.2021.101520. ae tivation. J Immunol. 2001 Nov 15;167 23. Woolnough K, Fairs A, Pashley CH, rev (10):5948-54. et al. Al ergic fungal airway disease: se 16. Menzies D, Holmes L, McCumesky G, Pathophysiologic and diagnostic consid- et al. Aspergil us sensitization is associ- erations. Curr Opin Pulm Med. 2015 ated with airflow limitation and bron- Jan;21(1):39-47. OSA in Patients with Severe Asthma-Alternative Overlap Syndrome 2.2 Ivan Čekerevac1,2, Bojan Djokić2 1 Faculty of Medical Sciences Abstract Kragujevac Bronchial asthma and obstructive sleep apnea ( OSA) are common chronic diseases of the res-2 Clinic for pulmonology, piratory system. During the last decade, there has been a growing interest in the connection University Clinical Center between these two disorders. Studies show that asthma patients are at increased risk for OSA, Kragujevac and the prevalence is on average around 70% in severe asthma patients. Rhinitis, gastroesophageal reflux disease and obesity are common comorbidities for both entities. OSA is an independent factor in the exacerbation of asthma and each condition in itself can contribute to the exacerbation of the other. Asthma, by its mechanical effect, has a direct impact on OSA, leading to greater col apse of the upper airway and worsening snoring and apnea symptoms in patients with OSA. On the other hand, OSA directly affects asthma through nerve reflexes, intermittent hypoxia, increases inflammation, increases the production of leptin and vascular endothelial growth factor as well as sleep fragmentation. Indirect effects in a bidirectional interaction are reflected in the prolonged effects of systemic corticosteroids, chronic diseases of the upper respiratory tract, tobacco use and increased body weight in asthmatics, which leads to worsening of OSA symptoms. It remains unclear whether OSA in asthmatics is merely a comorbidity or a specific new phenotype of asthma. In patients with asthma and OSA, CPAP treatment reduces asthma symptoms, improves morning expiratory flow, and improves quality of life parameters. Keywords: severe asthma, OSA, alternative overlap syndrome Bronchial asthma and obstructive sleep ap- chial asthma3. Studies show that asthma suf-nea (OSA) are frequent chronic diseases of ferers have an increased risk of OSA, and the the respiratory system. During the last dec- prevalence is on average around 70% in severe ade, there has been a growing interest in the asthma sufferers4. Many patients with asth-connection between these two disorders. For ma report poor sleep quality, daytime sleepi-this reason, the term Alternative Overlap Syn- ness and higher frequency of snoring during drome (Asthma and OSA) was introduced in sleep than in the general population5. These 2013, to distinguish it from the classic Over- symptoms are common in patients with OSA, lap Syndrome (COPD and OSA). There is indicating a connection between the two dis-more and more evidence that OSA is associat- orders6. Similar pathophysiological mecha-ed with increased bronchial hypersensitivity1 nisms are observed in both disorders, which and inflammation2 and thus may be an inde- are manifested by an increase in local and sys-pendent risk factor for exacerbation of bron- temic inflammation, and common comorbidi-https://doi.org/10.26493/978-961-293-297-8.47-51 ties such are gastroesophageal reflux, obesity, Frequent comorbidities in asthma and rhinitis7–9. and OSA Rhinitis: the prevalence of both al ergic and Asthma and OSA- alternative overlap non-al ergic rhinitis in asthma sufferers is es- syndrome timated at 80 to 90%, and rhinitis is a risk fac- OSA is the most common breathing disor- tor for the development of asthma17,18. Rhi- der during sleep, typical y occurring in obese nitis causes chronic inflammation and nasal people5. Like asthma, OSA has its own phe-obstruction, which results in an increase in notypes depending on the craniofacial mor- negative oropharyngeal pressure during in- phology. Common risk factors for OSA in- spiration and predisposes to airway col apse, 48 clude male gender, age, obesity, increased increased apnea-hypopnea index (AHI) and neck circumference (greater than 17 inches in OSA symptoms19. Chronic inflammation in men and 16 in women), craniofacial abnor-the upper and lower respiratory tract can po- malities (micrognathia, retrognathia), and the tentiate the development of OSA20. presence of cardiovascular comorbidities4. Gastroesophageal reflux disease (GERD): a Certain studies point out that the presence of a common disorder found in about 58 to 65% mh OSA in patients with asthma can be a sepa- of patients with OSA and as many as 80% of st a rate phenotype of asthma10,11. The frequency patients with asthma7,21. Persistent symptoms ere of OSA in severe asthma and difficult-to-treat of GERD lead to inflammation of the upper v se asthma ranges from 50 to 95%4. Such a large respiratory tract, which can cause sleep frag-in mentation, snoring during sleep. Frequent mi- s difference in frequency can be explained by it croaspirations and direct injuries to the air- a the different methodology of the studies. In r t earlier studies, the methodology was based on ways cause worsening of asthma by increasing e bl self-reporting of snoring during sleep and pe- the tendency to bronchial obstruction4. at Obesity: Obesity is a risk factor for the a riods of apnea12,13. Recent studies have includ- er development of OSA, but it is also an inde- t ed polysomnography in their methodology. dn After a four-year fol ow-up period, patients pendent risk factor for asthma4. As a complex ag with asthma had a 40% higher risk of sleep entity, it affects breathing through various inr apnea compared to patients without asth- mechanisms and physiological processes. Ac- oit ma14. In one retrospective study, asthma pa- cumulation of fatty tissue in the upper parts no tients with frequent exacerbations, high doses of the respiratory tract leads to an increase in - m resistance and col apsibility, while in the re- a of inhaled corticosteroids and frequent use of m gion of the chest and abdomen it leads to re- h systemic corticosteroids had a more frequent st strictive disorders where functional residual a diagnosis of OSA (15). Studies using pol- er ysomnography reported a higher incidence of capacity is reduced and ventilation is weak-ev sleep apnea (88 to 95%) compared to studies ened22. OSA is more common in obese men, 2: se using a respiratory polygraphy (49% in severe while asthma is more common in obese wom-mu asthmatics)16. The significant difference in en, which suggests a potential influence of r fo frequency can be explained by the fol owing: hormones23. am the respiratory polygraphy can underestimate h st the severity of OSA in patients with asthma; Pathophysiological correlation between ae asthma can have an impact on the phenotyp- OSA and severe asthma – bidirectional rev ic expression of OSA by reducing the Aurosal interaction se index14. All this shows that more prospective OSA is an independent factor for the exac-research is necessary to evaluate the develop- erbation of asthma and each condition in it- ment of these two disorders. self can have an effect on the worsening of the other in alternative overlap syndrome. Indirect effects in a bidirectional in- Asthma, with its mechanical effect, has a di- teraction are reflected in prolonged effects rect impact on OSA, leading to a reduction in of systemic corticosteroids, chronic diseases lung volume by reducing the diameter of the of the upper respiratory tract, use of tobac-airway, as well as by affecting the structure co and increased body weight in asthmatics, and function of the smooth muscles of the which leads to worsening of OSA symptoms4. airway. All of this leads to greater col apse GERD and cardiovascular comorbidities in of the upper airway and worsens snoring and patients with OSA affect the poor course of apnea symptoms in patients with OSA4. OSA bronchial asthma. (Figure 1) also directly affects asthma through nerve reflexes, intermittent hypoxia, increases in- Clinical significance of alternative flammation, increases the production of lep- overlap syndrome tin and vascular endothelial growth factor as It remains unclear whether OSA in asthmat-well as sleep fragmentation4. Intermittent hy- ics is only a comorbidity or a specific new phe- 49 poxia leads to systemic oxidative stress and notype of asthma. On the one hand, al ergic the development of systemic inflammation, asthma is accompanied by a T2 inflammato-em where an increase in tumor necrosis factor al- ry response and excessive production of in- ord pha (TNF-ά), interleukin-6( IL-6) and C re- terleukin 5 and interleukin 13, which lead to n active protein was observed in patients with eosinophilia and hyperreactivity of airway sypalre OPSTRUCTIVE v oe SLEEP ivta APNEA nre lt-aamh st aerev sehit wstniet pa Figure 1. Obstructive sleep apnea and asthma: pathophysiologic links insao AHI greater than 1524. Also, intermittent hy- smooth muscles and mucus hypersecretion, poxia can lead to stimulation of receptors of which are complicated by obesity and OSA. the carotid body and initiate reflex bronchoc- In contrast, obese patients who developed onstriction and participate in the occurrence non-al ergic asthma with late onset develop of nocturnal symptoms associated with asth-mechanical changes that lead to lung func- ma25. Leptin, a hormonal protein produced tion disorders and favor the onset of obstruc-by adipose tissue, has a proinflammatory ef- tive apnea5. In these patients, the adipose tis- fect and stimulates the release of IL-6 and sue secretes several cytokines and adipokines TNF-ά from adipocytes25. that have direct effects on the airway epitheli- um and can be a trigger for bronchial hyper-lustrative cytokines. Int J Mol Sci. activity26,27. From the above, polysomnogra- 2019 Jan 22;20(3):459. doi: 10.3390/ phy is recommended for asthma patients with ijms20030459. inadequate control of night symptoms despite 3. ten Brinke A. Risk factors of frequent proper treatment28. exacerbations in difficult-to-treat Mortality in patients with OSA and asthma. Eur Respirat J. 2005 asthma is poorly researched. In one study, Nov;26(5):812-8. it was shown that patients with asthma and 4. Pepito DL, Mohammed JM, Hardin sleep disorders have a higher risk of mortal-KA. Obstructive Sleep Apnea and Asth- ity compared to asthma patients without ma: More Than Chance?. Curr Pulmo- 50 sleep disorders29. In patients with asthma and nol Rep. 2021 Mar 12;10(9):84-91. OSA, CPAP treatment reduces asthma symp- 5. Ragnoli B, Pochetti P, Raie A, et al. toms, improves morning expiratory flow, and Interrelationship Between Obstruc- improves quality of life parameters tive Sleep Apnea Syndrome and Se- 30. In one prospective study, it was shown that the pro- vere Asthma: From Endo-Phenotype to Clinical Aspects. Front Med (Lau- a portion of adult patients with uncontrol ed m sanne). 2021 Jun 30:8:640636. doi: h asthma dropped from 41.4 to 17.2% with st 10.3389/fmed.2021.640636. a CPAP treatment. It was also shown that the e 6. Auckley D, Moal em M, Shaman Z, re proportion of patients who had worsening v et al. Findings of a Berlin Question- se asthma decreased from 35.4 to 17.2% after naire survey: comparison between pa- ins six months of CPAP machine use7. tients seen in an asthma clinic versus itar internal medicine clinic. Sleep Med. t Conclusion e 2008;9(5):494-9. bl The association between OSA and severe a 7. Serrano-Pariente J, Plaza V, Soriano ta asthma is based on coincident pathophysi- e JB, et al. CPASMA Trial Group. Asth- r t ological mechanisms, bidirectional interac- ma outcomes improve with continuous dn tions and the presence of similar comorbidi- a positive airway pressure for obstructive g ties. Similar to asthma, OSA also promotes an sleep apnea. Al ergy. 2017;72(5):802-12. inr inflammatory response through hypoxia and o 8. Lafond C, Sériès F, Lemière C. Impact it hypercapnia and sleep fragmentation leading n of CPAP on asthmatic patients with ob- o to an irreversible increase in C reactive pro- structive sleep apnoea. Eur. Respir. J. - ma tein, tumor necrosis factor and other proin- 2007;29(2):307-11. mh flammatory cytokines involved in airway col- 9. Franklin KA, Lindberg E. Obstructive st a lapse and hyperreactivity. Proinflammatory sleep apnea is a common disorder in the er factors tend to decrease when these patients e population-a review on the epidemiol- v are treated with a CPAP device, which leads ogy of sleep apnea. J Thorac Dis. 2015 2: se to improvement in asthma symptoms and a Aug;7(8):1311-22. mu better quality of life. 10. American Academy of Sleep Medicine. r fo International classification of sleep dis- am References orders. 3rd ed. Darien, IL: American h st 1. Lin C-C, Lin C-Y. Obstructive sleep ap- Academy of Sleep Medicine, 2014. 383 ae nea syndrome and bronchial hyperreac- p. rev tivity. Lung. 1995;173(2):117-26. 11. Damianaki A, Vagiakis E, Sigala I, et se 2. Kheirandish-Gozal L, Gozal D. Ob- al. The co-existence of obstructive sleep structive sleep apnea and inflamma- apnea and bronchial asthma: revela- tion: proof of concept based on two il- tion of a new asthma phenotype? J Clin Med. 2019;8(9):1476. doi: 10.3390/ munol Al ergy Clin North Am. 2005 jcm8091476. Feb;25(1):131-48. 12. Larsson LG, Lindberg A, Franklin KA, 22. Isono S. Obesity and obstructive sleep et al. Symptoms related to obstructive apnea: mechanisms for increased col- sleep apnoea are common in subjects lapsibility of the passive pharyngeal air- with asthma, chronic bronchitis and way. Respirology. 2012 Jan;17(1):32-42. rhinitis in a general population. Respir 23. Chen Y, Dales R, Tang M, Krewski D. Med. 2001 May;95(5):423-9. Obesity may increase the incidence of 13. Bhattacharyya N, Kepnes LJ. Ambula- asthma in women but not in men: longi- tory office visits and medical comorbidi- tudinal observations from the Canadi- ties associated with obstructive sleep ap- an National Population Health Surveys. Am J Epidemiol. 2002 Feb 1;155(3):191- nea. Otolaryngol Head Neck Surg. 2012 7. Dec;147(6):1154-7. 24. Cekerevac I, Jakovljevic V, Zivkovic V, 14. Teodorescu M, Barnet JH, Hagen EW, et al. Impact of severity of obstructive et al. Association between asthma and 51 sleep apnea (OSA) and body compo- risk of developing obstructive sleep ap- e sition on redox status in OSA patients. m nea. JAMA. 2015 Jan 13;313(2):156-64. o Vojn. Pregl. 2018;75(11):1089-93. r 15. Shen TC, Lin CL, Wei CC, et al. Risk dn 25. Alkhalil M, Schulman E, Getsy J. Ob- of obstructive sleep apnea in adult pa- sy structive sleep apnea syndrome and p tients with asthma: a population-based al asthma: what are the links? J Clin Sleep r cohort study in Taiwan. PLoS One. ev Med. 2009 Feb 15;5(1):71-8. 2015 Jun 11;10(6):e0128461. doi: oe 26. Sideleva O, Suratt BT, Black KE, et al. iv 10.1371/journal.pone.0128461. t Obesity and asthma: an inflammato- a 16. Prasad B, Nyenhuis SM, Imayama I, et nr ry disease of adipose tissue not the air- e al. Asthma and Obstructive Sleep Ap- way. Am J Respirat Crit Care Med. lt nea Overlap: What Has the Evidence -aa 2012;186(7):598-605. m Taught Us? Am J Respir Crit Care Med. h 27. Malerba M, Radaeli A, Olivini A, et al. st 2020 Jun 1;201(11):1345-57. Association of FEF25-75% impairment ae 17. Togias A. Rhinitis and asthma: evi- r with bronchial hyperresponsiveness and ev dence for respiratory system integra- airway inflammation in subjects with se tion. J Al ergy Clin Immunol. 2003 h asthma-like symptoms. Respiration. it Jun;111(6):1171-83;quiz 1184. 2016;91(3):206-14 ws 18. Leynaert B, Neukirch F, Demoly P, et t 28. Razak MRA, Chirakalwasan N. Ob- n al. Epidemiologic evidence for asth- ie structive sleep apnea and asthma. t ma and rhinitis comorbidity. J Al ergy Asian Pacific J Al ergy Immunol. 2016 pa Clin Immunol. 2000 Nov;106(5 Sup- in Dec;34(4):265-71. sa pl):S201-5. o 29. Han KT, Bae HC, Lee SG, et al. Are 19. Olsen KD, Kern EB. Nasal influences sleep disorders associated with increased on snoring and obstructive sleep apnea. mortality in asthma patients? BMC Mayo Clin Proc. 1990 Aug;65(8):1095- Pulm. Med. 2016 Nov 17;16(1):154. doi: 105. 10.1186/s12890-016-0313-2. 20. Braunstahl GJ. Chronic rhinosinusitis, 30. Alkhalil M, Schulman ES, Getsy J. Ob- nasal polyposis and asthma: the united structive sleep apnea syndrome and airways concept reconsidered? Clin Exp asthma: the role of continuous posi- Al ergy. 2011 Jun 14;41:1341-3. tive airway pressure treatment. Ann 21. Harding SM. Gastroesophageal re- Al ergy Asthma Immunol. 2008 flux: a potential asthma trigger. Im- Oct;101(4):350-7. 3 Asthma Monitoring and Evaluation Induced Sputum Role in Severe Asthma Phenotyping 3.1 Sanja Popović-Grle1,2, Gordana Pavliša1,2, Marina Lampalo1,3, Anamarija Štajduhar1, Branko Pevec1, Mira Pevec1, Dina Rnjak1, Valentina Fiket1, Ivana Rubil1, Silvana Smojver-Ježek1,4 1 University Hospital Centre Abstract Zagreb, Clinical Department Induced sputum is a method which, by inhaling hypertonic saline, provoke a person to expec-for Lung Diseases Jordanovac, Zagreb, Croatia torate certain amount of bronchial secretion. Sputum sample obtained consists of liquid and celul ar phase. It is used over the years to investigate airway inflammation in patients with 2 School of Medicine, University of Zagreb, Zagreb, asthma and chronic obstructive pulmonary disease (COPD). Results of cell counts in induced Croatia sputum is essential in differentiation of airway eosinophilia or neutrophilia or both, or a deter-3 Faculty of Health Studies, mination of paucigranulocytic phenotype. Obtained severe asthma phenotype due to airway University of Rijeka, Rijeka, Croatia inflammation help us to select biological therapy and predict responders. The correlation between “noninvasive” measures such as blood eosinophilia, or fraction of ex-4 University Hospital Centre Zagreb, Clinical Department haled nitric oxide (FeNO) with sputum eosinophils is suboptimal. Induced sputum is a good of Pathology and Citology, Zagreb, and reproducible discriminator for eosinophilic asthma. There are some safety concerns as in-Croatia duced sputum procedure can provoke adverse effects such as bronchoconstriction and dyspnea, which is reversible to standardized therapy. Sputum induction is safe and well tolerated by patients with severe asthma, which supports its use in clinical and research practice. Keywords: severe asthma, sputum induction, asthma phenotypes, safety Introduction valid results2 sputum induction quickly gained Asthma is a chronic inflammatory disease of an important place in clinical practice. The the airways that causes variable airflow ob- correlation between “noninvasive” measures struction and bronchial hyperresponsiveness. such as blood eosinophilia, or fraction of ex-Many cel s and cel ular elements play a role in haled nitric oxide (FeNO) with sputum eosin-the pathogenesis of asthma. Cel ular quantifi- ophils is suboptimal, making them poor surro-cation in sputum samples is one of the nonin- gate measures of airway eosinophilia3. Based vasive methods of assessing asthmatic airway on sputum eosinophil and neutrophil propor-inflammation. Sputum induction with hyper- tions in induced sputum we could categorized tonic saline is used frequently for investigation four inflammatory subtypes of an airway inflammation in asthma: neutrophilic asthma, of airway inflammation in patients with asth- eosinophilic asthma, mixed granulocytic ast-ma or chronic obstructive pulmonary disease hma and paucigranulocytic asthma4. Asthma (COPD). The method was introduced in asth- phenotypes based on different types of airway ma by Pin et al. in 1992 and has been evolv- inflammation al ow us to individual y tailor ing ever since1. As it is relatively non-inva- treatment. It has been well known for decades sive technique which provides repeatable and that sputum eosinophilia can predict response https://doi.org/10.26493/978-961-293-297-8.55- 61 to corticosteroid treatment, but the phenoty-subject with severe asthma who is going to do ping of the inflammatory response in asthma the induced sputum should be premedicated has gained even greater clinical significance with 200 µg salbutamol. Sputum induction with the introduction of biological therapy. A is performed by inhalation of increasing con-great advantage of the technique is that it ena- centrations of aerosolized saline (0.9%, 3%, bles sampling of the airways in a less-invasive 4% and 5%) through a mouthpiece without a manner, in contrast with other methods such nose clip. In our clinic we use an Omrone NE as bronchial biopsy, bronchial brushing and U07 ultrasonic nebulizer (Omron Healthcare bronchoalveolar lavage, all of which require Europe) with an output of 1.0 mL/min and bronchoscopy. This is particularly important particle size of 3.5 µm mass median diame-56 in the examination of patients with severe ai- ter to generate an aerosol. Each concentration rways disease where endoscopy poses signifi-should be inhaled over 7 minutes. After each cant risk to oxygen desaturation5. These tech- inhalation, the patient should be asked to ex- niques al ow sputum to be obtained from 80 pectorate into a container for an analysis and to 90% of patients, which is significantly more FEV or PEF is needed to be measured again. than patients can expectorate spontaneously. 1 a The procedure should be interrupted if dys- mh It has been shown that cel s in induced spu- pnea or wheezing occurred and immediately st a tum reflect wel the findings in bronchial wash appropriate treatment should be provided. er and lavage samples and are more viable than e If there is a fall in FEV or PEF on measure- v in spontaneous sputum6. Fahy et al. studied 1 se ment between different concentrations inha- in markers of inflammation and cel s in sam- s lation of 10-20% versus baseline, the same it ples obtained by sputum induction, bronc- a concentration of saline should be used in the r t hial washing and lavage samples from heal- next inhalation interval. If the fall is greater e thy and asthmatic subjects. Concentrations of bla than 20%, the procedure should be terminat- t cel s and inflammatory markers were higher ae ed.30 Patients should be instructed to interrupt r in induced sputum samples than in bronchial t the inhalation if they need to expectorate (in d washings or lavage materials. Induced spu- n a tum samples contained higher percentages of this case the clock was stopped and inhalation g continued after expectoration) or experience in neutrophils and eosinophils, and higher con- ro centrations of eosinophil cationic protein, al- dyspnea or wheezing. The volume of the in- itn duced sputum should be recorded. Sputum o bumin and mucin-like glycoprotein, probably sample should be immediately trasferred into - m because they were less diluted7. Induced spu- am tum was first developed as a research tool, and cytological laboratory. h st in the meanwhile, it became a valuable clini- ae Processing of induced sputum r cal tool8. ev for cytological analysis and differential cell counting 2: se Sputum induction procedure m It is recommended to process induced spu- u Induced sputum is quite a technical y de- r tum a soon as possible or within 2 hours to fo manding procedure. Each sputum induction a ensure optimal cell preservation. Two differ- m should proceed by spirometry, and patients h with FEV <40% of predicted, or less than 1 ent approaches can be fol owed for process-st a 1 e L, have to be excluded from induction pro- ing, entire sputum analysis or more often se- re lected sputum plugs method. Selected sputum v cedure.35 The highest FEV value as well as 1 se PEF value obtained were considered as base- plugs or „fishing“ method means selection of line and were used to calculate a relative fal dense viscid portions of samples for analysis in FEV and PEF during the procedure. Each with minimising of saliva contamination9,10. 1 It is necessary to weight sputum plugs be- – mixed granulocytic asthma: >61% fore the homogenisation. Homogenisation is sputum neutrophils and >3% eosino- performed by the use of fresh solution of 0,1% phils dithiothreitol (DTT) that breaks disulphide – paucigranulocitic asthma: <61% spu-bonds in mucin molecules and preserves cel s tum neutrophils and <3% eosinophils morphology. The added DTT volume is 2-4 times of recorded weight of the plugs, tubes Asthma inflammatory phenotypes with mixture are placed in the shaking water Asthma inflammatory subtypes are charac-bath on 37°C for 15 minutes to ensure com- terized by some important clinical differenc- plete homogenisation. It is necessary to stop es. Eosinophilic asthma is the most common the effect of DTT and preserve cel s morpho-phenotype. It is very prevalent in individuals logy by adding buffer solution (PBS) in a vo- with nonsevere disease, and also accounts for lume equal to the sputum volume plus DTT approximately 50% to 60% of the total severe volume.36 asthma population11. It has classical y been 57 Filtration of the fluid mixture through associated with al ergic sensitization and a g 48-52 μm nylon gauze can remove remaining T2-dominant inflammatory response. Eosin-pin debris and mucus. Next step is recording of ophilic group is characterised by the highest yto the filtrate volume, accessing cel viability and degree of airway hyperresponsiveness. Wood-ne measuring total cell count/mil ilitre using ha- ruff et al demonstrated that the percentage pha emocytometer. of eosinophils in induced sputum was inde- mh Dissolved induced sputum should be pro- pendently associated with more severe airflow st a obstruction and methacholine reactivity12. e cessed as any other liquid cytology sample in re cytocentrifuge and centrifuge. Cytospin slides Eosinophilic phenotype of asthma mainly re-v sponds well to corticosteroid treatment. Strat- se are usual y May Grunwald-Giemsa (MGG) in egies that are based on sputum examination e stained and used for cell counting. Remaining lo supernatant can be stored on -80°C for addi- to guide treatment decisions have been effec- rm tive in improving lung function and decreas- u tional analyses4. Cytological examination of t the slides should be performed under light mi- ing asthma symptoms and exacerbations. spud croscope high power magnifications (400x, Normalization of induced sputum eosino-ec phil counts has been shown to be an effective u 1000x). Adequate are samples with less than d strategy for preventing severe asthma exacer- in 20% of squamous cel s counting on 300-500 of all cel s. Differential cell count (%) sho- bations and hospitalizations. Sputum exami- uld be calculated on 300-500 non-squamous nation can detect an increase in airway eosin-cel s: eosinophils, neutrophils, macrophages, ophils up to 3 months before the development lymphocytes, columnar epithelial cel s and of a clinical exacerbation13. This approach re-mastocytes, if any. Both counts (%) should be quires frequent sputum analyses and is im-recorded in final report9,10. On the basis of cel practical for routine clinical use in most cen-differential counts in induced sputum diffe- tres. However, the ability to analyze sputum rent inflammatory phenotypes of acute asth- is necessary in centers dealing with more se- vere forms of asthma. The effectiveness of a ma can be divided in four types4: treatment strategy based on assessment of air- – eosinophilic asthma (EA): >3% spu- way inflammation was not as clear in patients tum eosinophils with mild asthma, suggests that sputum anal- – neutrophilic asthma (NA): >61% spu- ysis is not necessary in those with milder asth- tum neutrophils and <3% eosinophils ma that responds well to initial therapy14. Eosinophilic inflammation in the airway nophilic, due to results of severe asthma pa-mucosa that persists despite the use of high tient cohorts.38 doses of inhaled corticosteroids or system- Neutrophilic inflammation is also a com- ic corticosteroids is recognized as a separate mon finding among adults who have persis-phenotype, severe asthma. It has been shown tent asthma symptoms despite inhaled corti-that eosinophilic inflammation despite vigor- costeroid treatment and particularly during ous antiasthma treatment is associated with asthma exacerbations20. Douwes et al. also remodel ing of the airways, impaired lung found that only around 50% of asthma cas-function, and near-fatal asthma attacks15. In es was associated with eosinophilic inflam-addition to the classic al ergen-mediated Th2 mation, and that in most other cases asthma 58 paradigm, innate immune stimuli such as en- was accompanied by an increase in airway vironmental factors, air pol ution, weath-neutrophils and interleukin 8 (IL-8)21. In- er changes, and viral infections may be ca- creased neutrophils have been reported in pable of eliciting Th2 responses associated subjects with severe asthma requiring intuba-with eosinophilia16. Recruitment of eosino- tion and sudden onset fatal asthma, indicat- a ing a role for neutrophils in the most severe m phils into the airway in al ergic asthma is me- h diated by the coordinated action of cytokines forms of asthma22,23. The results of the study st a by Jatakanon et al. indicate that an increase in e and chemokines including IL-5, IL-13, eo- re the number of neutrophils is associated with v taxins, and the adhesion molecules P-selectin se and vascular cell adhesion molecule-1. IL-5 is a greater degree of severity of symptoms24. Li in et al. reported that a significant proportion of s a critical cytokine for eosinophil generation ita in the bone marrow, as well as eosinophil re- asthma and wheezing il ness in both adults r t and children is associated with neutrophilic e cruitment, activation, and survival17. The ef- bl airway inflammation and that this pattern is a fects of IL-13 include induction of goblet cel ta not limited to individuals with severe symp- e metaplasia and increased mucus secretion, in- r t creased airway hyperreactivity, and, indirect- toms25. Neutrophils in severe asthma were dn significantly increased compared with those a ly, trafficking of eosinophils to the site of tis- g with mild asthma and healthy controls but in sue injury via chemotaxis18. Based on that, r not when compared with those with moderate o sputum eosinophil count provides an effective it asthma26. This raises important and interest- no method to identify patients who will benefit ing questions regarding the mechanisms and - m from biological therapy. Drugs targeting spe- a consequences of neutrophilic inflammation, m cific Th2 cytokines, including monoclonal an- h as well as presenting a novel and inviting ther- st tibodies against IL-5 and IL-13, have shown a a apeutic target. Neutrophilic inflammation is e promising effect in the treatment of refractory r most frequently induced by infection or pol- ev eosinophilic asthma19. Steroid usage in severe lutant exposure 27 2: se asthma could mask the underlying eosino- The possibility of bacterial infections as mu philic inflammation. There are investigations a cause of the neutrophilia was evaluated by r fo showing that single sputum measures undere- examining for intracel ular bacteria, which am stimate the likelihood of asthma classificati- is a validated technique that correlates with h st on as eosinophilic phenotype.37 On some oc- quantitative microbiology in the detection of ae casions, like decreasing corticosteroid therapy respiratory tract infections. Interestingly, in-rev or after antibiotic treatment, it is neccessary tracel ular bacteria levels were higher in asth-se to repeat the induced sputum after few weeks, ma compared with healthy controls, which to see if the eosinophils demasking will appe-may indicate increased exposure of the low- ar.Asthma in most patients in reality is eosi- er airways to bacteria in asthma. This may be a consequence of airway impairment and Conclusion impaired local defence caused by airway mu-Induced sputum is a valuable tool for deter- cosal damage in asthma28. mining the asthma inflammatory pheno- types. Monitoring of airway inflammation Induced sputum analysis in research provide additional data which enables indi- and clinical practice vidual adjustment of treatment to each pa- Sputum induction analysis is non-invasive, tient. With the introduction of biological but quite a technical y demanding procedure. therapy, precise immunological phenotyping Besides, it has safety concerns, as inhaled hy-becomes even more significant. For this rea- pertonic saline can cause adverse effects such son, we would recommend that every severe as coughing, vomiting, bronchoconstriction asthma center should be familiar with this and lung hyperinflation29. The mechanism of method and its use in clinical practice. the effect is unknown but may involve the ac- tivation of airway mast cel s or sensory nerve References 59 endings. This makes the examination uncom- 1. Pin I, Gibson PG, Kolendowicz R, et al. fortable for some patient, and monitoring of Use of induced sputum cell counts to in- g lung function during the procedure is nec- pin vestigate airway inflammation in asth- yt essary. The safety of the method was thor- ma. Thorax. 1992 Jan;47(1):25-9. one oughly assessed in patients with airway ob- 2. Pizzichini E, Pizzichini MM, Efthi- ph struction characteristic for asthma29,30 and miadis A, et al. Indices of airway in- amh COPD31,32. Pretreatment with beta-agonists is flammation in induced sputum: repro- st a routine part of the procedure and is intend- ducibility and validity of cell and flu- aer ed to prevent bronchospasm. In our practice id-phase measurements. Am J Respir ev some subjects reported adverse events, most- Crit Care Med. 1996 Aug;154(2 Pt se ly dyspnea fol owed by drop in lung function, 1):308-17. inel but after bronchodilator and corticosteroid 3. Fleming L, Tsartsali L, Wilson N, et al o r therapy all recovered. During the sputum in- Longitudinal relationship between spu- mut duction procedure, the patient must be care- tum eosinophils and exhaled nitric oxi- ful y monitored by the medical staff, patients de in children with asthma. Am J Respir spude should be encouraged to expectorate quality Crit Care Med. 2013 Aug 1;188(3):400- cud and sufficient sample for cytological analysis, 2. in for which the procedure is rather demanding 4. Wang F, He XY, Baines KJ, et al. Dif-and complicated. That makes this procedure ferent inflammatory phenotypes in time-consuming. For these reasons, it is per- adults and children with acute asthma. formed only in specialized respiratory clinics Eur Respir J. 2011 Sep;38(3):567-74. and as a part of research projects. 5. Paggiaro PL, Chanez P, Holz O, et al. Induced sputum analysis has brought Sputum induction. Eur Respir J Suppl. new insights into innate and adaptive immu- 2002 Sep:37:3s-8s. nity processes in airways, but did not answer 6. Szefler SJ, Wenzel S, Brown R, et al. al questions33. It also al owed investigations Asthma outcomes: biomarkers. J Al er- in transcriptomics, proteomics, and genom- gy Clin Immunol. 2012 Mar;129(3 Sup- ics, which are in progress, hoping to eluci- pl):S9-23. date more about the complexity of inflamma- 7. Fahy JV, Wong H, Liu J, et al. Com- tion34. parison of samples col ected by spu- tum induction and bronchoscopy from asthmatic and from healthy sub- jects. Am J Respir Crit Care Med. 17. Wardlaw AJ, Brightling C, Green R, 1995;Jul;152(1):53-8. et al. Eosinophils in asthma and oth- 8. Djukanović R, Sterk PJ, Fahy JV, et al. er al ergic diseases. Br Med Bul . Standardised methodology of sputum 2000;56(4):985-1003. induction and processing. Eur Resp J 18. Wynn TA. IL-13 effector functions. Suppl. 2002 Sep:37:1s-2s. Annu Rev Immunol. 2003;21:425-56. 9. Weiszhar Z, Horvath I. Induced spu- 19. Dragonieri S, Elisiana Carpagnano G. tum analysis: step by step. Breathe. Biological therapy for severe asthma. 2013;9(4):300-6. Asthma Res Pract. 2021 Aug 13;7(1):12. 10. Efthimiadis A, Spanavel o A, Hamid doi: 10.1186/s40733-021-00078-w. 60 Q, et al. Report of Working Group 3. 20. Simpson JL, Scott R, Boyle MJ, Gib-Methods of sputum processing for cell son PG. Inflammatory subtypes in asth- counts, immunocytochmistry and in ma: assessment and identification us- situ hybridisation. Eur Respir J. Supp. ing induced sputum. Respirology. 2006 2002 Sep:37:19s-23s. Jan;11(1):54-61. 21. Douwes J, Gibson P, Pekkanen J, Pearce a 11. Wenzel SE. Asthma: defining of the per- m N. Noneosinophilic asthma: importance h sistent adult phenotypes. Lancet. 2006 st and possible mechanisms. Thorax. 2002 a Aug 26;368(9537):804-13. e Jul;57(7):643-8. re 12. Woodruff PG, Khashayar R, Lazarus v 22. Ordonez CL, Shaughnessy TE, Mat- se SC, et al. Relationship between airway thay MA, Fahy JV. Increased neutro- in inflammation, hyperresponsiveness, and s phil numbers and IL-8 levels in airway it obstruction in asthma. J Al ergy Clin ar secretions in acute severe asthma. Am J t Immunol. 2001 Nov;108(5):753-8. e Respir Crit Care Med. 2000 Apr;161(4 bl 13. Deykin A, Lazarus SC, Fahy JV, et al. a Pt 1):1185-90. t Sputum eosinophil counts predict asth- ae 23. Sur S, Crotty TB, Kephart GM, et al. r ma control after discontinuation of in- t Sudden-onset fatal asthma. Am Rev d haled corticosteroids. J Al ergy Clin Im- n a Respir Dis. 1993 Sep;148(3):713-9. g munol. 2005 Apr;115(4):720-7. 24. Jatakanon A, Uasuf C, Maziak W, Lim inr 14. Jayaram L, Pizzichini MM, Cook RJ, o SM, Chung KF, Barnes PJ. Neutro- it et al. Determining asthma treatment by n philic inflammation in severe persistent o monitoring sputum cell counts: effect asthma. Am J Respir Crit Care Med. - m on exacerbations. Eur Respir J. 2006 a 1999;Nov;160(5 Pt 1):1532-9. mh Mar;27(3):483-94. 25. Li AM, Tsang TWT, Chan DFY, et al, st a 15. Fabbri LM, Romagnoli M, Corbetta Cough frequency in children with mild er L, et al. Differences in airway inflam- e asthma correlates with sputum neutro- v mation in patients with fixed airflow phil count. Thorax. 2006 Sep;61(9):747- 2: se obstruction due to asthma or chron- 50. mu ic obstructive pulmonary disease, Am. 26. Pavord ID, Birring SS, Berry M, et al. r fo J. Respir. Crit. Care Med. 2003 Feb Multiple inflammatory hits and the am 1;167(3):418-24. pathogenesis of severe airway disease. h st 16. Garty BZ, Kosman E, Ganor E, et Eur Respir J. 2006 May;27(5):884-8. ae al. Emergency room visits of asth- 27. Chastre J, Fagon JY, Soler P, et al. Di- rev matic children, relation to air pol u- agnosis of nosocomial bacterial pneu- se tion, weather, and airborne al ergens. monia in intubated patients undergoing Ann Al ergy Asthma Immunol. 1998 ventilation: comparison of the useful- Dec;81(6):563-70. ness of bronchoalveolar lavage and the protected brush specimen. Am J Med. 37. Azim A, Newell C, Barber C, et al. Cli- 1988 Oct;85(4):499-506. nical evaluation of type 2 disease status 28. Taube C, Holz O, Mücke M, et al. Air- in a real-world population of difficult way response to inhaled hypertonic sa- to manage asthma using historic ele- line in patients with moderate to severe ctronic healthcare records of blood eo- chronic obstructive pulmonary disease. sinophil counts. Clin Exp Al ergy. 2021 Am J Respir Crit Care Med. 2001 Nov Jun;51(6):811-820. 15;164(10 Pt 1):1810-5. 38. Barber C, Azim A, Newell C, et al. Va- 29. Wong HH, Fahy JV. Safety of one lidation and further insight into the In- ternational Severe Asthma Registry method of sputum induction in asth- (ISAR) eosinophil gradient algorithm matic subjects. Am J Respir Crit Care in the Wessex AsThma CoHort of dif- Med. 1997 Jul;156(1):299-303. ficult asthma (WATCH) using histori- 30. de la Fuente PT, Romagnoli M, et al. cal blood eosinophil counts and indu- Safety of inducing sputum in patients ced sputum. Clin Exp Al ergy. 2022 61 with asthma of varying severity. Am J Jun;52(6):792-6. Respir Crit Care Med. 1998 Apr;157(4 g Pt 1):1127-30. pinyt 31. Kel y MG, Brown V, Martin SL, et al. one Comparison of sputum induction us- ph ing high-output and low-output ul- am trasonic nebulizers in normal subjects h st and patients with COPD. Chest. 2002 aer Sep;122(3):955-9. ev 32. Khan SY, O’Driscoll BR. Is nebu- se lized saline a placebo in COPD? BMC inel Pulm Med. 2004 Sep 30:4:9. doi: o r 10.1186/1471-2466-4-9. mut 33. Tiotiu A, Badi Y, Kermani NZ, et al. Association of Differential Mast spude Cell Activation with Granulocytic In- cud flammation in Severe Asthma. Am in J Respir Crit Care Med. 2022 Feb 15;205(4):397-411. 34. Fricker M, Qin L, Sánchez-Ovando S, et al. An altered sputum macropha- ge transcriptome contributes to the ne- utrophilic asthma endotype. Al ergy. 2022 Apr;77(4):1204-15. 35. Vlachos-Mazer H, Leigh R, Sharon RF, et al. Success and safety of sputum in- duction in the clinical setting. Eur Res- pir J. 2000 Nov;16(5):997-1000. 36. Pavord ID, Pizzichini MM, Pizzichini E, et al. The use of induced sputum to investigate airway inflammation. Tho- rax. 1997 Jun;52(6):498-501. Monitoring and Evaluation of Therapeutic Response in Patients 3.2 with Severe Asthma on Biologics Sanda Škrinjarić Cincar1,2 1 School of Medicine Osijek Abstract University J.J. Strossmayer Five biologics with different mechanisms of action have been available for uncontrol ed severe 2 Health Center Osijek T2 high asthma in clinical practice worldwide for years, and the first drug in a class of new biologics targeting the top of the inflammatory cascades, thymic stromal lymphopoietin (TSLP) is available from the beginning 2022. The results of randomized and real-life studies as well as experience in daily clinical practice confirm that the safety profile of biological drugs is very good. Biologics have a good potential to achieve remission during treatment, but not all patients respond equal y wel . The effectiveness of all biologics in severe asthma is approximately 60% in the real life conditions. An important task of the clinician is the correct assessment of the therapeutic response to biologics and the evaluation of patients who have a satisfactory response to treatment and those who do not. Therapeutic response to biologics should be assessed individual y according to pre-defined goals every 3 to 6 months. In patients with a good response to biological drugs, continuation of treatment and continuous monitoring of efficacy and safety is recommended. If there is no satisfactory response to the initial y introduced biologic, switching to another biologic is a rational option. During therapy with biologics, it is necessary to closely monitor the effect on exacerbations and symptoms. Research has shown that improving the overall quality of life is the most important outcome for most patients with severe asthma. Also, one of the most important effects of biological therapy is the possibility of excluding or reducing the dose of corticosteroids in patients who need them for disease control. The effect of biologics on improving lung function is important, but not critical for evaluating the effectiveness of treatment. However, previous reports have not yet provided precise instructions for long-term treatment with biologics in daily clinical practice, and there are questions still need to be answered. Keywords: severe asthma, biologics, therapeutic response, evaluation Introduction: a new treatment options tibodies has made it possible to attack cer- for uncontrolled severe asthma tain pathogenic pathways or mechanisms and Severe asthma is a disabling disease that ac- modifies them in order to control disease. In counts for not more than 5% of all asthmat- recent years the treatment of severe asthma ics1. Although patients with severe asthma with biological drugs in selected patients with represent a minority of the total asthma pop-T2-high inflammation has become very suc- ulation, they carry a majority of the morbid- cessful. The development of biological drugs ity and healthcare costs. Accurate treatment for T2-low asthma was not so successful3. with biologics in the form of monoclonal an- https://doi.org/10.26493/978-961-293-297-8.63-75 Patients with “problematic” asthma can be tested in randomized control ed tri-should be careful y examined and distin- als (RCTs) under control ed study conditions. guished from those whose asthma is uncon- Effectiveness can be tested in real-life trials trol ed due to poor adherence and/or poor in- under real living conditions. Efficacy results halation technique as well as difficult to treat show what we can expect in a population that for other reasons such as uncontrol ed asthma has the characteristics of the examined sam-triggers and comorbidities. Comorbidities in ple, and effectiveness results show what we patients with asthma need to be treated ap-have real y observed8. Both types of research propriately. Some comorbidities, such as nasal have shown that biologics are very successful polyps, al ergic rhinitis, or atopic dermatitis, in treating patients with severe asthma1. Bi-64 are favorably affected by biologics, while oth- ologics have good potential for achieving reers, such as gastroesophageal reflux disease, mission during treatment, but not all patients obesity, and bronchiectasis, do not diminish are good responders and usual y not all cri-the therapeutic response to biologics. Before teria for complete remission or good asth-assessing the severity of asthma itself, it is nec- ma control are met9. An important task for essary to address all factors that have a poten- am clinicians is to properly assess the therapeu- h tial effect on health status, and also to have tic response to biologics and to identify which st a them under control during treatment with bi- e patients have a satisfactory response to treat- r ologics1,4. e ment and which do not. v It is well known that asthma is a heter- se in ogeneous disease. Clinical diversity and in- s Licensed biologics for uncontrolled it flammatory phenotype are reflected as a con- a severe asthma r t sequence of the pathogenetic mechanism and e histopathological characteristics of asthma. A years ago, five biological drugs with differ-bla ent mechanisms of action are available in clin- t Clinical features such as frequent exacerba- ae ical settings worldwide for uncontrol ed severe r tions, emergency room visits, hospital admis- t asthma with high T2. These are: omalizumab d sions, lost days from work, school, or leisure n (Xolair, Genentech/Novartis), mepolizum- a time, poor asthma symptom control, poor g ab (Nucala, GlaxoSmithKline), reslizumab in lung function and poor quality of life, as wel r (Cinqair, Teva), benralizumab (Fasenra, As- o as oral corticosteroid use are characteristics of it traZeneca) and dupilumab (Dupixent, Sa- no severe asthma5. The clinical features and in- nofi/Regeneron). Tezepelumab (Tezspire, - m flammatory phenotype of severe asthma are a Amgen/Astra Zeneca) is available in clinical m currently fundamental determinants for as- h practice from the beginning of 2022 in the st sessing the indication for introduction as wel a United States of America. er as assessing the effect of treatment with bio- e The Institute for Clinical and Econom- v logic drugs. The phenotyping of severe asth- ic Review (ICER) analyzes the value of first 2: se ma is today embedded in clinical practice and five biological drugs treating moderate to se-m is used to assess the feasibility of available bi- u vere asthma associated with T2 inflamma- r fo ologics6. The use of monoclonal antibodies tion. The ICER Report suggests that all five am against immunoglobulin E (IgE) and interleu- approved biologics are effective and safe. h kin (IL) -5 and recently IL-13/IL-4 has been st Each of the five analyzed drugs significant- ae shown to be efficient and safe in clinical trials ly reduced the exacerbation of asthma com-rev as well as in everyday clinical practice7. pared with placebo and improved patient se Efficacy and effectiveness are not identi- quality of life. Treatment with omalizumab cal concepts and it is not possible to investigate and mepolizumab is carried out for the great-both in the same type of research. Efficacy est length of time. Thanks to long-term effi- cacy and safety data from extended studies of benralizumab every 8 weeks may also be im-key trials as well as experience from everyday portant for some patients. clinical practice, the uncertainties associated A weight-based dosing regimen of resli- with these treatments are very smal 10. zumab may provide a good response in cases The EAACI 2021 use the GRADE ap- that have failed to respond to other anti-IL5 proach in making recommendations for each biologics. Only reslizumab has to be given biologic both in terms of its use and therapeu-intravenously, which may be important for tic effect assessment11. some patients. Very rare cases of anaphylax- According to the 2021 EAACI Guide- is have been reported in clinical studies with- lines, a reduction in exacerbations, an im- in the first 20 minutes after reslizumab infu- provement in quality of life, a reduction in the sion20. use of ICS as well as the use of rescue drugs, Long-term efficacy of dupilumab has and global efficacy can be expected with high been demonstrated in both al ergic and eosin-certainty in patients treated with omalizum- ophilic phenotypes. The good safety profile of 65 ab. Improvement in asthma control is expect- dupilumab is known from previous studies for ed with moderate certainty11. Real-life studies atopic dermatitis. Dupilumab is well tolerat-sic have shown the efficacy of omalizumab re- ed, but ocular side effects are common21. gol gardless of blood eosinophil status12,13. Long- In endemic areas, patients treated with bio term treatment with omalizumab did not anti IL-5 biologics, should be screened for n o increase the risk of side effects, especial y ana- parasitic infections11. amh phylaxis14. Tezepelumab is the first drug in a class st The EAACI recommendations for treat- of new biologics that targets and blocks thy- aer ment with mepolizumab to reduce asthma ex- mic stromal lymphopoietin (TSLP), which ev acerbations and to resolve or reduce OCS are sits at the top of the inflammatory cascades. seh strong. The effect of mepolizumab on asthma The mechanism and site of action of tezepe-it control, quality of life and lung function in lumab stops the release of inflammatory cy-wst studies was good, but less clear15,16. The great- tokines at the very source and therefore this nie drug has the potential to treat a wide popu- t est positive change in symptoms and lung pa function observed during the first months lation of patients with severe asthma regardin of treatment with mepolizumab17. No seri- less of phenotype. Randomized trials of teze- sen ous side effects associated with mepolizumab pelumab showed fewer exacerbations, better spoe were reported in real-life studies18. lung function, better asthma control, and bet- ric According to the EAACI 2021 recom- ter health-related quality of life in patients t mendations, there is high certainty that ben- with severe asthma who received it22. Consid- peua ering that it has only recently been available r ralizumab reduces asthma exacerbations eh and OCS in a subgroup of adult asthmatics in daily clinical practice, the experiences of tf with severe asthma with > 150 eosinophils/ clinicians are still expected. on μL. There is also great certainty for patients iota treated with benralizumab that asthma con- Comparison between biologics lua trol and quality of life will improve11. Fol- The assessment of the therapeutic effect of bi- ve low-up of 1,600 asthma patients treated with d ologic drugs in severe asthma depends on a n benralizumab for 2 years did not indicate an a number of factors that differed significant- gin increased risk of infections or malignancies, ly between studies and that can modulate ro but further long-term fol ow-up is needed to the therapeutic response. In differed studies, itn assess possible risks of eosinophil depletion there are different inclusion or exclusion cri-om during benralizumab treatment19. Dosage of teria related to asthma severity, lung function, definition of atopic status, eosinophil count, clinical outcomes (lung function parameters, frequency and severity of exacerbations, and number of exacerbations), but also includes duration of asthma1,11. Due to this, the expert subjective outcomes assessed by the patient, opinion is that the indirect treatment compar-such as symptoms, activity level, quality of ison between these five biologics may be er- life and satisfaction. roneous or biased and should not be done11. Assessments of the therapeutic response Studies that directly compare the therapeu- could be hampered by disease heterogeneity, tic response of approved biologics have not yet comorbidities, complexity of care, and differ-been performed. ences in national and regional health systems. The recommendations for assessing the ther- 66 Key elements for evaluating responses apeutic response to biologics assumes that the to biological treatment in clinical diagnosis of severe asthma is correct and al practice. How and when to evaluate? co-morbidities and factors influencing asthma Estimation of response sizes to control are correctly addressed. Baseline asth- biological treatment of severe asthma ma severity and duration, dose of oral corti- a The effectiveness of all the biologics in severe costeroid, atopic status definition, eosinophil mh asthma is approximately 60% in a real-world cut-off, exacerbation severity and rate histo-st a setting23,24,25. Most of the afore mentioned ry as well as lung function are all important in ere clinical features of severe asthma represent assessing treatment efficacy or effectiveness11. v se the elements for assessing the outcomes and The therapeutic response to biologics in clinical benefits from treatment with biologics should be assessed individual y according to sit (Figure 1.). Asthma control includes objective pre-defined limits for outcomes focused on the ar te blataer tdn aginroitno - mamh st aerev 2: semur fo Figure 1. Monitoring of the therapeutic response after the introduction of biological drugs for severe asthma am (10) (Taken with permission from ICER Rewier 2018). h st a Note: AEs: adverse effects; FENO: fractional exhaled nitric oxide; FEV : forced expiratory volume in one second; SAEs: severe e 1 r adverse effects evse goals of asthma control11. All changes since guidelines corrected the recommendation to the previous visit should be careful y analyzed re-evaluate the therapeutic response every in terms of frequency and severity of exacer-3-4 months. The EAACI 2021 guidelines rec- bations, all elements of asthma symptom con- ommend an evaluation every 4-6 months. trol (frequency of symptoms, use of SABA, If therapeutic response to biologics is nocturnal awakening due to asthma, activi- good and asthma is well control ed, it is rec- ty limitation), treatment intensity (including ommended to consider reducing and eventu-OCS dose), quality of life, adherence and in- al y discontinuing oral corticosteroid treat- halation technique, pulmonary function, pa- ment, then other add-on therapies, and final y tient satisfaction, side effects and possible con- inhaled corticosteroids. Oral corticosteroids cerns. and all other asthma drugs should be reduced GINA and EAACI Guidelines for the gradually. Inhaled corticosteroids should nev-treatment of severe asthma with biologics dif- er be completely ruled out, but at least a mod- fer slightly about the time period for monitor- erate dose should be maintained. If after step- ing the therapeutic response, but agrees that 67 down during treatment with biologics there is it should be done between 3 and 6 months1,11. a loss of symptom control and/or exacerba-sic The GINA 2020 guidelines recommend that tions reoccur, the therapy should be intensi-gol the first assessment of the therapeutic response fied to the previous dose to re-establish good to biologics in severe asthma be made after 4 asthma control1. bion months. If the response is good, it is recom- Wel -defined criteria for assessing the oam mended to continue treatment with a reas- therapeutic response to biological therapy h st sessment every 3-6 months. The GINA 2021 in severe asthma do not currently exist, but aerev sehit wstniet pa insen spoe rict peuareh tf onio Figure 2. Response to treatment of severe asthma with biologics (all three anti-IL-5 drugs) after 2 years (26) ta (Taken from Eger K et al. J Alerg Clin Imunol Pract 2021) lua vedn it is clear that not all outcomes are of equal acerbation of severe asthma, control of asth-ag strength and importance. According to the ma symptoms assessed using the ACQ (Asth-inro latest EAACI 2021 guidelines, expected out- ma Control Questionnaire) or ACT (Asthma itn comes are classified into three groups. The Control Test), quality of life measured by the om most critical outcomes are considered to be ex- quality of life of the Asthma Questionnaire (AQLQ) and safety. Lung function, particu-are still met, switching to another biological larly FEV (forced expiratory volume in the agent is a rational option. 1 first second) and dose reduction of OCS and Studies have shown that switching to an- ICS, as well as the use of rescue drugs are con- other biologic drug can have a significant ef- sidered important outcomes, while FeNO and fect on improving FEV1, control ing asthma eosinophils in sputum and blood are consid-symptoms, and reducing OS in patients with ered less important. The EAACI Guidelines an initial y poor response to a previous bio-Development Group (GDG) for the treatment logic drug25,29,30. The exact time and manner of severe asthma with biologics has formulat-of switching from one biological drug to an- ed strong recommendations regarding dose other have not yet been defined. More precise 68 reduction of OCS and conditional recom- recommendations in this regard are expected mendations with respect to other outcomes11. from large ongoing studies aimed at switching In the observational cohort study by biologic drugs. In a report by Numate et al, an Eger and coworkers, 11% of patients were analysis of switching from one biological drug considered as non-responders, 69% as partial to another in randomized studies (omalizuma responders, and 14% as super-responders af- ab to mepolizumab, mepolizumab to benrali- mh ter 2 years of anti–IL-5 treatment for severe zumab, all three biologics from the IL5 / IL-5 st a eosinophilic asthma26. receptor group to dupilumab) showed effica- ere In patients with a good response on bi- cy. Most reports suggested switching to an- v se ologics to individual y predetermined goals, other drug after approximately 4 months. In in continued treatment is recommended, in ac- real-life studies, the effectiveness of biologics sit cordance with local regulatory authorities stabilized after 16 weeks in 80% of cases and ar t and continuous monitoring of effectiveness within 24 weeks in 90% of cases. The me-e dian time to change the first biologic in sub- bl and safety. The rationale for this recommen- at dation is the evidence that after discontinua- jects who did not respond to treatment was aer after 8.6 months and for the second after 2.7 t tion of biologics, their beneficial effect is lost11. d months. In clinical practice, if justified, the n A few clinical studies to date have shown that a large number of different biologics available g in many patients, after discontinuation of bi- in for severe asthma makes it possible to reduce r ologic therapy, symptom control deteriorates oit and / or exacerbations recur27,28. So far, there switching interval to each subsequent biolog-no are no precise instructions on how long treat- ic treatment25. - m A sustained suboptimal therapeutic re- a ment with biologics should last. mh If there is no therapeutic response to bi- sponse to a biological drug requires re-pheno- st a ologics, the clinicians are advised to find pos- typing and re-examination of biomarkers and er sible reasons. Uncontrol ed asthma, after ap- immune response pathways. Exacerbations in ev plied biological therapy, requires verification patients who do not respond to biologic ther-2: se of adherence because some patients, fol owing apy do not necessarily have to be eosinophil-mu first few administrations of the biologics, stop ic and the type of exacerbation cannot be r fo taking anti-inflammatory medications with- inferred without confirmation. The inflam- am out consulting their health care physicians matory phenotype of asthma exacerbations h st and become non-adherent to the overal man- may be distinguished using FeNO31, but in- ae agement plan. duced sputum is a more desirable option for rev If there is no satisfactory therapeutic re- reassessing whether airway inflammation is se sponse to the initial y introduced biological eosinophilic or neutrophilic. If the response drug after sufficient time, but the criteria for to treatment is unsatisfactory and a reassess-targeted biological treatment of severe asthma ment shows that there is no airway eosino- philia, biologics should be discontinued and the therapy with biologics. In some patients, T2 low asthma treatment measures should be exacerbations may not decrease significant-considered11. ly in a short period of time, so the other end- It is important to keep in mind that bio- points should be used to define a therapeutic logics may induce the production of antibod- response11,40. ies against drugs (ADAs) that may affect the loss of a therapeutic response or hypersensi- Effects of biologics on symptoms tivity reaction. The measurement of ADA in and quality of life everyday clinical practice has not yet been im-Symptoms of patients with severe asthma that plemented. As the detection of ADAs is essen- tial for immunogenicity assessment, future remain uncontrol ed despite the maximum tasks is to determine how and when to rou-intensity of treatment are the most obvious indicator of the severity of the disease if al tinely measure them in clinical practice32. If other measures are taken to exclude the fac-the reason for non-response is the develop- tors responsible for uncontrol ed disease. Giv- 69 ment of neutralizing anti- drug antibodies33,34 en the subjectivity, they need to be assessed or other dysfunctions and autoimmune re-s with questionnaires. A clinical y significant ic sponse, it is justified to switch to another bio- g smal est difference in the ACT score is con- ol logical drug fol owing the specific characteris- sidered to be three points41. The sum of symp- bio tic35. Possibilities of combining two biological n toms in severe asthma is usual y very low, and o drugs with different mechanisms were also a it is difficult to assess the actual improvement m considered but the rationale for such use is h based on differences in the ACT score. ACT st stil lacking. a has known limitations in severe asthma. It ere is recommended to reduce the ACT cut-off v Effect of biologics on exacerbations se for uncontrol ed asthma in severe asthma to h Asthma exacerbations are the most undesira- it ble adverse event that can occur during il ness score 1642. Improvement of symptoms dur-ws ing the treatment of severe asthma should be t and that can be life-threatening to the pa- nie assessed by their qualitative and quantitative t tient. Such exacerbations in patients with se- characteristics as well as by their timing, lo- pa vere asthma are frequent and significantly im- in pair their quality of life. According to EAACI cation, aggravating or al eviating factors, and sen 2021 recommendations, the impact on ex- associated manifestations. Of particular im- spo portance is the assessment and treatment of e acerbations of severe asthma during biologic r treatment are among critical, the most impor- co-morbidities as they may contribute to poor ict tant outcomes for assessing treatment suc- disease control by aggravating or mimicking peua cess11. Most studies, including a number of symptoms of asthma4. reh new ones, report that biologics significantly Symptoms greatly impair quality of life tf reduce the number and severity of exacerba- associated with health status (HRQoL) in pa- on tions in patients with severe asthma15–20,23,24, 28, tients with severe asthma, and the use of bio-iot 36–39 a . The results of a recently published MEX logics has proven promising in this sense. More lua study call into question the routine use of oral than 60% studies, dealing with the treatment ve corticosteroids to treat all asthma exacerba- of severe asthma included a HRQoL ques- dn tions without recognizing an inflammatory tionnaire as a primary, secondary, or research agin phenotype of asthma exacerbations which are outcome43. Research has shown that improv-ro not always eosinophilic31. ing overall quality of life is the most impor- itn The effect of biologic therapy on exac- tant outcome for most patients with severe om erbations should be closely monitored during asthma (44). Safety and the most of them are more wil ing to ac- The results of randomized and real-life stud- cept some degree of lung function deteriora- ies as well as experience in everyday clinical tion compared to other outcomes (worsening practice confirms that the safety profile of al of symptoms, quality of life) when reducing five biologics is very good. Side effects dur-OCS dose47. If the patients show a good re- ing treatment with biologics in clinical stud- sponse to biologics, it is recommended to con- ies were mild in most cases for all approved sider reducing OCS careful y and gradual y. biologics. Sometimes they did not differ from Reduction of corticosteroids in cases of a good the side effects seen in patients receiving pla-response to biologics should be gradual y as- cebo. The most common side effects were low- sessed at intervals of several months. Stud- 70 er respiratory tract infection, nasopharyngi- ies have shown that it sometimes takes a long tis, sinusitis, worsening of asthma, headache, time for a dose of corticosteroids to be signifi-pain or reaction at the injection site and ar- cantly reduced or completely ruled out48. thralgia14–21,36–39. Al owing a reduction in OCS therapy by Common immediate side effects after half or complete exclusion is the main criteria administration are local pain and discom- on for response to treatment. It is also recom- mh fort at the injection site. Very rarely, anaphy- mended to try to stop taking other additional st a lactic reactions occur during administration, medicines, but to maintain a medium dose of er which is why drugs should be given under the e inhaled corticosteroid at all times. v supervision of health professionals and pa- se According to the new GINA guidelines, in tients should be monitored for some time af- the introduction of a biologic is recommend- sit ter administration14. Reports of such adverse ed before the use of systemic corticosteroids in ar t reactions state that they have been successful- order to prevent their side effects. In patients e ly treated. with uncontrolled severe asthma who are not blat eligible for biologics or those who do not re- aer Effects of biologics on corticosteroids spond to biologic therapy, OCS treatment td treatment is still an important alternative to achieving n a control. Patients who do not respond to bio- g One of the most important effects of biolog- in logics may also not respond to systemic cor- r ic therapy is the possibility to exclude or re- oit duce the dose of corticosteroids in patients ticosteroids1. no who need them for disease control. The conse- - m quences of long-term of systemic corticoster- Effects of biologics on lung function am oids use are widely recognized. Price and cow- h Severe asthma that is refractory to treatment st orkers recently investigated that patients with a usual y significantly affects lung function and er asthma prescribed oral corticosteroid (OCS) the use of biologic drugs often significant-ev had a significantly increased risk of osteopo- ly improves it. In some patients, the changes 2: se rosis and osteoporotic fracture, pneumonia, may be permanent due to airway remodeling mu cardio and cerebrovascular diseases, cata- and result in fixed airway obstruction. r ract, sleep apnea, renal impairment, depres- fo Pulmonary function in patients with se- a sion and anxiety, type 2 diabetes and weight m vere asthma is very important, but during bi- h gain45. The short courses of systemic corticos- ologic treatment a certain degree of impair- st ae teroids are much safer, but are still associat- ment of pulmonary function is considered rev ed with increased risk of adverse events46. In more acceptable compared to other outcomes se project ROSA the majority physicians have such as exacerbations, symptoms and quality a favorable perception towords using bio-of life if oral corticosteroids may be excluded logical agents whenever patients are eligible or reduced47. According to EAACI Guidelines, the ef-markers, there was a significant difference in fect of biologic drugs on the improvement of response rate between the groups of biolog-lung function is an important but not criti- ics depended on the biomarker on which the cal outcome for assessing the effectiveness of drug was selected. When the biologics were treatment11. selected based on peripheral blood eosinophil counts (PBEC), IgE and FeNO the response Effects of biologics and biomarkers rate was 33% (PBEC), 36% (IgE) and 50% According to the Working Group of the Na- (FeNO) for omalizumab, 65% (PBEC), 67% tional Institute of Health (NIH), a biomarker (IgE) and 64% (FeNO) for mepolizumab/ is defined as “… a characteristic that is objec- benralizumab and 64% (PBEC), 50% (IgE) tively measured and evaluated as an indica- and 73% (FeNO) for dupilumab25. One of the tor of normal biologic processes, pathogen- goals of future research is to identify better ic processes, or pharmacologic responses to a clinical y relevant biomarkers in terms of pa-therapeutic intervention”. Simply, a biomark- tient selection and prognosis of therapeutic re- 71 er indicates an alteration in physiology from sponse to biologics, and which will better reflect the clinical response during treatment. s normal49. Ideal y, a biomarker might be the icg pathophysiological therapeutic target itself. ol Identification of specific biomarkers such as Conclusion bio peripheral blood absolute eosinophil count, All previous clinical studies as well as expe-n o total IgE, specific IgE and fractional exhaled riences from everyday practices have shown am that biologics in severe asthma are highly ef- h nitric oxide (FeNO) in biological materials al- st lowed precise treatment of patients with severe ficient and safe in precisely selected patients aer T2 high asthma. Biomarkers indicate certain with severe T2 high asthma. However, all pa-ev asthma endotypes and predict responses to tients treated with biologics are not good re-seh biological therapies5). During treatment with sponders and there are still many doubts and it unknowns regarding the treatment. w biologics, a reduction or complete eosinophil st It is estimated that the effectiveness of n depletion is observed which is usual y accom- ie biologics on severe asthma in real world set- t panied by a good clinical response to treat- pa ment, but this response to biomarkers is con- tings is about 60%11. For now, there are no in sidered a less important outcome than other se clearly defined criteria for assessing the effec- n clinical outcomes. Routine monitoring of IgE tiveness of biologics in everyday practice. Pa-spoe levels is not recommended during omalizum- tients treated with biologics should be closely ric ab treatment1,9. In many patients with T2 monitored and evaluated against baseline and t high asthma, known biomarkers overlap as against pre-defined treatment outcome goals. peuar shown in Figure 2. Overlapping of biomark- The critical outcomes of treatment with bio- eh ers often leads to doubts about drug choice logics are considered to be the impact on re-tf and existing biomarkers are often considered ducing exacerbation, improving symptoms on and quality of life as well as the safety of bi- io insufficient for a precise decision about the ta best biologic to administer. In the current sit- ological therapy. Important treatment out- lua uation, the overlapping of known biomarkers, comes are considered to be the effect on re-ve ducing the intensity of treatment (oral and d in case of poor response to the initial biologi- n inhaled corticosteroids, recue medications) a cal drug al ows switching to another biologic gin that targets another capture point, which of- and the effect on improving lung function11. ro ten results in a good response. In studies that Biologic drugs al ow specific inhibition of itn looked at the association between the effica- certain asthma pathways, which does not al- om cy of biological therapy and predictive bio- ways meet all set treatment goals equal y suc- cessfully51. Previous reports on therapeutic re-5. Albendiz VJ, de Castro FJ, Gutierrez IG sponses have not provided accurate answers et al. Characteristics of patients with se- to a number of questions about long-term bi- vere asthma in our population. J Al er- ological treatment in daily clinical practice. gy Clin Immunol. 2018 Feb;141(suppl Precise definition of therapeutic response, cri- 2):AB101. doi:10.1016/j.jaci.2017.12.323 teria for optimal and suboptimal response, 6. Moore WC, Bleecker ER, Curran-Ever-criteria for continuation or discontinuation ett D, et al. Characterization of the se- of biologics, duration of biological treatment vere asthma phenotype by the National in patients who responded to therapy, rules Heart, Lung, and Blood Institute’s Se- for switching to other biological drugs in pa- vere Asthma Research Program. J Al er- 72 tients who did not respond to therapy, rules gy Clin Immunol. 2007 Feb;119(2):405-for combining biological drugs and the bio- 13. logical treatment of al ergic comorbidities are 7. Jin HJ. Biological treatments for severe just some of the questions that need to be an-asthma. Yeungnam Univ J Med. 2020 swered. Oct;37(4):262-8. a It is also necessary to clarify issues re- 8. Porzsolt F, Rocha NG, Toledo-Arruda mh lated to the identification of factors associat- A, et al. Efficacy and effectiveness trials st a have different goals, use different tools, e ed with treatment failure and the possibility re of increasing the therapeutic response rate. and generate different messages. Prag- v se In particular, there is a great need to identify mat Obs Res. 2015 Nov 4:6:47-54. in 9. Menzies-Gow A, Szefler SJ, Busse WW. s new molecular targets in order to offer effec- it The Relationship of Asthma Biologics a tive treatments for those patients who do not r t to Remission for Asthma. J Al ergy Clin e respond to currently available biologics11. bl Immunol Pract. 2021 Mar;9(3):1090-8. ata 10. Institute for Clinical and Economic Re- e Literature r view. ICER Final Evidence Report td 1. Global Initiative for Asthma. Global 2018: Biologic Therapies for Treatment n a Strategy for Asthma Management and g of Asthma Associated with Type 2 In- in Prevention [Internet]. [place unknown]: r flammation; Effectiveness, Value, and o Global Strategy for Asthma Manage- it Value-Based Price Benchmarks. Boston, no ment and Prevention; c2022 [cited MA: Institute for Clinical and Econom- - m September 10, 2021]. Available from: ic Review; 2018. am http://www.ginasthma.org. h 11. Agache I, Akdis CA, Akdis M, et al. st 2. Bagnasco D, Passalacqua G, Camina- a EAACI Biologicals Guidelines-Recom- e ti M, et al. Evolving phenotypes to en- r mendations for severe asthma. Al ergy. ev dotypes: is precision medicine achieva- 2021 Jan;76(1):14-44. 2: se ble in asthma? Expert Rev Respir Med. 12. Busse W, Spector S, Rosén K, et al. m 2020 Feb;14(2):163-72. u High eosinophil count: a potential bio- r 3. Schoettler N, Strek ME. Recent Ad- fo marker for assessing successful omali- a vances in Severe Asthma: From Pheno- m zumab treatment effects. J Al ergy Clin h types to Personalized Medicine. Chest. st Immunol. 2013 Aug;132(2):485-6.e.11. ae 2020 Mar;157(3):516-28. 13. Bourgoin-Heck M, Amat F, Trouvé rev 4. Porsbjerg C, Menzies-Gow A. Co-mor- C, et al. Omalizumab could be effec- se bidities in severe asthma: Clinical im- tive in children with severe eosinophil- pact and management. Respirology. ic non-al ergic asthma. Pediatr Al ergy 2017 May;22(4):651-61. Immunol. 2018 Feb;29(1):90-9. 14. Di Bona D, Fiorino I, Taurino M, et al. 23. Kavanagh JE, d’Ancona G, Elstad M, Long-term “real-life” safety of omal- et al. Real-world effectiveness and the izumab in patients with severe un- characteristics of a “super-responder” control ed asthma: A nine-year study. to mepolizumab in severe eosinophil- Respir Med. 2017 Sep:130:55-60. ic asthma. Chest. Aug 2020;158(2):491- 15. Ortega HG, Liu MC, Pavord ID, et 500. al. Mepolizumab treatment in patients 24. Kavanagh JE, Hearn AP, Dhariwal J, et with severe eosinophilic asthma. N Engl al. Real-World Effectiveness of Benral- J Med. 2014 Sep 25;371(13):1198-207. izumab in Severe Eosinophilic Asthma. 16. van Toor JJ, van der Mark SC, Kappen Chest. 2021 Feb;159(2):496-506. JH, et al. Mepolizumab add-on therapy 25. Numata T, Araya J, Miyagawa H et al. in a real world cohort of patients with Effectiveness of Switching Biologics for severe eosinophilic asthma: response Severe Asthma Patients in Japan: A Sin- rate, effectiveness, and safety. J Asthma. gle-Center Retrospective Study. J Asth- 2021 May;58(5):651-8. ma Al ergy. 2021 Jun 3:14:609-618. 73 17. Caminati M, Cegolon L, Vianel o A, 26. Eger K, Kroes JA, ten Brinke A, et al. s et al. Mepolizumab for severe eosino- Long-Term Therapy Response to An- icgo philic asthma: a real-world snapshot ti-IL-5 Biologics in Severe Asthma- A l on clinical markers and timing of re- Real-Life Evaluation. J Al ergy Clin Im- bion sponse. Expert Rev Respir Med. 2019 munol Pract. Mar 2021;9(3):1194-200. oa Dec;13(12):1205-12. 27. Haldar P, Brightling CE, Singapuri A, mh 18. Harrison T, Canonica GW, Chupp G, et al. Outcomes after cessation of me- st a et al. Real-world mepolizumab in the polizumab therapy in severe eosino- ere prospective severe asthma REALI- philic asthma: a 12-month fol ow-up v TI-A study: initial analysis. Eur Respir analysis. J Al ergy Clin Immunol. 2014 sehit J. 2020 Oct 15;56(4):2000151. doi: Mar;133(3):921-3. ws 10.1183/13993003.00151-2020. 28. Ledford D, Busse W, Trzaskoma B, et tn 19. Jackson DJ, Korn S, Mathur SK, et al. al. A randomized multicenter study iet Safety of Eosinophil-Depleting Thera- evaluating Xolair persistence of re- pa py for Severe, Eosinophilic Asthma: Fo- sponse after long-term therapy. J Al er- inse cus on Benralizumab. Drug Saf. 2020 gy Clin Immunol. 2017 Jul;140(1):162- n May;43(5):409-25. 9.e2. spoe 20. Virchow JC, Katial R, Brussel e GG, et 29. Pepper AN, Hanania NA, Humbert M rict al. Safety of reslizumab in uncontrol ed et al. How to Assess Effectiveness of Bi- peu asthma with eosinophilia: a pooled ologics for Asthma and What Steps to ar analysis from 6 trials. J Al ergy Clin Im- Take When There Is Not Benefit. J Al- eh munol Pract. 2020 Feb;8(2):540-8.e.1. lergy Clinin Immunol Pract. 2021 tf 21. Hal ing AS, Loft N, Silverberg JI, et al. Mar;9(3):1081-8 onio Real-world evidence of dupilumab ef- 30. Drick N, Milger K, Seeliger B, et al. ta ficacy and risk of adverse events: A sys- Switch from IL-5 to IL-5-Receptor α lua tematic review and meta-analysis. J Am Antibody Treatment in Severe Eosino- ved Acad Dermatol. 2021 Jan;84(1):139-47. philic Asthma. J Asthma Al ergy. 2020 n a 22. Menzies-Gow A, Corren J, Bourdin A, Nov 11:13:605-614.. gin et al. Tezepelumab in Adults and Ad- 31. McDowell PJ, Diver S, Yang F, et al. ro olescents with Severe, Uncontrol ed Medical Research Council: Refracto- itn Asthma. N Engl J Med. 2021 May ry Asthma Stratification Programme om 13;384(19):1800-9. (RASP-UK Consortium). The inflam- matory profile of exacerbations in pa-Practice. Chest. 2021 May;159(5):1734- tients with severe refractory eosinophil- 46. ic asthma receiving mepolizumab (the 39. Hal ing AS, Loft N, Silverberg JI, et al. MEX study): a prospective observa- Real-world evidence of dupilumab ef- tional study. Lancet Respir Med. 2021 ficacy and risk of adverse events: A sys- Oct;9(10):1174-84. tematic review and meta-analysis. J Am 32. Matucci A, Nencini F, Vivarel i E, et Acad Dermatol. 2021 Jan;84(1):139-47. al. Immunogenicity-unwanted immune 40. Fitzpatrick AM, Szefler SJ, Mauger DT, responses to biological drugs – can we et al. Development and initial validation predict them?, Exp Rev Clin Pharma- of the Asthma Severity Scoring Sys- 74 col. 2021 Jan;14(1):47-53. tem (ASSESS). J Al ergy Clin Immunol. 33. Mukherjee M, Bulir DC, Radford K, 2020 Jan;145(1):127-39. et al. Sputum autoantibodies in pa- 41. Schatz M, Kosinski M, Yarlas AS, et al. tients with severe eosinophilic asth- The minimal y important difference of ma. J Al ergy Clin Immunol. 2018 the asthma control test. J Al ergy Clin Apr;141(4):1269-79. Immunol. 2009 Oct;124(4):719-23. am 34. Mukherjee M, Lim HF, Thomas S, et doi:10.1016/j.jaci.2009.06.053 h st al. Airway autoimmune responses in se- 42. Korn S, Both J, Jung M et al. Prospec- ae vere eosinophilic asthma fol owing low- tive evaluation of current asthma con- rev dose Mepolizumab therapy. Al ergy trol using ACQ and ACT compared se Asthma Clin Immunol. 2017 Jan 6:13:2. with GINA criteria. Ann Al ergy Asth- ins doi: 10.1186/s13223-016-0174-5. ma Immunol. 2011 Dec;107(6):474-9. itar 35. Rup B, Pal ardy M, Sikkema D, et al. 43. Lanario JW, Burns L. Use of Health te Standardizing terms, definitions and Related Quality of Life in Clinical Tri- bla concepts for describing and interpret- als for Severe Asthma: A Systemat- tae ing unwanted immunogenicity of bi- ic Review. J Asthma Al ergy. 2021 Aug r t opharmaceuticals: recommendations 12:14:999-1010. dn 44. Hossny, E., Carabal o, L., Casale, T. a of the Innovative Medicines Initiative g ABIRISK consortium. Clin Exp Immu- et al. Severe asthma and quality of inro nol. 2015 Sep;181(3):385-400. life. World Al ergy Organ J. 2017 Aug itn 36. Busse WW, Bleecker ER, FitzGerald 21;10(1):28. doi: 10.1186/s40413-017- o JM, et al: BORA study investigators. 0159-y. - ma Long-term safety and efficacy of benral- 45. Price DB, Trudo F, Voorham J et al. Ad- mh izumab in patients with severe, uncon- verse outcomes from initiation of sys- st a trol ed asthma: 1-year results from the temic corticosteroids for asthma: long- ere BORA phase 3 extension trial. Lancet term observational study. J Asthma Al- v Respir Med. 2019 Jan;7(1):46-59. lergy. 2018 Aug 29:11:193-204. doi: 2: se 37. Korn S, Bourdin A, Chuupp G et al. In- 10.2147/JAA.S176026. mu tegrated Safety and Efficacy Among pa- 46. Price D, Castro M, Bourdin A et al. r fo tients Receiving Benralizumab for Up Short-course systemic corticosteroids am 5 Years. J Al erg Clin Immunol Pract. in asthma: striking the balance be- h st 2021 Dec;9(12):4381-92.e4. tween efficacy and safety. Eur Respir ae 38. Wechsler ME, Peters SP, Hill TD, et al. Rev. 2020 Apr 3;29 (155):190151. doi: rev Clinical Outcomes and Health-Care 10.1183/16000617.0151-2019. se Resource Use Associated With Resli- 47. Loureiro CC, Ferreira MB, Ferreira J et zumab Treatment in Adults With Se- al. Reducing oral corticosteroids in se- vere Eosinophilic Asthma in Real-World vere asthma (ROSA Project): a nation- wide Portuguese consensus. Pulmonolo-gy. 2021 Jul-Aug;27(4):313-27. 48. Khurana S, Brussel e GG, Bel EH et al. Long-term Safety and Clinical Ben- efit of Mepolizumab in Patients With the Most Severe Eosinophilic Asthma: The COSMEX Study. Clin Ther. 2019 Oct;41(10):2041-56.e5. 49. Jain KK. Role of Biomarkers in Person- alized Medicine. In: Jain KK. Textbook of Personalized Medicine. Cham, Swit- zerland: Springer;2021. p. 110-13. 50. Wangberg H, Woessner K. Choice of biologics in asthma endotypes, Curr Opin Al ergy Clin Immunol. 2021 Feb 75 1;21(1):79-85 s 51. McCracken JL, Tripple JW, Calhoun icgo WJ. Biologic therapy in the manage- l ment of asthma. Curr Opin Al ergy bion Clin Immunol. 2016 Aug;16(4):375-82. oamh st aerev sehit wstniet pa insen spoe rict peuareh tf oniota lua vedn aginroitnom Contributors Assoc. Prof. Ivan Čekerevac, MD, PhD racic surgery, University Hospital Cen- Ivan Čekerevac was born in Čačak in tre Zagreb. During that time she finished 1970. He graduated from the Faculty of University of Applied Health Sciences Medicine, University of Kragujevac and and obtained the title “Bachelor of Nurs-earned a phD degree at the age of 40. He ing” (2001). After that she has been work-has been educated abroad on several oc- ing at Pulmonary Disease Clinic at differ-casions such as Germany and Hunga- ent departments such as Chemotherapy ry. He is a full professor of the Faculty of Unit, Pulmonary department, including Medicine Sciences, University of Kragu- Outpatient units. Her current position is jevac. He has published more than 80 a Head nurse of Outpatient Unit Clin-publications, of which 25 cited in inter- ic for Thoracic surgery. For the past few national databases, and more than 160 years she has actively participated in sev-times at the Scopus base. He co-authored eral clinical trials and acquired knowl-3 books and main author of the book Ba- edge in other European countries since sics of echosonography, chapter named last five years. She has been a the pioneer Thoracic ultrasound and COPD and sys- nurse at enforcement of induced sputum temic inflammation. He has given invited in Croatia on Clinic for Pulmonary Dis-lectures at international meetings. Special eases, Zagreb. interest in asthma, chronic obstructive pulmonary disease, obstructive sleep ap- Assoc. Prof. Ivan Kopitović, MD, PhD nea and non-invasive ventilation and tho- Professor of Internal Medicine at Uni-racic ultrasound and ergospirometry. versity of Novi Sad – Faculty of Medi- cine. Specialist in Internal Medicine and Valetnina Fiket, bacc. med. techn. subspecialist in Pulmonology at Insti- Valentina Fiket was born on May 25th tute for Pulmonary Diseases of Vojvodi-1977 in Zagreb, Croatia. After finishing na (IPDV) – Sremska Kamenica, Ser-Medical high School she started her ca- bia. He has been working for more than reer at ICU department at the Special two decades in ICU, HDU, lung function Hospital for chronic pulmonary diseas- testing unit and sleep lab (sleep disordered es and later in the ICU unit of the Tho- breathing - SDB). He is a consultant in the field of asthma, COPD, critical care med- Assist. Prof. Marina Lampalo, MD, PhD icine and SDB. He is an author and coau- Marina Lampalo was born in Šibenik, thor of monographic publications, book chapters and more than 250 papers pub- February 1st, 1975, graduated from The lished in national and international jour- University of Zagreb School of Medicine nals. He has been a principal investigator in 2001. She has been working as an in-in clinical trials related to obstructive lung ternist since March of 2008, and as a sub-diseases, PTE, PAH, SDB. He is current- specialist in pulmonology at Jordano-ly a Head of Department for Lung Patho- vac Clinic for Pulmonary Diseases since 2010. In March of 2019, she obtained the 78 physiology with Sleep Medicine Lab at IPDV. title of Primarius. She earned the PhD ti- tle by defending her dissertation „The ef- fect of ABO blood genotypes and tissue Prof. Mitja Košnik MD, PhD plasminogen activator inhibitor on lung He graduated at the Medical Faculty, ventilation in asthma” in 2017. She has a University of Ljubljana in 1987. In 1992 m been actively participating in numerous h he finished a specialisation of the inter- st national and international scientific and ae nal medicine, latter he was nominated as r professional meetings as an invited lec- ev a specialist in pulmonology and al ergolo- turer. Thus far, she has published multi-se gy. He earned a Ph.D. degree in 1998. In in ple scientific and professional papers. She s 2012 he was nominated as a full professor it is also the author of various chapters in ar of internal medicine. He is a medical doc- t books on pulmonology. She received the e tor and a head of the Department of Clin- bl Toraks Award for Best Scientific Work in at ical Research at the University Clinic of a 2016. Since 2019 she has been a research er Respiratory and Al ergic Diseases Golnik t associate at the School of Medicine, Uni- d and a head of the Chair of Internal medi- n versity of Zagreb. In July of 2022, she was ag cine at the Medical Faculty, University of awarded the Title Assistant Professor, in inr Ljubljana. His research interests are ana- o recognition of scientific and teaching mer- it phylaxis, venom and drug al ergy. He is n its. The specialty area she has been deal- o a project manager of a national research ing with for many years is obstructive - ma project P3 – 0360: Slovenian network of m lung diseases - primarily asthma, chronic h al ergy and asthma: from epidemiology to st obstructive pulmonary disease, as well as a genetics. He was a mentor of 8 Ph. D. stu- e lung function and al ergic diseases. re dents. He is a president of Slovenian As- v sociation of Al ergology and Clinical Im- 2: se Assoc. Prof. Zorica Lazić, MD, PhD m munology and od Slovenian Respiratory ur Society, a member of State expert body Dr. Zorica Lazic graduated from Medi-foa of internal medicine and a member of cal faculty at the University of Belgrade mh UEMS, section al ergology. He published (1981). She has been the specialist in in-st a over 150 articles in journals with impact ternal medicine and pneumonology since ere factor, his H-index is 42 and has 10.000 1989 and 2005 respectively. Dr Lazic vse pure citations. earned the MSc degree (1993) at the Uni- versity of Belgrade and the PhD degree at the University of Kragujevac (1996). She was appointed as a Professor of internal monary disease, respiratory infections, medicine at the Faculty of Medical Scienc- acute and chronic respiratory failure. es, University of Kragujevac (2006). She From 2020-2022. she was the coordinator has held several senior positions at the of the COVID-19 departments of UHC University Clinical Centre Kragujevac, Zagreb. Since 2022, she has been working including the Director of Clinic for Pul- at the Department for Al ergic and Ob-monary Diseases from 1992 until 2022, structive Diseases. She is a member of the when she retired. She has been involved ERS Severe Heterogeneous Asthma Re-in many educational programs covering search Collaboration. topics including asthma, COPD, and in- terstitial lung diseases. She has participat- Assoc. Prof. Sanja Popović-Grle, MD, PhD ed as a guest lecturer at many national and international conferences through- Sanja Popović-Grle is a Professor of Respiratory Medicine at University of Za- 79 out her career. She has been involved in drafting national guidelines for treatment greb, Croatia, and Chief of Department sr for al ergic and obstructive lung diseas- o of Asthma and COPD in Serbia. Prof. La- t zic has been a member of various medical es at University Hospital Centre Zagreb. ibur After obtaining her Doctor of Medicine t associations including the ERS, CHEST, no degree from the University of Zagreb in c ATS, Respiratory Society of Serbia, and Fel owship American Col ege of Chest 1983., prof. Grle started her professional Physicians (FCCP). She was active as the career in the central state Pulmonary hos-National Lead of the Severe Heterogene- pital Jordanovac in Zagreb, as an employ-ous Asthma Research col aboration, Pa- ee from the Medical faculty, fol owed ob-tient-centred (SHARP) ERS Clinical Re- ligatory praxis for 2 years as a GP. Prof. search from 2019 to 2022. Grle main research interest is in the field of asthma, al ergy, and COPD, especial y Assoc. Prof. Gordana Pavliša, MD, PhD in diagnostic methods and management. She has published papers in peer-reviewed Gordana Pavliša, MD, graduated in 1997 journals and book chapters for students, from the University of Zagreb, School of residents, specialists or patients, and held Medicine. She is a specialist in internal many educative lectures on the topic. In medicine (2007), pulmonology (2009) and intensive care medicine (2020). In addition to the clinical duties, prof. Grle 2006 she got her PhD degree at the Uni- was involved in scientific projects and tri-versity of Zagreb with the the topic of re- als. She has been Member of Organizing search on erythropoietin, angiogenic fac- and Scientific Committees of many pro-tors and inflammatory cytokines in severe fessional meetings and congresses. hypoxemia in COPD patients. She is a professor of internal medicine at the Uni- Dina Rnjak, MD versity of Zagreb, School of Medicine. She was born on the 11th of December From 2011 to 2022, she was the head of 1989 in Osijek, Croatia. She graduated the Intensive Care Unit at the Clinic for from the School of Medicine in Osijek in Respiratory Disease, UHC Zagreb. Her 2014. She has been a specialist in pulmo-primary area of interest is obstructive pul- nology since 2021 at University Hospital Centre Zagreb, Clinic for Lung Diseas- greb. 2004. to now: Head of Laboratory es. Currently, she works as a pulmonol- – Clinical Unit of Pulmonary Cytology. ogist in Intensive and postintensive care Assistant professor on Postgraduate Stud-unit. She is an author of many abstracts ies, Medical School Zagreb, University and articles, mainly in field of asthma and of Zagreb. Teacher on University of Ap-interstitial lung diseases. She is a member plied Health Studies, Zagreb. Member of of Croatian Thoracic Society, Croatian Croatian Medical Association, Croatian Pulmonology Society and European Res- Society for Clinical Cytology (co-vice piratory Society. president), Croatian Respiratory Socie- 80 ty. Member of the Organizing Commit- Ivana Rubil tee of Croatian Congress of Clinical Cy- She was born in Zagreb, Croatia on April tology, Toraks Congress, co-organizer of 27th 1979. From 1999. She started with the 37th European Congress of Cytopa-her career in 1999 as a nurse on ICU on thology 2012., invited speaker. Author a of 150 scientific and professional papers, m Clinic for lung diseases Jordanovac. She h book chapters, poster and oral presenta- st has been active participant on many in- a tions dedicated to lung, mediastinum and er ternational and domestic congresses. Af- e pleural cytology. v ter enrolment the University for baccalau- se in reate in 2000 (graduated with B grade) s Assist. Prof. Maja Šereg Bahar, MD, PhD it she enrol ed the Masters study in Za- ar t greb and got the title Master of nursing Maja Šereg Bahar has finished study of e bl in 2003. Currently she is a head nurse of medicine at University of Ljubljana (UL), ata day hospital on Clinic for lung disease Jor- Slovenia. She obtained her MSc (2006), er t danovac, University hospital center Za- and PhD (2015) degree at the same uni-dn greb. She has been a secretary of patient versity. Since 1996 she has been employed ag association Udah Života (Breath of Life) at the University Medical Centre Ljublja-inro since 2020 , which promotes and raises na, Department of ORL & HNS in Lju-itn awareness for a population health. Its im- bljana, Slovenia. She finished her train-o - m portant point is rising the quality of pa- ing in otorhinolaryngology and started am tients life through education of patients working also at Faculty of Medicine, UL h st and their families. in 2002. At the moment she works in the ae Center for Voice, Speech and Swal owing rev Assist. Prof. Silvana Smojver-Ježek, MD, Disorders at the University hospital as a 2: se PhD phoniatrician and in the Department of mu Otorhinolaryngology at Faculty of Med- r Head of Clinical Unit of Pulmonary Cy- fo icine, Ljubljana, Slovenia. She is the au- a tology, Department of Pathology and Cy- m thor of more than 120 published papers. h tology, University Hospital Center Za- st a greb, Croatia. Graduated on Medical er Assoc. Prof. Sanda Škrinjarić-Cincar, MD, e School Zagreb, University of Zagreb. v PhD se Specialist in medical/clinical cytology, Laboratory for Cytology, University Hos- Assoc. Prof. Sanda Škrinjarić-Cincar was pital for Lung Diseases Jordanovac, Za- born in 1959 in Osijek. She has many years of work experience as a pulmonol- asthma by PhD mentoring. She is also ogist at Clinical Medical Center Osijek the ERS SHARP (Severe Heterogenous and as a teacher at the School of Medi- Asthma Research Col aboration) Nation-cine, University of Osijek. She held the al lead. Dr. Škrgat is a member of Slove-position of head of the Department of nian Respiratory Society steering com-Pulmonology until 2020. She is current- mittee and a member of SHARP steering ly employed at the Osijek Health Center. committee since 2021. She launched the Her special area of interest is obstructive first Severe asthma forum-joint meeting pulmonary diseases. She participated as of South East Europe which was held in the main researcher in numerous clinical Bled, Slovenia in 2018. studies, published a large number of sci- entific and professional papers and is one Anamarija Štajduhar, MD of the authors of the Croatian guidelines for asthma. From the very beginning of She was born in 1989 in Zagreb, and 81 the biological treatment of severe asthma graduated from the School of Medicine, s University of Zagreb in 2014.After grad- r in Croatia, she participated in the assess- ot ment and fol ow-up of patients with se- uation, she worked in the family medicine ibu offices until 2016. She became a pulmo- rt vere asthma and established the Severe n nologist in 2021, and she has been work- o Asthma Team within the Department of c Pulmonology of Clinical Medical Center ing at the Clinic for Pulmonary Diseases Osijek. Jordanovac. Currently she is PhD student at the Faculty of Medicine, University of Zagreb, under the mentorship of prof. S. Assist. Prof. Sabina Škrgat MD, PhD Popović - Grle. She has been participating Sabina Škrgat, MD, graduated from the in the implementation of medical studies Faculty of Medicine at the University of in English (School of Medicine, Univer-Ljubljana (1996). She is a specialist of in- sity of Zagreb) since 2023. Her particu-ternal medicine (2004) and pneumonolo- lar field of interest are obstructive lung gy (2011). She got her PhD degree at the diseases, she is a member of the Croatian University of Ljubljana (2009) with the Thoracic Society, the Croatian Pulmonol-topic of investigation, related to angiogen- ogy Society, ERS and EAACI as wel . esis and complement activation in asth- ma and chronic obstructive pulmonary disease. Her main clinical work consists of management of patients with severe asthma and other obstructive lung diseas- es. She is an Assistant professor at Medi- cal Faculty of Ljubljana and she curently has a leading position in Slovenian Na- tional recommendations for asthma man- agement. She is the clinical lead of Se- vere asthma Clinic at University Medical Centre Ljubljana, Slovenia. Beside clini- cal work, she is active in research of severe Index A L allergic bronchopulmonary aspergillosis 41, language therapy 13 42 allergic fungal airway disease 41, 42 M alternative overlap syndrome 47, 48, 49 maneuvers 13, 18 asthma phenotypes 55 O B obstructive sleep apnea 47, 77 biologics 63, 64, 65, 66, 67, 68, 69, 70, 71, OSA 47, 48, 49, 50 72 blood eosinophilia 43, 55 P pulmonary function tests 23 D S dysfunctional breathing 23, 24, 25, 26, 32 dyspnea 13, 14, 16, 18, 19, 20, 55, 56, 59 safety 55, 59, 63, 65, 68, 70, 71 severe asthma 28, 30, 33, 41, 42, 43, 44, 47, E 48, 50, 55, 56, 57, 58, 59, 63, 64, 65, 66, 67, 68, 69, 70, 71 evaluation 16, 28, 63, 67 speech 13, 17, 18, 19, 20 sputum eosinophilia 55 F sputum induction 55, 56, 59 fungal bronchitis 42, 44 T H T2 high asthma 63, 71 T2 low asthma 69 hyperventilation 14, 23, 24, 25, 26, 27, 28, therapeutic response 63, 64, 65, 66, 67, 68, 29, 30, 31, 32, 33 69, 71, 72 I V IgE sensibilisation 41 vocal cords dysfunction 13 Benefactors Severe Asthma Forum - Monitoring and Treatable Traits in Severe Asthma Edited by Sabina Škrgat Reviewers Mitja Košnik, Zorica Lazić, Sanja Popović-Grle, S abina Škrgat Severe Asthma Forum, 2 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, 2023 © Authors ISBN 978-961-293-297-8 (pdf) http://www.hippocampus.si/ISBN/978-961-293-297-8.pdf ISBN 978-961-293-298-5 (html) http://www.hippocampus.si/ISBN/978-961-293-298-5/index.html DOI: https://doi.org/10.26493/978-961-293-297-8 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 173907459 ISBN 978-961-293-297-8 (PDF) ISBN 978-961-293-298-5 (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. 2023. Severe Asthma Forum - Monitoring and Treatable Traits in Severe Asthma. Koper: University of Primorska Press. Severe Asthma Forum, 2 Contents Sabina Škrgat • Predgovor ︲ Preface 1.0 • Dysfunctional Breathing 1.1 • Maja Šereg Bahar • Dysfunctional Breathing – View of Otorhinolaryngologist Abstract Introduction Epidemiology Vocal cord anatomy and function Pathogenesis of VCD Specific triggers of VCD The role of psychogenic factors – triggers Irritant triggers The role of gastroesophageal reflux disease – GORD Exercise as a trigger Other possible etiologies for VCD Clinical features of VCD Important differential diagnosis od VCD Diagnosis of VCD Assessment of symptoms Physical examination Continuous laryngoscopy during exercise – CLE test Other tests Treatment Speech therapy Treatment of VCD – maneuvers EILOBI breathing techniques Psychotherapy Surgical treatment Botulinum toxin Treatment of VCD with medications – pharmacotherapy Prognosis Conclusions References 1.2 • Ivan Kopitović and Milica Mirić • Dysfunctional Breathing – View of Pulmonologist Abstract Abbreviations Introduction Dysfunctional breathing in the modern era? Definition Aetiology and pathophysiology Epidemiology Presentation Classification Associated conditions Diagnostic methods Treatment Conclusion References 2.0 • Asthma Phenotypes and Comorbidities 2.1 • Sabina Škrgat and Katarina Pelicon Slabanja • Aspergillus Sensitisation and Severe Asthma Clinical Outcomes Abstract Introduction Evolution of terminology toward AFAD Pathophysiological abnormalities and clinical outcomes related to airway fungal allergy Basic immunology Mucus impaction Immaging, functional impairment and comorbidities Fungal bronchitis Management of AFAD Conclusions Literature 2.2 • Ivan Čekerevac and Bojan Djokić • OSA in Patients with Severe Asthma-Alternative Overlap Syndrome Abstract Asthma and OSA-alternative overlap syndrome Frequent comorbidities in asthma and OSA Pathophysiological correlation between OSA and severe asthma – bidirectional interaction Clinical significance of alternative overlap syndrome Conclusion References 3.0 • Asthma Monitoring and Evaluation 3.1 • Sanja Popović-Grle, Gordana Pavliša, Marina Lampalo, Anamarija Štajduhar, Branko Pevec, Mira Pevec, Dina Rnjak, Valentina Fiket, Ivana Rubil and Silvana Smojver-Ježek • Induced Sputum Role in Severe Asthma Phenotyping Abstract Sputum induction procedure Processing of induced sputum for cytological analysis and differential cell counting Asthma inflammatory phenotypes Induced sputum analysis in research and clinical practice Conclusion References 3.2 • Sanda Škrinjarić Cincar • Monitoring and Evaluation of Therapeutic Response in Patients with Severe Asthma on Biologics Abstract Introduction: a new treatment options for uncontrolled severe asthma Licensed biologics for uncontrolled severe asthma Comparison between biologics Key elements for evaluating responses to biological treatment in clinical practice. How and when to evaluate? Estimation of response sizes tobiological treatment of severe asthma Effect of biologics on exacerbations Effects of biologics on symptoms and quality of life Safety Effects of biologics on corticosteroids treatment Effects of biologics on lung function Effects of biologics and biomarkers Conclusion Literature Contributors Index A B D E F H I L M O P S T V Benefactors Colophone