Median Survival in Cystic Fibrosis Soars

Ricki Lewis, PhD

August 20, 2014

Life expectancy for children born and diagnosed with cystic fibrosis (CF) in 2010 is 37 years for females and 40 years for males, according to conservative estimates in a study published online August 19 in the Annals of Internal Medicine.

The estimates are based on survival trends from 2000 to 2010, and the authors note that many factors have contributed to increased life expectancy for people with CF.

The Role of the Registry

Since 1966, the Cystic Fibrosis Foundation Patient Registry has documented the natural history of the disease, including gathering data on approximately 26,000 of the nearly 35,000 individuals with CF in the United States. When the registry began, life expectancy was limited to early childhood, and deaths were more often a result of malnutrition than compromised lung function.

As patients began to live longer, the respiratory component emerged and presented a new therapeutic target. "Preventing or controlling pulmonary exacerbations has contributed to survival," Paul Quinton, PhD, professor of biomedical sciences at the University of California, Riverside, School of Medicine and medical advisor to Cystic Fibrosis Research Inc, told Medscape Medical News. "We have a much better comprehension of the pathogenesis, and are much more cognizant of the need to keep the airways clear." Dr. Quinton has CF.

The registry also tracks success of interventions. These include daily airway clearance exercises, inhaled antibiotics and mucolytics, a high-fat high-calorie diet, and ivacaftor (Kalydeco, Vertex Pharmaceuticals Inc) to correct misfolding of the CF transmembrane conductance regulator (CFTR) protein. In addition, universal newborn screening since 2009 and increasing diagnosis of adults with milder forms of the disease have boosted the number of patients in the registry from 21,000 to 26,000 during the decade beginning in 2000, and they also have led to improved longevity.

The Landscape of CF

Patients in the current study had genotype-confirmed CF and a clinical phenotype. Mortality analysis considered age at diagnosis and death, sex, race or ethnicity, delta F508 deletion mutation status, and year of death.

Between 2000 and 2010, median age of patients enrolled in the database increased from 14.3 to 16.7 years, and adjusted annual mortality decreased by 1.8% (95% confidence interval [CI], 0.5% - 2.7%). Males had a 19% (95% CI, 13% - 24%) lower adjusted risk for death than females. The sex effect could be a result of differences in sex hormones and/or creatinine levels

Projected median survival for individuals born in 2010, assuming constant mortality rate and no further improvements in survival, is 37 years (95% CI, 35 - 39 years) for females and 40 years (95% CI, 39 - 42 years) for males. However, if mortality rate continues to fall at the rate observed from 2000 to 2010, then median survival projection is 54 years (95% CI, 50 - 58 years) in females and 58 years (95% CI, 55 - 60 years) in males.

The researchers also found that nationalized newborn screening has dropped the median age at diagnosis from 6 months to 1 month. The proportion of individuals homozygous for the delta F508 deletion has decreased as more mutations are identified and detected.

A vulnerability during adolescence has also emerged. Until age 10 years, annual mortality is less than 0.5%. Then it spikes before plateauing at age 25 years, at 3% to 4% per year in women and 2% to 3% per year in men. In an accompanying editorial, Joseph M. Pilewski, MD, from the University of Pittsburgh, Pennsylvania, and journal executive deputy editor Darren B. Taichman, MD, PhD, suggest that the age effect could be a result of poor nutrition and adherence to therapies, as well as acquisition of pathogens such as Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus.

Challenges Ahead

The aging population of patients with CF will present clinical challenges, including the effects of decades of taking aminoglycoside antibiotics, microvascular complications from CF-related diabetes, and depression and anxiety.

Comorbidities associated with aging that are more prevalent among people with CF include colon cancer, hypertriglyceridemia, and chronic renal insufficiency.

"Caring for adults with CF requires a village," write the editorialists.

"Pulmonologists, nephrologists, gastroenterologists, and other adult specialists have not been trained to manage the complexity of diseases such as CF," David Whitcomb, MD, PhD, professor of cancer genetics at the University of Pittsburgh, told Medscape Medical News.

However, the adult medical system has had practice treating patients with pediatric-onset diseases. "What we're seeing in CF has been a trend across all pediatric-onset health conditions," Lisa Tuchman MD, MPH, a specialist in adolescent medicine at Children's National Medical Center, told Medscape Medical News, mentioning pediatric cancers, HIV disease, and sickle cell disease.

The study tracked natural history during a decade of great change. More treatments have become available, and older and healthier patients have joined the registry. "The study focuses on the worst cases. The number of people with CFTR-related disorders is likely much larger, but these individuals would benefit from specific treatments that are of value to the most severe cases on an organ-by-organ basis," said Dr. Whitcomb.

The results are conservative. "New treatments are emerging that could cause a huge jump in predicted survival, approaching that of the general population. However, we remain cautiously optimistic because the solution to one problem often causes or uncovers other unanticipated problems. This concern, however, should result in vigilance, rather than discouragement, and spur the relentless pursuit of optimal care," said Dr. Whitcomb.

"All of us think we will keep improving, especially if we have additional success with therapy at the molecular level," added Dr. Quinton.

The Cystic Fibrosis Foundation supported the study. Dr. Pilewski receives funding from CFF Therapeutics and Vertex Pharmaceuticals. Dr. Goss consults for Vertex Pharmaceuticals, Gilead Sciences, and F. Hoffmann-La Roche Ltd. The other authors and commentators have disclosed no relevant financial relationships.

Ann Intern Med. Published online August 19, 2014. Article abstract, Editorial extract

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