Prognosis in Cystic Fibrosis: Trends and Predictors

Abstract

Cystic fibrosis (CF) is a multisystem disease affecting the digestive system, sweat glands, and the reproductive tract, but progressive lung disease continues to be the major cause of morbidity and mortality. Patients develop chronic infection of the respiratory tract with a characteristic array of bacterial flora, leading to progressive respiratory insufficiency and eventual respiratory failure. Birth prevalence and survival in patients with CF in the Netherlands were last investigated over 30 years ago. We showed that the actual birth prevalence of CF in the Netherlands is clearly lower than it was 30 years ago and that survival in CF has dramatically improved. Furthermore, we demonstrated that young children with CF who have acute respiratory failure (ARF) have a good prognosis, but that ARF in adult CF patients is associated with high mortality. There is a wide range in the severity of CF lung disease and survival, with some patients facing death or lung transplantation during childhood while others have very mild disease well into adulthood. Furthermore, some CF patients suffer from complications such as CF-related liver disease (CFRLD) or nasal polyps early in life, whereas others will never develop these complications. A better understanding of risk factors for an adverse pulmonary course and for complications of CF is the basis for early diagnosis, and an important step in targeting populations for early intervention and prophylactic treatments. We showed that in families with 2 or more siblings with CF, younger siblings have a better lung function than their older counterparts, probably due to an earlier age at diagnosis. We also demonstrated that the presence of CFRLD or sinonasal polyps does not negatively influence pulmonary disease in children with CF, and that nasal polyps are even associated with better lung function. Finally, we found that, beside lung function and nutritional status, inflammatory status and P. aeruginosa colonization independently affect aerobic capacity in children and adolescents with CF. Increasing evidence suggests that phenotypic variation in CF can be attributed to genetic variation in genes other than the CFTR gene, the so-called modifier genes. Most of the recently investigated modifier genes are genes that are involved in the control of infection, immunity and inflammation. The majority of studies on modifier genes in CF have included rather small numbers of patients. Furthermore, they are mainly cross-sectional, mostly not replicated, and often show conflicting results. We performed a large single-center modifier gene study in a well-defined population consisting of over 300 CF patients and analyzed data both cross-sectionally and longitudinally. We found that genetic polymorphisms associated with decreased production of mannose-binding lectin, toll-like receptor 4 and interleukin-6 were associated with better lung function. We hypothesize that the decreased production of these proteins leads to a less intense inflammatory response in response to pathogens, and consequently less damage to the airways.