Editorial
Annals of Internal Medicine
Cystic Fibrosis: Recent Successes Present New Challenges
R
emarkable progress has been made in the care and survival of patients with cystic fibrosis (CF). First described in 1938 as a life-shortening disease characterized by cystic changes of the pancreas, CF is now known to be caused by any of many known mutations in a single gene, resulting in abnormal function of a chloride channel and multisystem disease (1). Before the development of pancreatic enzymes and nutritional supplements, most patients with CF died early from malnutrition related to pancreatic insufficiency. After this early threat became more controllable, progressive pulmonary disease characterized by chronic airway infection, inflammation, bronchiectasis, and respiratory failure emerged as the predominant cause of morbidity and mortality. Today, with supportive therapies targeting mucus obstruction and infections, most patients survive to adulthood and CF is no longer strictly a pediatric disease. Estimates of CF survival help older patients and parents of newly diagnosed infants consider important life choices. Newborn screening, which is now universal across the United States, increases the need for better prognostication. The Cystic Fibrosis Foundation, which was founded by parents of children with the disease, established a patient registry (“CFFPR”) in the 1960s to track care and patient outcomes. In this issue, MacKenzie and colleagues (2) analyze CFFPR data to assess changes in mortality from 2000 to 2010 and to estimate median survival for children born and diagnosed in 2010. They document a progressive increase in survival for patients with CF. If improvements continue at the rate observed between 2000 and 2010, the median projected survival of children born with the disease in 2010 exceeds 50 years. Even if mortality remains at 2010 levels, the median projected survival of newborns diagnosed in 2010 is 37 years, suggesting that more patients with CF will survive into adulthood. The analyses confirmed that survival is better among males and with increasing age at the time of diagnosis. More important, adolescence and young adulthood seem to be particularly vulnerable periods: Annual mortality is low until age 10 years, then increases until age 25 years before reaching a plateau. Reasons for this vulnerability are unknown but could include challenges to treatment adherence, nutritional status, and acquisition of bacterial pathogens associated with more rapid decline in lung function. The long-term effect of recently developed therapies on mortality is also unclear. Mucus obstruction is managed with bronchodilators, mechanical devices that promote airway clearance, and judicious use of systemic antibiotics to treat infectious exacerbations—a critical determinant of short-term morbidity, lung function decline, and progressive airway obstruction. Other therapies further reduce symptoms and prevent acute exacerbations, including inhaled tobramycin (3) and recombinant deoxyribonuclease
to solubilize CF mucus (4). Inhaled hypertonic saline also reduces exacerbation frequency and restores depleted airway surface liquid that seems to be the root cause of mucus obstruction (5, 6). Younger patients in the CFFPR probably had greater exposure to these now-standard CF therapies through most of their growth and development, perhaps leading to better lung function in adolescence. If so, MacKenzie and colleagues’ survival estimates are, as they propose, probably conservative because they are based on data from a large population of patients who received these airway treatments later in life. Indeed, pulmonary morbidity and mortality will probably decrease further with “eradication therapy” approaches to acquisition of pathogens (7) and the new reality of personalized CF medicine, which was signaled by the recent approval of the first CF mutation–specific therapy that targets the molecular defect and was shown to improve lung function and nutrition and decrease exacerbation frequency (8). These findings are worth celebrating. However, continuing to ensure the kind of care that has resulted in a growing number of patients with CF living far into adulthood will not be simple or inexpensive. MacKenzie and colleagues’ predictions are based solely on patients followed at CF Foundation–accredited centers, which provide coordinated, multidisciplinary care from nurses, dietitians, social workers, respiratory therapists, and physicians dedicated to and expert in CF. Furthermore, the interventions that have improved survival result in an increased daily burden of care for patients and their families, including hours of respiratory care. In addition to being at risk for diabetes, osteoporosis, and cancer, adults with CF frequently have depression, anxiety, and psychosocial stress. These complications require additional resources and health care specialists, including endocrinologists, psychologists, psychiatrists, and palliative care specialists. Caring for adults with CF requires a village. The CF care model has evolved to meet these challenges, in most instances by engaging dedicated pediatric and, increasingly, adult pulmonologists to serve as primary medical providers for most elements of care. As such, CF care centers matured to provide patient- and familycentered care ahead of the current “patient-centered medical home” concept being advanced to improve health care more broadly (9). Cystic fibrosis care is primary care. Unfortunately, as with other primary care scenarios, coordination and multifaceted management of the complex medical and social issues of patients with the disease can be time-intensive, stressful, and poorly reimbursed. And, as in primary care (10), recruiting and retaining dedicated and expert physicians to treat CF is challenging. Physician reimbursement is not the only problem. The outpatient care that resulted in today’s brighter future involves designated nursing, so-
298 © 2014 American College of Physicians
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Cystic Fibrosis: Recent Successes Present New Challenges
cial work, nutrition, and respiratory therapy services not frequently supported outside accredited CF care centers. Salary support for these professional outpatient services has been enabled by the requirements for accreditation and the Cystic Fibrosis Foundation funding that comes with it. In addition, this model has provided an infrastructure and environment to partner scientists, physician investigators, drug developers, patients, and families, thus enabling the rapid execution of clinical studies and development of the therapeutic approaches reflected in today’s survival. Is a care model sustainable when the health of its population depends largely on funding from a single nongovernmental organization? Will the remarkable community support that has enabled progress in CF care and survival continue in an era when growing proportions of patients are no longer children, for whom it may be easier to solicit donations? If not, we will need to think hard about other solutions because, although survival of patients with CF has improved, many still suffer and die prematurely. We need continued progress to ensure that MacKenzie and colleagues’ projections are, indeed, too conservative. Joseph M. Pilewski, MD University of Pittsburgh Pittsburgh, Pennsylvania Darren B. Taichman, MD, PhD Executive Deputy Editor, Annals of Internal Medicine Disclosures: Disclosures can be viewed at www.acponline.org/authors /icmje/ConflictOfInterestForms.do?msNum⫽M14-1534. Requests for Single Reprints: Joseph M. Pilewski, MD, University of Pittsburgh, Department of Medicine, PACCM Division, NW 628 MUH, 3459 Fifth Avenue, Pittsburgh, PA 15213.
Current author addresses are available at www.annals.org.
www.annals.org
Editorial
Ann Intern Med. 2014;161:298-299. doi:10.7326/M14-1534
References 1. O’Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009;373:1891-904. [PMID: 19403164] doi:10.1016/S0140-6736(09)60327-5 2. MacKenzie T, Gifford AH, Sabadosa KA, Quinton HB, Knapp EA, Goss CH, et al. Longevity of patients with cystic fibrosis in 2000 to 2010 and beyond: survival analysis of the Cystic Fibrosis Foundation Patient Registry. Ann Intern Med. 2014;161:233-41. doi:10.7326/M13-0636 3. Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, WilliamsWarren J, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med. 1999;340:23-30. [PMID: 9878641] 4. Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N Engl J Med. 1994;331:637-42. [PMID: 7503821] 5. Elkins MR, Robinson M, Rose BR, Harbour C, Moriarty CP, Marks GB, et al; National Hypertonic Saline in Cystic Fibrosis (NHSCF) Study Group. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med. 2006;354:229-40. [PMID: 16421364] 6. Donaldson SH, Bennett WD, Zeman KL, Knowles MR, Tarran R, Boucher RC. Mucus clearance and lung function in cystic fibrosis with hypertonic saline. N Engl J Med. 2006;354:241-50. [PMID: 16421365] 7. Treggiari MM, Retsch-Bogart G, Mayer-Hamblett N, Khan U, Kulich M, Kronmal R, et al; Early Pseudomonas Infection Control (EPIC) Investigators. Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis. Arch Pediatr Adolesc Med. 2011;165:847-56. [PMID: 21893650] doi:10.1001/archpediatrics .2011.136 8. Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevı´nek P, et al; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365:1663-72. [PMID: 22047557] doi:10.1056/NEJMoa1105185 9. Jackson GL, Powers BJ, Chatterjee R, Bettger JP, Kemper AR, Hasselblad V, et al. The patient centered medical home. A systematic review. Ann Intern Med. 2013;158:169-78. [PMID: 24779044] doi:10.7326/0003-4819-158-3 -201302050-00579 10. Warm EJ, Goetz C. Too smart for primary care? Ann Intern Med. 2013; 159:709-10. [PMID: 24247675] doi:10.7326/0003-4819-159-10-201311190 -00009
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Annals of Internal Medicine Current Author Addresses: Dr. Pilewski: University of Pittsburgh, De-
partment of Medicine, PACCM Division, NW 628 MUH, 3459 Fifth Avenue, Pittsburgh, PA 15213. Dr. Taichman: American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106.
www.annals.org
19 August 2014 Annals of Internal Medicine Volume 161 • Number 4
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/930674/ by a Tufts University User on 07/30/2017
Annals of Internal Medicine
Cystic Fibrosis: Recent Successes Present New Challenges
R
emarkable progress has been made in the care and survival of patients with cystic fibrosis (CF). First described in 1938 as a life-shortening disease characterized by cystic changes of the pancreas, CF is now known to be caused by any of many known mutations in a single gene, resulting in abnormal function of a chloride channel and multisystem disease (1). Before the development of pancreatic enzymes and nutritional supplements, most patients with CF died early from malnutrition related to pancreatic insufficiency. After this early threat became more controllable, progressive pulmonary disease characterized by chronic airway infection, inflammation, bronchiectasis, and respiratory failure emerged as the predominant cause of morbidity and mortality. Today, with supportive therapies targeting mucus obstruction and infections, most patients survive to adulthood and CF is no longer strictly a pediatric disease. Estimates of CF survival help older patients and parents of newly diagnosed infants consider important life choices. Newborn screening, which is now universal across the United States, increases the need for better prognostication. The Cystic Fibrosis Foundation, which was founded by parents of children with the disease, established a patient registry (“CFFPR”) in the 1960s to track care and patient outcomes. In this issue, MacKenzie and colleagues (2) analyze CFFPR data to assess changes in mortality from 2000 to 2010 and to estimate median survival for children born and diagnosed in 2010. They document a progressive increase in survival for patients with CF. If improvements continue at the rate observed between 2000 and 2010, the median projected survival of children born with the disease in 2010 exceeds 50 years. Even if mortality remains at 2010 levels, the median projected survival of newborns diagnosed in 2010 is 37 years, suggesting that more patients with CF will survive into adulthood. The analyses confirmed that survival is better among males and with increasing age at the time of diagnosis. More important, adolescence and young adulthood seem to be particularly vulnerable periods: Annual mortality is low until age 10 years, then increases until age 25 years before reaching a plateau. Reasons for this vulnerability are unknown but could include challenges to treatment adherence, nutritional status, and acquisition of bacterial pathogens associated with more rapid decline in lung function. The long-term effect of recently developed therapies on mortality is also unclear. Mucus obstruction is managed with bronchodilators, mechanical devices that promote airway clearance, and judicious use of systemic antibiotics to treat infectious exacerbations—a critical determinant of short-term morbidity, lung function decline, and progressive airway obstruction. Other therapies further reduce symptoms and prevent acute exacerbations, including inhaled tobramycin (3) and recombinant deoxyribonuclease
to solubilize CF mucus (4). Inhaled hypertonic saline also reduces exacerbation frequency and restores depleted airway surface liquid that seems to be the root cause of mucus obstruction (5, 6). Younger patients in the CFFPR probably had greater exposure to these now-standard CF therapies through most of their growth and development, perhaps leading to better lung function in adolescence. If so, MacKenzie and colleagues’ survival estimates are, as they propose, probably conservative because they are based on data from a large population of patients who received these airway treatments later in life. Indeed, pulmonary morbidity and mortality will probably decrease further with “eradication therapy” approaches to acquisition of pathogens (7) and the new reality of personalized CF medicine, which was signaled by the recent approval of the first CF mutation–specific therapy that targets the molecular defect and was shown to improve lung function and nutrition and decrease exacerbation frequency (8). These findings are worth celebrating. However, continuing to ensure the kind of care that has resulted in a growing number of patients with CF living far into adulthood will not be simple or inexpensive. MacKenzie and colleagues’ predictions are based solely on patients followed at CF Foundation–accredited centers, which provide coordinated, multidisciplinary care from nurses, dietitians, social workers, respiratory therapists, and physicians dedicated to and expert in CF. Furthermore, the interventions that have improved survival result in an increased daily burden of care for patients and their families, including hours of respiratory care. In addition to being at risk for diabetes, osteoporosis, and cancer, adults with CF frequently have depression, anxiety, and psychosocial stress. These complications require additional resources and health care specialists, including endocrinologists, psychologists, psychiatrists, and palliative care specialists. Caring for adults with CF requires a village. The CF care model has evolved to meet these challenges, in most instances by engaging dedicated pediatric and, increasingly, adult pulmonologists to serve as primary medical providers for most elements of care. As such, CF care centers matured to provide patient- and familycentered care ahead of the current “patient-centered medical home” concept being advanced to improve health care more broadly (9). Cystic fibrosis care is primary care. Unfortunately, as with other primary care scenarios, coordination and multifaceted management of the complex medical and social issues of patients with the disease can be time-intensive, stressful, and poorly reimbursed. And, as in primary care (10), recruiting and retaining dedicated and expert physicians to treat CF is challenging. Physician reimbursement is not the only problem. The outpatient care that resulted in today’s brighter future involves designated nursing, so-
298 © 2014 American College of Physicians
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/930674/ by a Tufts University User on 07/30/2017
Cystic Fibrosis: Recent Successes Present New Challenges
cial work, nutrition, and respiratory therapy services not frequently supported outside accredited CF care centers. Salary support for these professional outpatient services has been enabled by the requirements for accreditation and the Cystic Fibrosis Foundation funding that comes with it. In addition, this model has provided an infrastructure and environment to partner scientists, physician investigators, drug developers, patients, and families, thus enabling the rapid execution of clinical studies and development of the therapeutic approaches reflected in today’s survival. Is a care model sustainable when the health of its population depends largely on funding from a single nongovernmental organization? Will the remarkable community support that has enabled progress in CF care and survival continue in an era when growing proportions of patients are no longer children, for whom it may be easier to solicit donations? If not, we will need to think hard about other solutions because, although survival of patients with CF has improved, many still suffer and die prematurely. We need continued progress to ensure that MacKenzie and colleagues’ projections are, indeed, too conservative. Joseph M. Pilewski, MD University of Pittsburgh Pittsburgh, Pennsylvania Darren B. Taichman, MD, PhD Executive Deputy Editor, Annals of Internal Medicine Disclosures: Disclosures can be viewed at www.acponline.org/authors /icmje/ConflictOfInterestForms.do?msNum⫽M14-1534. Requests for Single Reprints: Joseph M. Pilewski, MD, University of Pittsburgh, Department of Medicine, PACCM Division, NW 628 MUH, 3459 Fifth Avenue, Pittsburgh, PA 15213.
Current author addresses are available at www.annals.org.
www.annals.org
Editorial
Ann Intern Med. 2014;161:298-299. doi:10.7326/M14-1534
References 1. O’Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009;373:1891-904. [PMID: 19403164] doi:10.1016/S0140-6736(09)60327-5 2. MacKenzie T, Gifford AH, Sabadosa KA, Quinton HB, Knapp EA, Goss CH, et al. Longevity of patients with cystic fibrosis in 2000 to 2010 and beyond: survival analysis of the Cystic Fibrosis Foundation Patient Registry. Ann Intern Med. 2014;161:233-41. doi:10.7326/M13-0636 3. Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, WilliamsWarren J, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med. 1999;340:23-30. [PMID: 9878641] 4. Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N Engl J Med. 1994;331:637-42. [PMID: 7503821] 5. Elkins MR, Robinson M, Rose BR, Harbour C, Moriarty CP, Marks GB, et al; National Hypertonic Saline in Cystic Fibrosis (NHSCF) Study Group. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med. 2006;354:229-40. [PMID: 16421364] 6. Donaldson SH, Bennett WD, Zeman KL, Knowles MR, Tarran R, Boucher RC. Mucus clearance and lung function in cystic fibrosis with hypertonic saline. N Engl J Med. 2006;354:241-50. [PMID: 16421365] 7. Treggiari MM, Retsch-Bogart G, Mayer-Hamblett N, Khan U, Kulich M, Kronmal R, et al; Early Pseudomonas Infection Control (EPIC) Investigators. Comparative efficacy and safety of 4 randomized regimens to treat early Pseudomonas aeruginosa infection in children with cystic fibrosis. Arch Pediatr Adolesc Med. 2011;165:847-56. [PMID: 21893650] doi:10.1001/archpediatrics .2011.136 8. Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevı´nek P, et al; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365:1663-72. [PMID: 22047557] doi:10.1056/NEJMoa1105185 9. Jackson GL, Powers BJ, Chatterjee R, Bettger JP, Kemper AR, Hasselblad V, et al. The patient centered medical home. A systematic review. Ann Intern Med. 2013;158:169-78. [PMID: 24779044] doi:10.7326/0003-4819-158-3 -201302050-00579 10. Warm EJ, Goetz C. Too smart for primary care? Ann Intern Med. 2013; 159:709-10. [PMID: 24247675] doi:10.7326/0003-4819-159-10-201311190 -00009
19 August 2014 Annals of Internal Medicine Volume 161 • Number 4 299
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/930674/ by a Tufts University User on 07/30/2017
Annals of Internal Medicine Current Author Addresses: Dr. Pilewski: University of Pittsburgh, De-
partment of Medicine, PACCM Division, NW 628 MUH, 3459 Fifth Avenue, Pittsburgh, PA 15213. Dr. Taichman: American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106.
www.annals.org
19 August 2014 Annals of Internal Medicine Volume 161 • Number 4
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/930674/ by a Tufts University User on 07/30/2017
