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Management of comorbidities in older patients with cystic fibrosis Barry J Plant, Christopher H Goss, William D Plant, Scott C Bell Lancet Respir Med 2013; 1: 164–74 Published Online March 19, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70025-0 See Review pages 137, 148, and 158 Adult Cystic Fibrosis Centre, Department of Respiratory Medicine (B J Plant MD) and Department of Renal Medicine (W D Plant MD), Cork University Hospital, University College Cork, Cork, Ireland; Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA, USA (Prof C H Goss MD); Department of Thoracic Medicine, The Prince Charles Hospital, Brisbane, QLD, Australia (Prof S C Bell MD); and Queensland Children’s Medical Research Institute, Royal Children’s Hospital, Brisbane, QLD, Australia (S C Bell) Correspondence to: Dr Barry J Plant, Adult Cystic Fibrosis Centre, Department of Respiratory Medicine, Cork University Hospital, Wilton, Cork, Ireland [email protected]

Several key advances have been made in the treatment and management of people with cystic fibrosis in the past two decades. Substantial improvements in survival have resulted from the introduction of key drugs, coordinated care packages, improved nutritional support, and the intensive use of antibiotics. The age profile of people with cystic fibrosis has changed greatly during this time—some countries now have more adult than paediatric patients with the disease. With their increasing age and more advanced lung disease, several important sequelae (both pulmonary and extrapulmonary) occur in these adult patients including pulmonary disease, cystic fibrosis-related diabetes, renal disease, metabolic bone disease, cancers, drug allergies and toxic effects, and complications associated with lung transplantation.

Introduction Several key advances have been made in the care of people with cystic fibrosis in the past two decades, resulting in substantial improvements in survival. For example, in the USA the median survival increased from 28 years in 1990 to 38 years in 2010.1,2 This improvement is probably the result of the introduction of key drugs (eg, nebulised tobramycin, colistin), coordinated care packages, improved nutritional support, and the intense use of antibiotics.3,4 The effects of treatments aimed at the basic defect of cystic fibrosis,5,6 of recently approved pulmonary therapies such as nebulised aztreonam and dry powder mannitol for inhalation,7,8 and of eradication protocols for Pseudomonas aeruginosa9 are still unknown, but are likely to be substantial. Improved survival has led to an increasing proportion of adults with cystic fibrosis (figure 1); some countries now have more adult than paediatric patients.10 As a result, the adult population with severe lung disease continues to increase, both in absolute terms and as a proportion of patients with cystic fibrosis (figure 2).11

The ageing lung in cystic fibrosis With their increasing age and more advanced lung disease (figure 3), several important sequelae occur in adult patients with cystic fibrosis, including massive haemoptysis,12 pneumothoraces,13 and pulmonary exacerbations. The proportion of people with cystic fibrosis who need intravenous antibiotics for pulmonary exacerbation each year increases with increasing age (from 23% in patients younger than 6 years to 63% in those older than 18 years).14 The ageing lungs of people with cystic fibrosis become host to increasingly resistant bacteria. Registry data have shown a rise in multiresistant strains of P aeruginosa and meticillin-resistant Staphylococcus aureus, with an associated negative effect on clinical outcome.15,16 As well as increasing age, another major change to the patient population in recent decades has been an increase in the number of patients with a non-classic disease phenotype (diagnosed by genotyping of cystic fibrosis transmembrane regulator [CFTR] mutations) that is milder than the classic form of the disease. 164

Rodman and colleagues17 analysed the genotypes and phenotypes of 55 patients with cystic fibrosis aged 40 years or older between 1992 and 2004 and identified two different populations: those diagnosed early (median age at diagnosis 2 years) and late (median age at diagnosis 49 years). The late-diagnosis group were predominantly female and had a lower prevalence of pancreatic insufficiency, a lower proportion of patients with chronic P aeruginosa infection, and a greater proportion infected with non-tuberculous mycobacterium than did the early-diagnosis group. In a subsequent study,18 the investigators showed that patients diagnosed as adults were more likely to have a non-classic cystic fibrosis phenotype than those diagnosed in childhood. At age 40 years, adult-diagnosed patients had higher lung function than those diagnosed in childhood; however, annual average rate of decline was the same in both groups after age 40 years. The effect of sex on survival differed by age of diagnosis—women diagnosed in adulthood survived longer than men, whereas men survived longer than women among patients diagnosed in childhood.18 Long-term survivors (older than 40 years) in a UK study10,19 were less likely to be homozygous for CFTR ΔF508 than were those who did not survive to age 40 years, and were more likely to have colonisation with P aeruginosa and allergic bronchopulmonary aspergillosis. These studies show that long-term survivors are a heterogeneous group. Survival in patients with cystic fibrosis who have severe lung disease is also improving, as was shown in a study20 of patients with a forced expiratory volume in 1 s (FEV1) of less than 30% of predicted; median survival without lung transplant improved from 1·2 years in a 1991–92 cohort to 5·3 years in a 2002–03 cohort. Despite such improvements, respiratory failure remains the most common cause of death in patients with cystic fibrosis. Noninvasive ventilation is emerging as a treatment for respiratory failure in both acute and chronic settings.21,22 Longevity in patients with cystic fibrosis has been associated with newly recognised or evolving complications, which not only add to the challenges of health– care provision for adult patients, but also suggest www.thelancet.com/respiratory Vol 1 April 2013

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45

Normal function to mild impairment Moderate impairment Severe impairment

100

1990 2010

40 80

30 Proportion of patients (%)

Proportion of patients (%)

35

25 20 15 10

60

40

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30+

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Figure 1: Proportions patients with cystic fibrosis in the USA by age, 1990 and 2010 Data are from the Cystic Fibrosis Foundation patient registry data report 2010.2

important messages for the delivery of care to younger patients with the disease who are likely to live much longer than anticipated when care is started early in life. Many of the complications of cystic fibrosis and its treatment have important implications for clinical status and quality of life (panel).

Cystic fibrosis-related diabetes Cystic fibrosis-related diabetes (CFRD) is a common and serious complication,23 and its prevalence increases with increasing age.23,24 Less than 5% of children with cystic fibrosis have diabetes mellitus, but this proportion increases to 20% in adolescence. Prevalence then increases steadily with age, especially during the fourth decade of life (and particularly in women), with 40–50% of patients older than 40 years affected.24 The primary defect is insulin deficiency due to destruction of pancreatic β cells,23,25–27 further mediated by various oxidant stresses.28 The reason why all older patients are not affected is unknown; however, CFRD is more common in patients with severe cystic-fibrosis gene mutations and pancreatic insufficiency. Insulin resistance is less important, but can contribute to hyperglycaemia during periods of clinical instability.23,29 The results of a single-centre study24 of more than 800 patients with cystic fibrosis during a 15-year interval show changes over time in incidence, prevalence, and mortality of CFRD. Incidence ranged from 2·7 to 4·0 cases per 100 patient-years. For the period 1992–97, mortality was 6·7 (SE 1·3) deaths per 100 patient-years; by the period 2003–08, it had fallen to 3·5 (0·3) deaths per 100 patient-years. Mortality in these patients, however, remained substantially higher than in cystic fibrosis patients without CFRD during the same time period, which was 1·0 (0·2) deaths per 100 patient-years. www.thelancet.com/respiratory Vol 1 April 2013

0

6–17

18–29

30+

Age (years)

Figure 2: Severity of lung function impairment by age group in patients with cystic fibrosis in the USA, 2011 Normal function to mild impairment is defined as forced expiratory volume in 1 s (FEV1) that is 70% of predicted or higher; moderate impairment is FEV1 of 40–69% of predicted; severe impairment is FEV1 of less than 40% of predicted. Reproduced from reference 11, by permission of the Cystic Fibrosis Foundation.

As well as increased mortality, CFRD can be associated with adverse effects on pulmonary function and nutritional status, and an increase in frequency of hospital admissions.23,24,30 Whether CFRD is more likely to occur in patients with worse pulmonary disease remains unknown, as does whether or not CFRD contributes to worsening of pulmonary function.23,30,31 Miller and colleagues32 followed patients with CFRD matched with other (non-diabetic) cystic fibrosis patients who had similar disease severity for four years, and reported that the diabetic patients had a more rapid reduction of pulmonary function than the non-diabetic patients (although the difference was only seen in women). CFRD incorporates a continuum of disorders of glucose tolerance including impaired glucose tolerance, indeterminate glycaemia (in which plasma glucose is raised during the oral glucose tolerance test), and CFRD with and without fasting hyperglycaemia. A consensus statement from American Diabetes Association, the US Cystic Fibrosis Foundation, and the US Pediatric Endocrine Society31 has lessened the focus on fasting glycaemia status, since recent data have suggested that treatment of CFRD even in the absence of fasting hyperglycaemia is associated with improved clinical outcomes, including pulmonary function and body-mass index (BMI).33 Ketoacidosis is very rare. How best to screen for, diagnose, and decide when to start treatment for CFRD is unclear.23,31,34 Traditional screening strategies for diabetes in patients without cystic fibrosis are designed to detect the extent of hyperglycaemia at which metabolic symptoms and the risks for 165

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Figure 3: From chest radiograph of a patient with end-stage bronchiectasis with an upper-lobe-predominant distribution

microvascular complications first develop. This approach might not be appropriate for detection of CFRD, because the injurious effects of the disorder could occur well before traditional diagnostic criteria are met. In stable outpatients with cystic fibrosis, annual screening with a 2-hour, 75-gram oral glucose tolerance test is recommended for patients aged 10 years and older.31 This recommendation needs to be further emphasised, since one US registry shows that only about 30% of patients in this age group were tested in 2011 (although the proportion had increased from 25% in 2010).11 During acute cystic fibrosis exacerbation or treatment with oral corticosteroids, fasting hyperglycaemia or raised 2-h postprandial plasma glucose that persists for 48 h should also be viewed as diagnostic of CFRD.31 In the early stages of CFRD, glycosylated haemoglobin and fasting plasma glucose concentrations are not sensitive enough markers for detection.23,31,34 A multidisciplinary team should provide treatment with a focus on adequate caloric intake, regular exercise, and early insulin. Insulin is usually prescribed as a basalbolus delivery regimen with targets similar to those recommended for diabetic patients without cystic fibrosis.31 Insulin has been shown to reverse weight loss in early CFRD; however, its effect on pulmonary function is unknown.33

Other vascular problems Microvascular complications do not develop until CFRD has been present for 5–10 years, and not usually before fasting hyperglycaemia is evident. Neuropathy occurs in 166

about 50% and retinopathy, nephropathy, or both in about 15% of those who have had CFRD for more than 10 years.35 Macrovascular complications, including coronary artery disease, have been reported infrequently.36 As survival continues to improve, such complications might be seen more frequently in the coming decades. Patients with inflammatory lung disease have increased cardiovascular risk and premature vascular ageing.37 In a study of adults with cystic fibrosis,38 patients had an increased augmentation index (a measure of vascular stiffness) compared with age-matched controls, and this measure increased with age and was higher in patients with CFRD. In populations without cystic fibrosis, raised total-to-HDL cholesterol ratio is an independent predictor of cardiovascular disease.39 A 2-year, single-centre study36 in adults with cystic fibrosis showed raised lipid profiles in some of the patients. Raised lipids were noted in 43% of pancreatic-sufficient and 24% of pancreatic-insufficient patients, and were more likely in those with a high BMI. In all patients, total cholesterol and LDL cholesterol increased substantially with age, which suggests a need for improved awareness of this association and routine screening in older patients with cystic fibrosis. Long-term venous access devices are often needed for the delivery of intravenous antibiotic treatment in patients with cystic fibrosis who require several courses. Several reports have described catastrophic complications from such devices, which can cause difficulties for the delivery of care; the devices might need to be removed and continued vascular access can prove difficult. 40–43

Kidney disease Acute kidney injury is fairly common in cystic fibrosis, with an estimated incidence of 4·6–10·1 cases per 10 000 children with the disease per year.44 This incidence is 100 times higher than the incidence of acute kidney injury in children in the general population (0·075 cases per 10 000 children per year).45 Patients with cystic fibrosis who have acute kidney injuries are much more likely to have been exposed to a recent course of intravenous aminoglycosides, to have another risk factor for acute kidney injury (pre-existing renal disease, dehydration, or the use of a nephrotoxic drug—eg, non-steroidal antiinflammatory drugs),45 or to have sustained a pulmonary exacerbation than are the population of patients with cystic fibrosis in general. Acute kidney injury should be treated in the standard way, but with fastidious care in aminoglycoside dosage and monitoring, and correction or withdrawal of other risk factors. CFTR malfunction leads to a defect in the proximal tubular handling of lowmolecular-weight proteins, which causes low-molecularweight proteinuria.46 This malfunction therefore enhances renal aminoglycoside excretion in patients with cystic fibrosis. Electrolyte abnormalities are also seen, with chloride depletion and associated metabolic alkalosis prominent. Hyponatraemia, hypokalaemia, and profound extracellular-fluid volume depletion can also www.thelancet.com/respiratory Vol 1 April 2013

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Panel: Comorbidities in older patients with cystic fibrosis Pulmonary disease • Older patients could have the classic cystic fibrosis phenotype (diagnosed at an early age) or a milder presentation with late diagnosis • Severity increases with age • Multidrug-resistant infections, pneumothoraces, and haemoptysis increase in prevalence in the older patient and are associated with reduced survival Cystic fibrosis-related diabetes (CFRD) • Increases with increasing age (affects about 50% of patients older than 40 years) • Associated with increased severity of cystic fibrosis-related lung disease • Associated with reduced survival, diminished nutritional status, and increased loss of lung function • Microvascular complications can develop after 5–10 years of CFRD with fasting hyperglycaemia evident Renal disease • Acute kidney injury is associated with recent treatment of pulmonary exacerbations (including intravenous aminoglycosides, use of non-steroidal anti-inflammatory drugs, and extracellular fluid volume depletion) • Chronic kidney disease is rare, but becomes more common with increasing age • Risk factors for chronic kidney disease include lung transplantation, CFRD, and frequent episodes of acute kidney injury Metabolic bone disease • Associated with severe lung disease, poor nutrition, specific CFTR genotypes, and physical inactivity • Can be associated with increased fracture risk

occur.47 Such electrolyte abnormalities can in some cases be the initial presentation that leads to an adult-age diagnosis of cystic fibrosis.48 Chronic kidney disease is also a complication that becomes more common with increasing age. In a study49 of 112 children with cystic fibrosis, decreased renal function was not evident. However, chronic kidney disease can occur in adults with cystic fibrosis.50 Investigators of a large, population registry-based, adultcohort study of roughly 12 000 patients, followed up for a median of 4 years, reported an overall annual prevalence of stage 3 chronic kidney disease (estimated glomerular filtration rate [eGFR] less than 60 mL/min/1·73 m²) of 2·3%. Prevalence doubled with every additional 10 years of age, and was increased in patients who had CFRD, who had undergone organ transplantation, or who had a previous diagnosis of acute kidney injury. Although the question is much debated,51,52 in one study53 cumulative exposure to aminoglycosides over 4 years did not lead to an increased risk of chronic kidney disease. Longer-term reduction in kidney function might be more likely to be www.thelancet.com/respiratory Vol 1 April 2013

• Prevalence could be decreasing • Screening is recommended for all adults with cystic fibrosis Cancer • Although still uncommon, adult patients with cystic fibrosis have a higher prevalence of gastrointestinal cancer than do age-matched controls • The biological mechanism for this association is unclear • Optimum screening protocols have not been established • Whether risk of non-gastrointestinal cancers is also increased in patients with cystic fibrosis is unclear • Lifetime exposure to diagnostic radiation is becoming an important consideration as median survival increases Drug allergies and toxic effects • Risk factors for β-lactam allergy include increasing age, severity of lung disease, and lifetime cumulative exposure to antibiotics • Desensitisation can allow the safe administration of antibiotics in allergic patients • Aminoglycoside toxic effects (including acute kidney injury and otovestibular toxic effects) are related to cumulative exposure Complications of lung transplantation • Age at transplantation is increasing • Comorbidities are often challenging after transplantation • Chronic kidney disease and CFRD are common post-transplantation complications • Some multiresistant organisms are associated with poor outcomes after transplantation • Cancer is fairly common in long-term survivors who have undergone lung transplantation

related to recurrent episodes of acute kidney injury rather than to cumulative antibiotic exposure.51 Chronic kidney disease in patients with cystic fibrosis is associated with increasing age, female sex, and poor pulmonary function.53 Once stage 3 chronic kidney disease is established it is typically progressive—53% of cases progress to stage 4 (eGFR less than 30 mL/min/1·73 m²) and 44% to stage 5 (eGFR less than 15 mL/min/1·73 m²).53 However, the prevalence of advanced chronic kidney disease remains low, at 0·7% for stage 4 disease and 0·6% for stage 5 disease. Hypertension is fairly rare in patients with cystic fibrosis.38 It is seen more frequently in patients with CFRD and those who have received a lung transplant.31 In patients with CFRD and hypertension, guidelines suggest treatment modalities similar to those for other patients with diabetes mellitus, with the exception that dietary salt restriction is not as necessary and is potentially harmful.31 Although transient microalbuminuria does not occur more frequently than in the general population,54 permanent microalbuminuria occurs in more than 6% of 167

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patients with cystic fibrosis, most of whom either have CFRD or have received an organ transplant. The results of one study35 suggest that permanent microalbuminuria is very rare unless patients have had CFRD for more than 10 years and have fasting hyperglycaemia.35 14% of such patients are affected, which is a much smaller proportion than in diabetic patients without cystic fibrosis. Proteinuria is rare and is almost always caused by an established underlying kidney disease. Renal biopsy should be regarded as a useful diagnostic approach in patients with cystic fibrosis. It can be used to identify a wide range of pathologies, including diabetic nephropathy,55 diffuse and nodular glomerulosclerosis,55,56 toxic effects of non-steroidal anti-inflammatory drugs,55 renal amyloidosis,55 nephrocalcinosis,55 IgA nephropathy,55 and fibrillary glomerulopathy.55 After lung transplantation it can be used to identify IgA nephropathy, pigmented tubulopathy, and toxic effects of calcineurinphosphatase inhibitors.56 The presence of nodular glomerulosclerosis could be a cystic fibrosis-specific nephropathy that occurs in older patients with the disease who do not have CFRD as a response to chronic inflammatory stimuli and oxidative stresses (figure 4).57,58 Kidney stones occur in 3–6% of people with cystic fibrosis every year, which is three times as many as are seen in age-matched controls.59 Kidney stones are regarded as multifactorial in origin, with factors including decreased urine output, hypocitraturia, and absorptive hyperoxaluria. Hyperoxaluria is thought to be caused by a A

B

C

D

Figure 4: Nodular glomerulosclerosis in a non-diabetic patient with cystic fibrosis The patient presented with proteinuria and progressive chronic kidney disease. (A) Haematoxylin-stained and eosin-stained section showing increased mesangial matrix with Kimmelstiel–Wilson-like mesangial nodules. (B) Periodic acid-Schiff-positive stain of the nodular glomerulosclerotic lesion. (C) Periodic acid methenamine silverstained section showing the nodular lesion. (D) Electron microscopy of glomerulus showing absence of amyloid fibrils and absence of evidence for monoclonal immunoglobulin deposition disease and fibrillary glomerulonephritis. Reproduced from reference 58, by permission of the author.

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reduction in enteric colonisation by Oxalobacter formigenes,60 an oxalate-degrading bacterium, as a result of recurrent and long-term antibiotic use. A high fluid intake combined with a low-oxalate and high-calcium diet is appropriate for patients with kidney stones.

Metabolic bone disease Osteopenia and osteoporosis are becoming more important as the absolute numbers of adults with cystic fibrosis increase.61 Causes are multifactorial and include exocrine pancreatic insufficiency; vitamin D, vitamin K, and calcium insufficiency; inadequate accrual of peak bone mass in adolescence and young adulthood;62 recurrent infection with cytokine-stimulated, osteoclastmediated bone resorption; physical inactivity; and CFRD.61,63,64 A CFTR-mediated component might also be implicated.65,66 In a meta-analysis,67 pooled prevalence of osteoporosis was 23·5% (95% CI 16·6–31·0) and of osteopenia was 38·0% (95% CI 28·2–48·3) in adults with cystic fibrosis. However, prevalence seems to be decreasing. A large, single-centre study68,69 of 114 adolescent and adult patients showed a significant reduction in the prevalence of osteoporosis from 18·8% to 5·8%, and of osteopenia from 48% to 34·5% between 1999 and 2011 in response to improved treatment of cystic fibrosis.68,69 Several cross-sectional studies have shown an increase in the incidence of fractures, with vertebral fractures being the most common (pooled prevalence 23·5%, 95% CI 16·6–31·0)—these were almost exclusively thoracic, which emphasises the importance of screening and treatment for osteoporosis.67 Rib fractures and kyphosis are also important in adults with cystic fibrosis, because these affect the effectiveness of chest physiotherapy and potentially contribute to the development of pulmonary exacerbations.70 The finding that the prevalence of vertebral fractures decreased with age could mean that this problem is less relevant in adults with cystic fibrosis who survive past 30 years. Guidelines to improve bone health in patients with cystic fibrosis recommend that adults should have a baseline bone mineral density assessment at age 18 years.70 A combination of preventive strategies are recommended, including vitamin D, vitamin K, and calcium supplementation; strategies to optimise nutritional status; tight glycaemic control for patients with CFRD; aggressive treatment of pulmonary exacerbations; and exercise (including weight-bearing regimens). Bisphosphonate treatment remains the preferred therapeutic strategy for those with a T score (the number of standard deviations above or below the mean for a healthy 30-year-old adult of the same sex and ethnicity as the patient) or Z score (the number of standard deviations above or below the mean for the patient’s age, sex, and ethnicity) of –2 or less, or of –1 or less if a fragility fracture has occurred in a patient awaiting transplant, and for those with accelerated loss of bone mineral density of more than 3–5% per year.61,70 www.thelancet.com/respiratory Vol 1 April 2013

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Drug allergies and toxic effects Antibiotic allergies are a common challenge in the management of patients with cystic fibrosis. Several studies71–73 have shown that allergies complicate treatment in adults with the disease. In a retrospective survey from Australia,72 risk factors for β-lactam allergy included increasing age, severity of lung disease, and cumulative exposure to antibiotics. Although overall 36% of patients in the study had a β-lactam allergy, the burden of allergy was substantially higher in older patients; in patients aged 25 years and older, 70% had at least one β-lactam allergy, whereas in patients younger than 25 years only 5% had an allergy (p=0·015). Drugs from other classes, such as sulfamethoxazole and trimethoprim, can also be associated with allergic reactions. In view of the emergence of multiresistant infections and the narrow range of antibiotics available, antibiotic allergy can further limit clinical choice and compromise the successful treatment of pulmonary infection in cystic fibrosis. Desensitisation protocols can allow safe and successful use of intravenous antibiotics in patients with allergies; however, such procedures are resource intensive, need repeated application, and are not uniformly successful.74,75 With increasingly aggressive protocols for the treatment of infection in young patients and the increasing survival of people with cystic fibrosis, allergies are likely to increase in parallel with further increases in the cumulative antibiotic exposure. Inhalational antibiotics can also be associated with intolerance, especially in patients with severe airflow obstruction, which can result in acute wheeze, cough, haemoptysis, and even bronchospasm. Long-term use of systemic aminoglycosides, in addition to acute kidney injury, can cause otovestibular toxic effects, which are quite common in adults with cystic fibrosis.76 Overall, balancing the need for effective treatment of pulmonary exacerbations and the potential for druginduced toxic effects is a growing therapeutic dilemma.53

Cancer In healthy populations, the risk of malignant disease with increasing age is well established.77 In people with cystic fibrosis, early studies showed an increased risk of gastrointestinal cancer compared with healthy populations, and that the risk also increases with increasing age in those with cystic fibrosis.78–80 As a measure of relative risk, studies have used standardised incidence ratios (SIRs), which are the ratios of reported compared with expected cancers in a cohort, extrapolated from general population data. In a large study81 based on data from a US patient registry between 1990 and 1999, non-transplanted patients with cystic fibrosis had a significantly increased risk of cancers in the gastrointestinal tract (23·0 reported vs 4·5 expected; SIR 5·1, 95% CI 3·2–7·6). The increased risk was associated with cancers detected in the small intestine (SIR 24·8, 95% CI 6·8–63·6), colon (SIR 7·4, 95% CI 3·7–13·2), and www.thelancet.com/respiratory Vol 1 April 2013

biliary tract (SIR 39·0, 95% CI 8·0–114·0). Mean age of diagnosis was 39 years, with only one out of 23 cancers diagnosed before age 20 years. The importance of gastrointestinal cancer in ageing patients with cystic fibrosis was further shown by an absolute excess risk of 153·2 per 100 000 patients per year for those aged 40–49 years and 400·8 per 100 000 patients per year for those older than 50 years. Previous gastrointestinal disorders were not associated with an increased risk of gastrointestinal cancer in cystic fibrosis. In ageing populations, anaemia can sometimes be a sign of gastrointestinal cancer; however, anaemia is common in patients with cystic fibrosis, becomes more common with age and reduced lung function, and can be associated with iron deficiency.82,83 Assessment of anaemia is complex because of the underlying inflammatory nature of cystic fibrosis, which complicates the interpretation of iron status. The decision of when and how to investigate anaemia is a difficult clinical question in patients with cystic fibrosis.84 Features that might suggest an increased probability of gastrointestinal cancer include a history of failure to thrive and homozygosity for the CFTR ΔF508 mutation. Increased risk of gastrointestinal cancer was also seen in the posttransplant cystic fibrosis cohort of the US registry study81 (gastrointestinal cancer SIR 21·0, 95% CI 5·8–54·2), and this finding is lent further support by the results of a study85 at a single transplant centre, in which the incidence of colon cancer in patients with cystic fibrosis was reported to be 5·7%, compared with 0·3% in postlung transplant patients who do not have the disease. Screening by colonoscopy identified polyps in 35% of post-transplant patients with cystic fibrosis, which suggests that screening could be useful in this cohort. Data about whether cystic fibrosis confers an increased risk of non-gastrointestinal cancers are conflicting.80,81,86 The causes of cancer in cystic fibrosis are unclear, with several potential factors identified.87,88 One possibility, in view of the location of malignant disease in the gastrointestinal tract, is the potential role of iatrogenic radiation. In a study89 from Ireland in which 17 years (2240 person-years) of data were assessed, the mean annual cumulative effective dose of radiation per patient increased consecutively from 0·39 mSv to 0·47 mSv to 1·67 mSv over three equal tertiles from 1992 to 2009. In parallel, CT scanning per patient had increased by 5·9 times during this period, with thoracic imaging accounting for 47% and abdominopelvic imaging for 43% of the cumulative effective dose. With increased survival, the burden of repeated radiographic investigations will need to be considered, and low-dose CT imaging should be adopted wherever possible.90,91

Non-malignant gastrointestinal changes Severe cystic fibrosis-related liver disease, which affects roughly 5% of patients with the disease, is usually diagnosed between ages 10 and 20 years and often results 169

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in portal hypertension. Although severity can increase with age, decompensated liver failure does not seem to be overrepresented in older adult patients.10 Chronic constipation is common in patients with cystic fibrosis, although little data is available to suggest that its prevalence increases with increasing age. An early study92 showed an increased burden of Clostridium difficile infection in patients with cystic fibrosis (36% of clinically stable adults with cystic fibrosis compared with 17% of respiratory patients without the disease and 3% of healthy controls). Helicobacter pylori is less prevalent in patients with cystic fibrosis than in healthy controls,93 and the absence of O formigenes in the gastrointestinal tract predisposes to hyperoxaluria.60 Further changes in the gut microflora have been shown in a whole genome study,94 in which reduced temporal stability and species richness were seen in patients with cystic fibrosis compared with their siblings. With data emerging that emphasise the effect that gastrointestinal mucosal responses have on immune function, modification of such responses could potentially become more important with age.95 The changes seen in gut microflora suggest a possible future role for probiotics in the treatment of cystic fibrosis. So far, the results of two small studies96,97 have suggested benefits from this approach.

Lung transplantation Lung transplantation is an important modality of care for patients with end-stage cystic fibrosis pulmonary disease. Since 2005, 150–210 patients per year have received lung transplants in the USA.2 Improving median survival and lung function in early adult life (median FEV1 at age 18 years was 67% in 2000 and 78% in 2010) and prolonged lifespan in patients with advanced lung disease are likely to result in increased age at which patients with cystic fibrosis receive lung transplants.2,20 For example, in Australia the mean age of transplant recipients has increased by 1 year every 5 years since 1995. From 1995 to 1999, the mean age of transplant recipients was 25·6 years; by the period 2010–12 the mean age had increased to 28·3 years (Bell SC, unpublished). Furthermore, more than 25% of patients were aged 35 years or older at the time of transplant. Similar changes have taken place in the USA; mean age at the time of lung transplantation was 27·6 years in 2000, compared with 30·2 years in 2010. In 2009–10, 43·7% of lung transplant recipients were older than 30 years and 18·8% were older than 40 years (Marshall B, personal communication). As noted previously, disease-associated and treatmentassociated comorbidities, including CFRD, chronic kidney disease, and antibiotic allergies, increase with the increasing age of the cystic fibrosis population. Thus, any increase in the age of the transplant recipients is likely to present further challenges for care after transplantation. CFRD is present in 40–50% of patients with cystic fibrosis at the time of transplant assessment and develops after transplantation in roughly an additional 20% of 170

patients.98–101 The effect of pretransplant diabetes on outcomes after transplantation is unclear. In some studies99,102 increased mortality, infection, and rejectionrelated hospital admissions have been reported in patients with CFRD diagnosed before transplantation. On the other hand, data from a single centre100,101 has shown better 1-year and 5-year survival in patients who had CFRD before transplantation compared with those who did not. Renal dysfunction is common in the early posttransplant recovery phase. Causes are multifactorial,103 and include tubulointerstitial lesions due to oxalate nephropathy. Such renal lesions are encountered very rarely in other patient groups, but have been identified in 33% of patients with cystic fibrosis who have had biopsy samples taken for early renal dysfunction after lung transplantation.56 Chronic kidney disease develops in a substantial proportion of lung transplant recipients, some of whom progress to end-stage kidney disease, necessitating long-term dialysis or renal transplantation. In a study104 of almost 1000 adult lung transplant recipients with cystic fibrosis, about one in three developed stage 3 chronic kidney disease (eGFR less than 60 mL/min/1·73 m²) in the first 2 years after transplantation. Older patients, women, patients with insulin-treated CFRD, and those with a low pretransplant eGFR (60–90 mL/min/1·73 m²) were at increased risk of developing chronic kidney disease.53 The investigators of the study104 were unable to establish to what extent longterm use of aminoglycosides before transplantation affected renal function after transplantation. Calcineurinphosphatase inhibitors, hypertension, and CFRD have been associated with chronic kidney disease after transplantation.50 This association emphasises the interdependence of diabetes and renal function in older people with cystic fibrosis, especially in the setting of transplantation. Antibiotic-resistant bacteria including multiresistant P aeruginosa, meticillin-resistant S aureus, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Burkholderia cenocepacia are more common in adult patients than in paediatric patients with cystic fibrosis.2 B cenocepacia has a major effect on survival after transplantation and in most centres is a contraindication for the procedure.105 Lung transplantation for patients with other Burkholderia cepacia complex species results in survival outcomes similar to those in patients without the bacteria.106 In one study107 survival after lung transplantation was reduced in patients with multiresistant P aeruginosa, although other studies108,109 did not report an adverse effect on survival. Meticillin-resistant S aureus, S maltophilia, and A xylosoxidans do not have any known adverse effects on transplantation outcomes.110 The increased burdens of allergic bronchopulmonary aspergillosis and non-tuberculous mycobacterial infection in older people with cystic fibrosis can cause difficulties after transplantation.10,17 Allergic bronchopulmonary www.thelancet.com/respiratory Vol 1 April 2013

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aspergillosis is not a contraindication for transplant per se, but the long-term use of systemic corticosteroids can add to postoperative complications such as reduced bone density and poor glycaemic control. Mycobacterium abscessus is innately resistant to antibiotics and can recur within the lung and at distant sites, with a propensity to cause abscess formation, which necessitates very intensive and protracted treatment.111–113 Whether M abscessus should be a contraindication is uncertain. Mycobacterium avium complex, which is also fairly common in older people with cystic fibrosis, does not seem to be of much concern after transplantation.112,113 Cancer is a fairly common complication of long-term transplant survivors and is likely to be related to loss of immune surveillance in the setting of long-term immunosuppressive therapies. As noted previously, gastrointestinal cancers are common, particularly in older patients.85 The best strategy for screening, particularly for bowel cancer, at the time of transplant assessment and after transplantation is unclear; however, with the increasing age of the cystic fibrosis population and improving post-transplant survival, malignant disease is likely to emerge as an even greater challenge for post-transplant care in the future. Metabolic bone disease in post-transplant patients necessitates surveillance with regular dual energy x-ray absorptiometry and treatment with bisphosphonates for patients with osteoporosis.114 Disease-related and treatment-related complications of cystic fibrosis in parallel with improved survival of patients with advanced lung disease provide the potential for contradictions in the timing of assessment for transplant. On one hand, the continued aggressive treatment of chronic lung disease might contribute to longer life and delay the need for transplantation; however, such treatments can result in complex challenges (including increased treatment-related morbidity in post-transplant care). This dilemma is likely to continue with further increases in the age of the cystic fibrosis population.

Conclusions The combination of the rapidly increasing size of the adult population with cystic fibrosis and the associated complications (panel) in these patients creates substantial challenges for the delivery of care. Training for physicians and other members of the multidisciplinary teams that care for adult patients with cystic fibrosis has often been uncoordinated and ad hoc. As such, a joint task force has been formed by the European Respiratory Society and the European Cystic Fibrosis Society (ECFS); this task force draws on membership from across Europe and includes delegates from North America and Australia. The aims of the project are to survey available services to model future needs and to develop a curriculum for clinicians for the care of adults with the disease. A consensus statement will be produced that will complement the present review of www.thelancet.com/respiratory Vol 1 April 2013

Search strategy and selection criteria We searched Medline (Jan 1, 1966, to Dec 31, 2012) and Embase (Jan 1, 1974, to Dec 31, 2012) using the search terms “cystic fibrosis” or “CF” or “lung transplantation” or “ageing” in combination with the terms “complications” or “consequences” or “survival” or “epidemiology” or “prognosis”. We largely selected publications from the past 5 years, but did not exclude widely referenced and highly regarded older publications. We also searched the reference lists of articles identified by this search strategy and selected those we judged to be relevant. Review articles and registry reports and data are cited to provide readers with relevant background material. Articles published in German, French, English, Spanish, and Dutch were included.

European standards of cystic fibrosis care currently being undertaken by the ECFS, which is focused on facilities, resources, and staffing to support cystic fibrosis care into the next decade. Substantial differences in patient outcomes in Europe are important drivers for this initiative.115 Both of these groups are expected to report in late 2013. Finally, health-service funding bodies and governments are often unaware of the complexity and demands of providing care to the increasing population of older patients with cystic fibrosis. Advocacy to ensure continued investment in resources for cystic fibrosis care will be essential to allow further improvement in outcomes internationally for all people with the disease. Contributors All authors contributed to the writing and editing of the Review and approved the final version. The corresponding author had final responsibility for the decision to submit for publication. Conflicts of interest We declare that we have no conflicts of interest. Acknowledgments We are grateful to the Australian Lung Transplants Services at Royal Perth Hospital (Perth, WA), St Vincent’s Hospital (Sydney, NSW), The Alfred Hospital (Melbourne, VIC), and The Prince Charles Hospital (Brisbane, QLD) for providing data for the numbers and ages of lung transplant recipients with cystic fibrosis. We also thank Bruce Marshall and the US Cystic Fibrosis Foundation for providing data for patient population demographic characteristics and the lung function and age of lung transplant recipients in the USA. Finally we thank Michael J Harrison (University College Cork) for his assistance in proofreading and formatting this Review before submission. SCB is supported by a Queensland Health Fellowship (Health Research Fellow) and his research is supported by a programme grant from the Queensland Children’s Medical Research Institute programme grant. BJP is supported by a Research Fellowship from Cystic Fibrosis Ireland. References 1 Kulich M, Rosenfeld M, Goss CH, Wilmott R. Improved survival among young patients with cystic fibrosis. J Pediatr 2003; 142: 631–36. 2 Cystic Fibrosis Foundation patient registry: annual data report 2010. Bethesda: Cystic Fibrosis Foundation, 2011. http://www.cff.org/ UploadedFiles/LivingWithCF/CareCenterNetwork/PatientRegistry/ 2010-Patient-Registry-Report.pdf (accessed Oct 31, 2012). 3 Elborn JS, Hodson M, Bertram C. Implementation of European standards of care for cystic fibrosis—provision of care. J Cyst Fibros 2009; 8: 348–55.

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