Changing epidemiology and clinical issues arising in an ageing cystic fibrosis population

Psychosocial challenges in the ageing CF cohort

Clinicians are increasingly aware of the distinction between suffering from CF and living with CF. Increasingly, patients are achieving higher levels of social integration owing to improvements in physiological functioning when entering adulthood. Of adults with CF up to 70% are gainfully employed, or pursuing advanced education, whereas only 5–15% are reported as disabled [Cystic Fibrosis Trust, 2008; Canadian Cystic Fibrosis Foundation, 2007]. Marriage is now a common prospect for individuals with CF and 32–42% of adults on CF registries are married [Cystic Fibrosis in Australia, 2008; Canadian Cystic Fibrosis Foundation, 2007]. With the assistance of medical technology CF patients are increasingly becoming parents. The development of sperm aspiration techniques, and intracytoplasmic sperm injection has enabled men who had previously been considered infertile owing to congenital bilateral absence of the vas deferens to father children. Outcomes of women with CF pursuing pregnancy have dramatically improved and, although associated with increased short-term medical needs and complications, does not seem to confer long-term survival disadvantage [Goss et al. 2003; Johannesson, 2002; Gilljam et al. 2000]. As a consequence, the number of women pursuing pregnancy has increased fourfold from 1986 to 2004 [Sueblinvong and Whittaker, 2007]. However, despite these successes, individuals with CF and their partners pursuing pregnancy must accept the very real possibility that their child will prematurely lose a parent.

Those same medical regimens credited with improving life spans are unfortunately, costly, laborious and time consuming, consequently limiting quality of life. A recent survey of 204 patients attending 10 different centres conducted by Sawicki and colleagues found that the mean daily time dedicated to CF treatment regimens was 108 minutes [Sawicki et al. 2009]. Such burdens pose tremendous challenges to patient self-management strategies, in particular in those adults trying to balance family life, careers/education, and other responsibilities with management of their CF. New treatments and modalities will need be mindful of further contributing to patient treatment burden as these are typically supplementary measures rather then replacement therapies. As such, the pursuit of dry powder inhalers and high efficiency nebulization devices for use of established and new aerosolized antimicrobials and mucolytics is encouraging.

Clinicians are increasingly aware of the impact of chronic medical conditions on psychological health. The prevalence of both depression and anxiety have (variably) been shown to be increased in CF adults relative to the general population at approximately 30% [Riekert et al. 2007; Pearson et al. 1991]. As both anxiety and depression have been shown to vary with increasing burden of lung disease it would be expected that these conditions will increasingly be observed in the ageing adult cohort. The expected increase in psychosocial needs of the ageing CF cohort will not be met with existing clinic staffing in social work or psychology. As such, the psychosocial impact of ageing in CF remains an area which requires significant study in order to identify new and emerging needs and develop the infrastructure and expertise to meet these needs.

Pancreatitis

Pancreatitis is a recognized complication of adults with CF and in many instances a presenting complaint in those diagnosed late in life. In classical CF, pancreatic ductal secretions of enzyme-rich material are blocked by inspissated mucins owing to defective CFTR function and result in the autodigestion of the pancreas from retained secretions. In the vast majority, pancreatic insufficiency manifests in infancy and is readily diagnosed. However, in those individuals with milder mutations resulting in a partially active CFTR (class IV or V) secretions are semiviscid resulting in maintenance of pancreatic sufficiency but potentially punctuated by episodes of intermittent ductal obstruction manifesting as pancreatitis [Walkowiak et al. 2008].

For an individual to develop pancreatitis they must have a residual portion of normal pancreatic acinar tissue. Exocrine pancreatic sufficiency can continue to be displayed in individuals until almost 98% of reserve function has been lost. Pancreatitis occurs only in those CF individuals with at least partial pancreatic sufficiency [Augarten et al. 2008]. It is estimated that only 10.2–19% of individuals with CF retain pancreatic sufficiency [Dray et al. 2003; Durno et al. 2002; Gaskin et al. 1982]. The incidence of pancreatitis varies from 1.2–4.0% in the overall CF population [Augarten et al. 2008; De Boeck et al. 2005; Durno et al. 2002]. However, in individuals who retain exocrine pancreatic function its incidence ranges from 10.3–14.2%. These individuals are characterized by an older age (mean 24.4 years), milder genetic mutations, and usually a milder course of respiratory disease [De Boeck et al. 2005; Gaskin et al. 1982]. Furthermore, both a chronic low-grade inflammatory process punctuated by acute episodes of pancreatitis contribute to the destruction of residual pancreatic acinar tissue which can convert pancreatic sufficient to pancreatic insufficient status later in life [Durno et al. 2002]. In one study, 45% of individuals with CF and pancreatitis were >35 years of age [Krysa and Steger, 2007].

CF-related diabetes

While CF-related diabetes (CFRD) shares features with both type I and II diabetes mellitus it represents a unique clinical entity and requires a distinct management strategy. The disease is characterized by a progressive fibrotic disruption and fatty infiltration of pancreatic micro-architecture resulting in a loss of islet cells and an increasing insulin deficiency. Increased peripheral insulin resistance has also been suggested, but recent data suggests this may not play as significant a role as lack of insulin [Mohan et al. 2009; Dobson et al. 2004]. However, ketoacidosis is extremely rare in CFRD. The spectrum of disease ranges from impaired glucose intolerance to CFRD with or without fasting hyperglycaemia. To add further complexity, an individual’s glucose tolerance and insulin resistance remain plastic and fluctuate with periods of infection/inflammation and gastrointestinal absorption and motility. Most patients with CFRD without fasting hyperglycaemia will progress with time to develop fasting hyperglycaemia [Schwarzenberg et al. 2007].

CFRD has an overall reported prevalence of 11–21.5% [Cystic Fibrosis Foundation, 2008; Cystic Fibrosis Trust, 2008] depending on regional database. While less well documented, IGT prevalence in CF has been documented in smaller centre-specific cohort studies to be 13.7–16% [van den Berg et al. 2009; Schwartz et al. 1992]. Although numerous risk factors have been associated with CFRD, increasing age is most notable. Prevalence increases from 2–3% in those aged 6–10 to 5–10% in those aged 11–17 to 13.5–17.5% in young adults 18-24 years of age [Cystic Fibrosis Foundation, 2008; Canadian Cystic Fibrosis Foundation, 2007]. In those CF adults over the age of 40 its prevalence in studies ranges from 27–52% [Simmonds et al. 2009; van den Berg et al. 2009; Hodson et al. 2008]. Not only does CFRD exist more frequently in the adult cohort of CF patients but it also develops more frequently in adults. In a population based longitudinal study using data from UK CF Registry, Adler and colleagues followed 5196 individuals with CF without CFRD to determine the incidence of CFRD from 1996–2005 [Adler et al. 2008]. The incidence of CFRD was observed to increase with increasing age up to the fourth decade of life at (7.2% for females, 6.5% for males) before again declining. Other independent variables associated with the development of CFRD in decreasing order included declining pulmonary function, pancreatic insufficiency, CFTR class (I and II versus others), female sex, liver disease and corticosteroid use.

The development of CFRD has been associated with increased rate of pulmonary function decline and increased rates of pulmonary exacerbations [Koch et al. 2001]. It is also a marker of poorer nutritional status and an independent predictor of mortality [Chamnan et al. 2010; Marshall et al. 2005; Koch et al. 2001; Rosenecker et al. 2001; Milla et al. 2000]. The diagnosis and correct management of CFRD can correct the pulmonary function decline in CF, confirming that CFRD independently contributes to disease progression and is not merely a marker of advanced disease [Lanng et al. 1994]. As such, the characterization of a patient’s glucose tolerance is critical. In addition to currently recommended annual screens (with 75 g oral glucose tolerance tests) and symptom directed monitoring (polydipsia/polyuria, growth failure, weight loss, otherwise unexplained pulmonary function decline), centres are increasingly observing for postenteral nutrition hyperglycaemia or exacerbation-induced postprandial hyperglycaemia.

Microvascular complications of CFRD are more common in individuals with CFRD with fasting hyperglycaemia, CFRD of longer duration and with poorer control of disease [Schwarzenberg et al. 2007]. The prevalence of diabetic retinopathy ranges from 10% to 27% [van den Berg et al. 2008; Schwarzenberg et al. 2007; Andersen et al. 2006]. Neuropathy has been reported to be present in up to 42% of individuals, with autonomic abnormalities detected in 34% and somatic abnormalities in 17% [Schwarzenberg et al. 2007]. Microalbuminuria as a manifestation of diabetic nephropathy is a common in individual with CFRD with a prevalence of 13–21% [van den Berg et al. 2008; Schwarzenberg et al. 2007; Andersen et al. 2006]. Furthermore, concomitant CFRD even in the absence of nephropathy is likely to predispose individuals to antibiotic-induced acute kidney injury, an increasingly commonly recognized event [Etherington et al. 2007]. As microvascular complications associated with CFRD accumulate with time, their presence will increasingly be observed in the ageing CF cohort. Whereas there is significant evidence in the type 1 and type 2 literature that strict glycaemic control reduces microvascular complications, the same has not yet been documented for CFRD. It is hoped that by achieving glycaemic targets, CF patients can not only enjoy improved pulmonary health but also fewer diabetic complications. To this end, it is vital that all patients with CFRD be screened yearly for retinopathy, nephropathy and neuropathy.

Metabolic bone disease in cystic fibrosis

Metabolic bone disease is common in CF. Osteoporosis is characterized by low bone mass, poor bone quality with a consequent increase in risk of bone fragility and fracture. In CF, this process is multifactorial. The pathogenesis relates in part to the gastrointestinal complications of CF: malnutrition, insufficient absorption of vitamins D and K (primarily owing to pancreatic insufficiency) and impaired absorption/excess secretion of calcium from the gastrointestinal tract altogether resulting in a low BMI. It also is affected by pulmonary factors: physical inactivity owing to burden of disease and chronic infection/inflammation cause increased cytokine activity. There are also hormonal factors: low levels of insulin-like growth factor 1 (IGF-1) and delayed puberty/hypogonadism. Finally, complications of medical management including the use of corticosteroids play a large role [Aris et al. 2005]. As a consequence of these events adolescents with CF often fail to reach peak bone mass and furthermore all individuals with CF suffer accelerated bone losses [Lutz et al. 2001; Bhudhikanok et al. 1998]. Dual-energy X-ray absorptiometry (DXA) represents the current gold standard for bone mineral density (BMD) measurement and is performed at the lumbar spine (L2–4), femoral neck and total hip. Via this measurement osteoporosis is defined as a T score of <−2.5 (relative to a gender-matched young population) and osteopenia as between −1 and −2.5.

Increased rates of fractures of long bones, ribs, and vertebrae have all been reported in CF. Not only are fractures associated with significant pain and suffering but they can also contribute to worsening pulmonary disease status. Acute fractures of ribs and vertebrae can significantly impair chest physiotherapy regimens and contribute to pulmonary exacerbation [Aris et al. 2005]. Furthermore, exaggerated kyphosis owing to loss of vertebral body height with repeated fractures can also introduce a restrictive lung disease element [Aris et al. 1998; Logvinoff et al. 1984].

A recent meta-analysis of 10 studies involving 888 patients assessing bone disease in CF patients, Paccou and colleagues estimated the pooled prevalence of osteoporosis in the adult CF population of 23.5% (CI 16.6–31.0) [Paccou et al. 2010]. The pooled prevalence of osteopenia was 38% (CI 28.2–48.3). Pooled prevalence of vertebral and other fractures were 14% (CI 7.8–21.7) and 19.7% (CI 6–38.8). Vertebral fractures occur almost exclusively in thoracic vertebrae. This fracture rate exceeds that of age-matched healthy controls by a factor of 100 and that of untreated postmenopausal osteoporotic women [Aris et al. 2005; Liberman et al. 1995]. Interestingly, the presence of fractures paradoxically decreases with increasing age likely reflecting a survivor bias.

Strides in the management of CF-related metabolic bone disease continue to be made. First and foremost, the early recognition of risk and enhanced surveillance for metabolic bone disease following published guidelines is required [Aris et al. 2005]. Management strategies using calcium, vitamin D and K supplementation, sex hormone therapy, and antiresorptive agents are implemented as individual circumstances dictate. Although stabilizing BMD can be achieved, prevention of bone disease through the improved pulmonary and nutritional management strategies holds greater promise. To this end, the foundation for a lifetime of bone health begins in childhood and is dependent upon nutrition, adequate weight gain and physical activity. This will allow the appropriate hormonal milieu in which to accrue normal bone mass as a child and not to have accelerated bone loss as an adult. For the ageing CF patient, the future will hold treatment for bone disease at both a frequency and chronologic age similar to the general population.

Urinary incontinence

Stress incontinence is a frequent and under-reported condition commonly affecting women with CF, and is often only divulged after direct questioning. Defined as an involuntary leakage of urine, stress incontinence symptoms are exacerbated in CF during spells of coughing or during physiotherapy. Symptoms are more severe during pulmonary exacerbations and may impede performance of effective chest physiotherapy [Nixon et al. 2002]. Prevalence estimates vary from 30% to 74% in different cohorts [Vella et al. 2009; Moran et al. 2003; Cornacchia et al. 2001]. Prevalence increases with increasing age [Vella et al. 2009; Cornacchia et al. 2001] and decreasing FEV₁ [Cornacchia et al. 2001]. In those CF females over 35 years of age, the prevalence is 80–100% [Orr et al. 2001]. Proper identification of patients can enable teaching of pelvic floor muscle exercises, which can reduce symptoms and improve quality of life.

Malignancies in CF

An association between malignancies and CF was first proposed in the 1980s when several independent cases were reported. Since then, several epidemiologic investigations have sought to further elucidate this association. These studies use standardized incidence ratios (SIRs), the ratio of observed compared with the ratio of expected cancers in a cohort extrapolated from general population data, as a measure of relative risk.

A clear and consistent increase in the risk of gastrointestinal and pancreatic malignancies has since been established. Gastrointestinal malignancies have been found to occur at SIRs 5.1–6.5 times that of the general population [Johannesson et al. 2009; Maisonneuve et al. 2003; Schoni et al. 1996]. In particular, cancer diagnoses involving the small intestine (SIR 24.8), colon (SIR 7.4), biliary tract (SIR 39), liver (SIR 4.1), oesophagus (SIR 5.4) and pancreas (SIR 2.6–5.3–31.5) are increased in CF [Maisonneuve et al. 2007, Maisonneuve et al. 2003; Neglia et al. 1995]. The mechanism of the increased risk of gastrointestinal malignancies has not been established. This risk can be observed to increase with increasing age in the CF cohort [Maisonneuve et al. 2003]. Furthermore, the frequent and varied gastrointestinal complaints common in CF (distal intestinal obstruction syndrome, fibrosing colonopathy, rectal prolapse, etc.) may delay the diagnosis of more ominous causes of gastrointestinal disturbances [Brown et al. 2000]. Not only do CF patients have an increased risk of developing malignancy, they manifest disease at an earlier age. CF patients developed gastrointestinal malignancies at a mean age of 32.2 years (±12.6) compared with 58.2 years (±14.3) in the general White population [Neglia et al. 1995].

There are, however, conflicting data as to whether CF confers an increased risk of all types of cancer [Johannesson et al. 2009; Maisonneuve et al. 2003; Schoni et al. 1996; Neglia et al. 1995, 1991; Sheldon et al. 1993]. In the largest of these studies Nelgia and colleagues using a retrospective cohort study assessed malignancy risk independently in both North American and European CF populations comprising more than 38,000 individuals and did not detect an increased risk of cancer [Neglia et al. 1995]. More recently, Johannesson and colleagues, using a retrospective general population-based study using multiple Swedish National Registries, reported on 883 CF patients followed from 1968 to 2003 where they observed an increased risk of any cancer of 3.2 (CI 2.1–4.6) [Johannesson et al. 2009]. In addition to reaffirming the increased incidences of gastrointestinal and pancreatic malignancies in CF, these investigators also observed increased incidences of thyroid and renal cancers, nonmelanoma skin cancers and lymphoma. The increased incidences of these malignancies, all of which are increased with radiation exposure could be explained by the repeated exposure of CF patients to radiographic imaging studies at an early age. Accordingly, the routine use of computed tomography (CT) for monitoring lung disease in CF needs to be followed with great care for future implications [de Gonzalez et al. 2007].

Investigators have sought to identify particular risk factors associated with malignancy in CF [Maisonneuve et al. 2003; Neglia et al. 1995]. Genotype does appear to have an impact on the risk of gastrointestinal malignancies as individuals who are homozygous for the F508del mutation had the highest risk, intermediate risk for F508del compound heterozygotes and lowest for individuals with other mutations [Maisonneuve et al. 2003]. This is interesting as there is no increased incidence of malignancies in family members of individuals with CF [Johannesson et al. 2009]. Individuals whose diagnosis was made on the basis of failure to thrive were also noted to be at increased risk of gastrointestinal malignancies [Maisonneuve et al. 2003]. CF lung transplant recipients have an increased risk of cancer over all (SIR 6.3; CI 3.4–10.8) and specifically an elevated risk of gastrointestinal malignancy (SIR 21; CI 5.8–54.2) and lymphoma (SIR 43.8; CI 17.7–90.7). These have largely been attributed to the intense immune suppressive regimen required [Maisonneuve et al. 2003].

Despite the clear and consistent increased risk of gastrointestinal malignancies in CF, individual risk remains very low. However, as the life span of individuals with CF continues to increase, the absolute risk of malignancies is expected to increase. There are no recommendations for enhanced surveillance for cancer in patients with CF. Screening should be considered on an individual basis after a thorough evaluation of one’s symptoms, perceived risk factors and the risk of the required procedure.

Macrovascular disease

To date, coronary artery disease (CAD) has only rarely been reported in CF individuals outside of the posttransplant setting [Onady and Farinet, 2006; Fraser et al. 1999; Schlesinger, 1997]. Indeed, the favourable blood pressure and lipid profiles of patients with CF [Rhodes et al. 2010; Figueroa et al. 2002], combined with increased mortality at a younger age have long been suggested to protect this population from CAD. Recently, Hull and colleagues compared the arterial stiffness of 50 adult CF patients (mean age 28 ± 8.2 years) with age-, sex- and BMI-matched controls [Hull et al. 2009]. After adjustment for confounders, augmentation index (AIx; a composite vascular endpoint comprising both arterial stiffness and global peripheral wave reflection) was observed to be significantly elevated in individuals with CF and increase with age. In particular, those individuals with concomitant CF-related diabetes had the highest AIx. Increased arterial stiffening is a hallmark of the ageing process, and an independent predictor of atherosclerotic CAD evident even in those without obvious risk factors for CAD [Laurent et al. 2006]. These findings suggest that premature vascular ageing occurs in CF, as the large artery haemodynamics of individuals with CF were behaving approximately a decade in advance of those expected for their chronologic age. Whether this is related to CF itself or a complication of its treatment is unknown. Importantly, family history is a well-documented risk factor for both early CAD and dyslipidaemia. As CF patients age, this genetic background will figure more prominently in the development of CAD. Thus, it is possible that an increase in the incidence of symptomatic CAD will occur in CF.

Iatrogenic complications of medical management

The cumulative effects of therapies need be considered as well. Acute kidney injury as a result of nephrotoxic antibiotics such as aminoglycosides and polymixins are increasingly being reported [Smyth et al. 2008; Al-Aloul et al. 2005b]. Furthermore, evidence suggests that repeated exposure to nephrotoxic antimicrobials may result in cumulative subclinical renal injury with the potential to manifest later in life with overt chronic renal disease [Etherington et al. 2007]. In a prospective cohort study by Al-Aloul and colleagues reduced renal function as measured by 24-hour urine creatinine clearance (CCL) in a cohort of 80 patients chronically infected with P. aeruginosa was observed in up to 42% of individuals with a CCL of <80 ml/min/1.73 m² and 21%L with a CCL of <60 ml/min/1.73 m² [Al-Aloul et al. 2005a]. As glomerular filtration decreases with increasing age, it is possible that in the ageing CF cohort renal complications will increasingly occur with standard exacerbation therapies. In a similar fashion neuropathies (secondary to linezolid [Bressler et al. 2004; Frippiat and Derue, 2004], chloramphenicol [Godel et al. 1980] and oto-vestibular toxicities with aminoglycosides [Cheng et al. 2009; McRorie et al. 1989]) may ensue.