663 Stanislav Šuškovič, MD, PhD University Clinic of Respiratory and Allergic Diseases Golnik 4204 Golnik Slovenia Systemic inflammation in chronic pulmonary diseases – are we here now? Sistemske okužbe pri kronični pljučni bolezni–ali smo že tu? Stanislav Šuškovič It was strongly confirmed that patients with lung cancer compared to healthy people have significantly higher levels of inflammatory markers such as C-reactive protein (CRP).1-3 What is the relationship between elevated CRP levels and cancer? One possibility is that elevated CRP levels are a result of inflammatory stimulus by cancer, whereas other researchers believe that chronic inflammation and elevated CRP might have a causal role in carcino- genesis. Some studies in fact suggested that CRP is not merely a marker of current, but is also associated with incident cancer.4 Prognostic importance of CRP for sur- vival of patients with lung cancer5 was re- cently confirmed by Ovčariček et al.6 The authors found that duration of progression free survival time in patients with advanced non-small cell lung carcinoma treated by chemotherapy critically depends on the level of CRP and hemoglobin concentra- tion, but only borderline on comorbidities. Many other pulmonary diseases have very well known systemic consequences. Obvious examples are sepsis in pneumo- nia or metastatic spread of lung cancer. On the other hand, there is accumulating evi- dence that very complex and probably even bidirectional relationship exists between chronic pulmonary diseases and systemic response.7-9 An interesting example of such systemic disease is chronic obstructive pulmonary disease (COPD), which affects not only the lungs but also skeletal muscles and the brain.10-11 Comorbidities associ- ated with COPD are hypertension, diabe- tes, ischemic heart disease, heart failure, pulmonary infections, pulmonary vascular disease and – last but not least – lung can- cer. COPD and heart diseases even share a complex interrelationship between neuro- hormonal activation and chronic inflam- mation.11 Many patients with COPD die of non-respiratory disorders such as car- diovascular diseases or lung cancer.12 Pa- tients with chronic obstructive pulmonary disease (COPD) present with increased se- rum levels of CRP. This may be related di- rectly to COPD and its associated systemic inflammation or occurs secondary to con- comitant ischemic heart disease or smok- ing status. Diagnosis of acute or chronic pulmo- nary embolism is far from easy and there is still lively debate as to which test or score is the most appropriate.13 It was recently found that CRP levels were increased in chronic thromboembolic or primary pul- monary artery hypertension compared with those in control subjects, these lev- els being even a predictor of outcome and response to therapy, thus revealing that systemic inflammation is also involved in these two pulmonary vascular diseases.14 Systemic inflammation of non-meta- static lung cancer was studied extensively while systemic inflammatory manifes- Uvodnik/EDitoRiAl 664 UvoDnik/EDitoRiAl References 1. Jones JM, McGonigle NC, McAnespie M, Cran GW, Graham AN. Plasma fibrinogen and serum C-reactive protein are associated with non-small cell lung cancer. Lung Cancer 2006; 53: 97–101. 2. Heikkilä K, Ebrahim S, Lawlor DA. A systematic review of the association between circulating con- centrations of C reactive protein and cancer. J Epi- demiol Community Health 2007; 61: 824–833. 3. Walsh D., Mahmoud F, Barna B. Assessment of nutritional status and prognosis in advanced can- cer: interleukin-6, C-reactive protein, and the prognostic and inflammatory nutritional index. Support Care Cancer 2003; 11: 60–2. 4. Allin KH, Bojesen SE, Nordestgaard BG. Base- line C–reactive protein is associated with incident cancer and survival in patients with cancer. J Clin Oncol 2009; 27:2217–24. 5. Wilop S, Crysandt M, Bendel M, Mahnken AH, Osieka R, Jost E. Correlation of C-reactive protein with survival and radiographic response to first- line platinum-based chemotherapy in advanced non-small cell lung cancer. Onkologie 2008; 31: 665–70. 6. Ovčariček T, Triller N, Sadikov A, Čufer T. Na- povedna vrednost C-reaktivnega proteina in drugih dejvanikov pri bolnikih z napredovalim nedrobnoceličnim karcinomom pljuč zdravljenih rutinsko v klinični praksi. Zdrav Vestn 2010; 79: 669–76. 7. Fabbri LM, Luppi F, Beghé B, Rabe KF. Complex chronic comorbidities of COPD. Eur Respir J 2008; 1: 204–12. 8. Magnussen H, Watz H Systemic inflammation in chronic obstructive pulmonary disease and asth- ma: relation with comorbidities. Proc Am Thorac Soc 2009; 8:648–51. 9. Barnes PJ, Celli BR Systemic manifestations and comorbidities of COPD. Eur Respir J 2009; 33: 1165–85. 10. Šuškovič S. COPD is not COPD is not allergy. Wien Klin Wochenschr 2009; 121: 289–92. 11. Doehner W, von Haehling S, Anker SD, Lainščak M. Neurohormonal activation and inflammation in chronic cardiopulmonary disease: a brief sys- tematic review. Wien Klin Wochenschr. 2009; 121: 293–6. 12. Lainščak M, Hodoscek LM, Düngen HD, Rauch- haus M, Doehner W, Anker SD, von Haehling S. The burden of chronic obstructive pulmonary disease in patients hospitalized with heart failure. Wien Klin Wochenschr 2009; 121: 309–13. 13. Marin A, Požek I, Eržen R, Košnik M. Improv- ing diagnostics of Pulmonary Embolism with Clinical Prediction Models. Zdrav Vestn 2010: 79: 698–706. 14. Quarck R, Nawrot T, PHD, Meyns B, MD, Del- croix M. C-reactive protein. A new predictor of adverse outcome in pulmonary arterial hyperten- sion J Am Coll Cardiol 2009; 53: 1211–8. tations of metastatic lung cancer were much less studied. Studies as performed by Ovčariček6 are obviously more than welcome, especially since mechanisms by which inflammation influences survival are virtually unknown. Elevated CRP may be a marker of a higher total tumor mass. Another possible explanation is that higher release of CRP has catabolic effects on the host metabolism with significant effects on the survival.11,15 However, some results of this not-so- small study with excellently performed statistical analysis should be regarded care- fully as COPD or heart failures were not reported individually for studied patients. Comorbidities were estimated only by gen- eral comorbidity index, which is a mixture of very divergent pathologies. Patients with COPD or heart failure without clinical signs of infection have usually small yet some- times quite high levels of CRP and most of them are not polycythemic but rather ane- mic. So, those diseases with different basic inflammatory processes could significantly influenced CRP or hemoglobin concentra- tions and probably even prognosis of stud- ied patients. Patients diagnosed with lung cancer wait too long before seeking appropriate medical assistance.16 Perhaps routine mea- surements of CRP could help to identify patients who need accelerated diagnostics. Still, this study6 can be viewed as very interesting and should encourage further similar but preferably prospective and bet- ter designed studies, not only in cancer but also in patients with COPD or heart failure. By improving our knowledge of the role of chronic inflammation in many pulmonary diseases – not only in cancer– new approaches, involving–besides rather nonspecific CRP changes–also other mark- ers of systemic inflammation, which could be more specific for individual pulmonary diseases,17 or with better understanding of the established treatments, may direct fu- ture therapeutic approaches. Certainly we are “not here”–yet. | Systemic inflammation in chronic pulmonary diseases – are we here now? 665 UvoDnik/EDitoRiAl 15. Tan BH, Fearon KC Cachexia: prevalence and impact in medicine. Curr Opin Clin Nutr Metab Care 2008; 11: 400–7. 16. Triller N, Bereš V, Rozman A. Delays in the diag- nosis and treatment of lung cancer: can the length of time between the appearance of symptoms and diagnosis and treatment be shortened? Zdrav Vestn 2010: 79. V tisku. 17. Van der Vlist J, Janssen TW. The potential anti- inflammatory effect of exercise in chronic ob- structive pulmonary disease. Respiration 2010; 2: 160–74.