cystic fibrosis today

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1 Key points Median srvival in CF is crrently 36 years and contines to improve. A child born today with CF may expect to live into their 6th decade. CF is a spectrm of disease, ranging from severe to mild lng disease; lone sinsitis, pancreatitis and male infertility are also linked to mtations in the CF gene. Treatment focses on preventing and treating infection and optimising lng fnction and ntritional stats. A significant treatment brden is involved in order to stay well. Despite this, most patients lead a relatively normal life, and many CF adlts work and have families.

2 REVIEW The ERS designates this edcational activity for a maximm of 1 CME credit. For information on how to earn CME credits, see page 99. The ftre for a child born with cystic fibrosis today Edcational aims To make readers aware of the improved prognosis for patients with CF. To recognise that CF is a spectrm of disease. To familiarise readers with the management options and the brden of treatment involved. Smmary Cystic fibrosis (CF) was previosly considered to be a childhood disease, with very few patients srviving into adlthood. The past few decades have seen major advances in or knowledge and nderstanding of this disease. As a reslt, a child born with CF today can expect a mch improved life expectancy and qality of life. This article aims to give an overview of the considerable treatment that is involved and discss some of the emerging problems associated with this improvement in srvival. CF is a complex, mlti-system disease, with a predilection for the lngs and gastrointestinal tract. It is cased by mtations in the gene that codes for the cystic fibrosis transmembrane condctance reglator (CFTR) protein. It is the most common fatal inheritable disease in Cacasian poplations, and chronic lng infection and inflammation leading to bronchiectasis (figre 1) and ltimately respiratory failre accont for most of the morbidity and mortality associated with the disease. Prevalence varies considerably, not jst between ethnicities, bt also within Cacasian poplations. Across Erope, prevalence is as low as 1 in 25,000 in Finland and as high as 1 in 1,800 in the Repblic of Ireland [1]. Over the past few decades, there have been considerable advances in CF care and srvival has improved dramatically. However, there is still no cre for this devastating disease and, while a child born with CF today can expect a mch-improved qality of life and prognosis compared with 20 years ago, this comes at a significant cost to the individal. There is a hge brden of daily treatment, with freqent hospital visits. As patients live longer, new and complex isses are evolving, which pose frther challenges for treatment and additional morbidity for the individal. Evoltion of improved life expectancy In 1938, when CF was first recognised as a specific disease entity, >70% of CF babies died before their 1st birthday. Following the introdction of antibiotics and relatively crde pancreatic extracts in the 1940s (treatments which are still pillars of modern-day management), srvival improved. However, the otlook remained poor, with two-thirds of patients failing to reach 7 years of age. Key developments over the following decades significantly advanced the nderstanding of the disease. The observation that a disproportionately high C. Elston 1, N. Simmonds 2, D. Geddes 2 1 Adlt Cystic Fibrosis Dept, Kings College Hospital, and 2 Adlt Cystic Fibrosis Dept, Royal Brompton Hospital, London, UK. Correspondence C. Elston Adlt Cystic Fibrosis Dept Kings College Hospital Denmark Hill London SE5 9RS UK Fax: caroline.elston@kch.nhs.k Breathe September 2007 Volme 4 No 1 17

3 REVIEW The ftre for a child born with cystic fibrosis today Figre 1 Bronchiectasis in CF. The disease starts to damage the lng from an early age by a process of infection and inflammation, reslting in mcs plgging and significant widespread bronchiectasis. Figre 2 Median srvival of CF patients between Data from US Cystic Fibrosis Fondation Registry Srvival years nmber of children with CF were presenting to hospital with heat exhastion dring the New York heatwaves in the 1950s led to the discovery of an abnormal sweat composition in CF, with high sodim and chloride levels. Following this came the development of a reliable techniqe for stimlating and collecting sweat by GIBSON and COOKE [2] in 1959, and hence the introdction of a reliable means of diagnosis. This "sweat test" is still the pivotal diagnostic test sed today. It was not ntil the 1980s that a mch greater nderstanding of the basic celllar and genetic defect was realised, with the recognition that the basic defect was CFTR, a protein reqired for chloride transport on the apical srface of epithelial cells. A seminal pblication followed in 1989, with the discovery of the CF gene that encodes for this protein [3]. Since this discovery, >1,300 CF-casing mtations have been identified, with ΔF508 being the most common in the Cacasian poplation (>70%). Median life expectancy has contined to improve over the past few decades, from 20 years in the 1970s to 36.8 years in 2005 (most recent estimate from the USA; figre 2). Recent data sggest a child born with CF today has a predicted median srvival into their 6th decade of life [4]. A nmber of factors are thoght to have contribted to this improved srvival, most notably the development of anti-psedomonal antibiotics, better ntrition, treatment in specialist centres and early diagnosis. CF is a spectrm of disease The majority of patients with CF are diagnosed in infancy or early childhood with "classic" or "typical" CF. They sally present with one or more of the phenotypic characteristics associated with CF (chronic plmonary disease, gastrointestinal symptoms and malabsorption, ntritional abnormalities, sins disease, azoospermia), a high sweat chloride concentration, and in most cases identification of one disease-casing mtation on each CFTR gene. Most (85%) will be pancreatic insfficient. Otcome in CF is inflenced by a nmber of factors. Pancreatic sfficiency and "milder" genotypes are associated with a better long-term prognosis, whereas poor lng fnction, repeated lng infections, chronic Psedomonas and Brkholderia cepacia infection, and poor ntritional stats are all associated with redced srvival. Importantly, there can be qite marked phenotypic variation even in patients with the same genotype: those with classic disease may have a severe corse with rapid disease progression or a milder corse with very little deterioration over time. The recognition that some patients may present with only one characteristic featre of CF, with a borderline or normal sweat test, bt either a disease-casing mtation on both CFTR genes or an abnormal nasal potential difference measrement has led to the term "non-classic" or "atypical" CF (figre 3) [5]. These patients are sally diagnosed mch later, often as adlts, are mainly pancreatic sfficient, have milder disease and in general have a better prognosis. Interestingly, the UK CF Trst reported that 12% of new CF diagnoses in 2003 were in patients aged >16 years, and a recent review of patients aged 40 years demonstrated that 32% were diagnosed after 16 years of age and 18% were pancreatic sfficient. With the introdction of newborn screening programmes in many contries, CF will increasingly be diagnosed at birth. Where newborn screening programmes are already in place, stdies have demonstrated long-term benefits from early ntritional treatment inclding improved 18 Breathe September 2007 Volme 4 No 1

4 The ftre for a child born with cystic fibrosis today REVIEW growth and, in one stdy, cognitive development. In addition, early intervention and diagnosis may lead to redced hospitalisations and ltimately improved srvival. How is a child managed today? The primary aims of management are to delay the onset of lng infection and to keep the child well norished and able to enjoy a healthy and happy life. For most, this will involve a daily management regimen; 3-monthly clinic review, with close monitoring of weight, lng fnction (figre 4) and microbiology; and intermittent hospitalisation. The otcome for patients with CF is improved by care provided by teams of experienced healthcare professionals in specialist centres [6]. Treatment of lng infections The lngs of CF patients become infected with a srprisingly limited nmber of pathogens. Initially, Staphylococcs ares and Haemophils inflenzae are the major pathogens bt ltimately chronic infection with Psedomonas aerginosa occrs. Recrrent lng infections characterise the disease and most patients will need repeated corses of antibiotics. The most recent respiratory tract cltres shold be sed to gide the choice of antibiotic, and oral treatment is often sfficient, althogh prolonged corses (2 4 weeks) are sally reqired. More severe infections may reqire i.v. antibiotics. These can be given at home bt hospitalisation is sometimes necessary with resltant time away from home, school or work. Chronic P. aerginosa infection is associated with a more rapid decline in lng fnction and redction in long-term srvival, and preventing or delaying the onset of chronic infection is a crcial part of management. When Psedomonas is first isolated, a corse of treatment to eradicate the organism can delay the onset of chronic infection. A combination of oral ciprofloxacin with neblised colomycin for 3 months is often sed, with clearing of the organism in the majority of cases. Repeated attempts to eradicate the organism when it is cltred intermittently may also be sccessfl and can frther delay the inevitable onset of chronic infection [7]. Clinical sspicion Sweat test <30 mmol L mmol L -1 >60 mmol L -1 <30 mmol L mmol L -1 >60 mmol L -1 0 mtation Clinical review other diagnosis 1 mtation Yes No Nasal PD CFTR DNA test 2 mtations Normal Inconclsive Abnormal Mtation scanning of CFTR gene 0 mtation 1 mtation CF nlikely 2 mtations Inconclsive Consider FU (at CF centre) Consider alternative diagnosis Appropriate investigations and follow-p CF centre Repeat sweat test CFTR dysfnction - non classic CF - WHO diagnostic list CFTR DNA test 0 mtation 1 2 mtations Conslt genetic lab Consider CF heterogeneity? False + sweat test? Follow-p at CF centre Classic CF Figre 3 The diagnostic algorithm for CF. Often diagnosis is straightforward, bt with non-classic disease an extensive work-p may be reqired. Reprodced from [5], with permission from the pblisher. PD: potential difference; FU: follow-p. Figre 4 Lng-fnction measrement in a CF clinic. Breathe September 2007 Volme 4 No 1 19

5 REVIEW The ftre for a child born with cystic fibrosis today Figre 5 An in-patient ndergoing reglar treatment. Preventing exacerbations Mch of the treatment for CF is aimed at preventing exacerbations and maintaining lng fnction, becase repeated infections and poor lng fnction are associated with redced srvival. Neblised antipsedomonal antibiotics, neblised hman recombinant DNase, neblised hypertonic saline, and oral azithromycin have all been shown to decrease the freqency of exacerbations and maintain lng fnction. There is considerable debate abot the ideal time to introdce each of these therapies. In general, neblised antibiotics are introdced once a patient has become infected with Psedomonas. The macrolide antibiotic azithromycin seems to act primarily as an anti-inflammatory agent and has been associated with improved lng fnction and redced freqency of plmonary exacerbations even before infection with Psedomonas has occrred [8]. DNase (which redces sptm viscosity) aids airway clearance, althogh not all patients respond and a trial of treatment is sally recommended before longterm therapy is commenced [9]. Hypertonic saline again aids airway clearance and is often sed as an additional therapy to DNase [10]. It may also have a role in those patients who do not respond to DNase. Physiotherapy For those patients with respiratory symptoms, daily physiotherapy is an integral part of treatment. A nmber of techniqes are available, althogh none have been shown to be sperior to any other. These inclde active cycle of breathing, atogenic drainage and mechanical devices, sch as the positive expiratory pressre mask, fltter and external oscillation jacket. Physical exercise is actively encoraged as an adjnct to formal airway clearance sessions. Ntrition There is a strong relationship between ntritional stats, severity of lng disease and prognosis [11]. As most patients with CF have pancreatic insfficiency, they reqire pancreatic enzyme replacement with meals and snacks to prevent malabsorption and optimise ntritional stats. Fat-solble vitamins are poorly absorbed and vitamin spplements are sally necessary. Patients are advised to eat a high-fat, highenergy diet as their energy reqirements are generally increased to % when compared with healthy individals of the same age and sex. Those who strggle to maintain their weight within the normal range may reqire spplemental feeding, and some will reqire nasogastric feeding or gastrostomy. Compliance The average patient with CF may need to take >40 tablets per day, in addition to their neblised treatments and twice-daily physiotherapy, jst to stay well (figre 5). Both neblised therapies and physiotherapy are time consming, and nderstandably compliance is often an isse, particlarly as many of these preventative treatments provide no immediate benefit. Complications As patients get older, a nmber of other diseaserelated complications may develop, often reqiring yet more treatment. Low bone mineral density occrs in 15 25% of adlts and leads to an increased risk of fragility fractres [12]. CFrelated diabetes (CFRD) affects p to 50% of patients by the age of 40 years and is associated with an accelerated decline in lng fnction, weight loss and redced life expectancy by p to 10 years. Most patients with CFRD reqire treatment with inslin and, nlike other forms of diabetes, dietary restriction is not advised. Longterm diabetic complications have been reported and are likely to occr more freqently as CF patients live longer with diabetes [13]. 20 Breathe September 2007 Volme 4 No 1

6 The ftre for a child born with cystic fibrosis today REVIEW Constipation is a relatively common occrrence in CF, bt sally responds to a modification of diet, pancreatic enzyme dose and laxative therapy. At the more severe end of this spectrm is distal intestinal obstrction syndrome, which occrs almost exclsively in those who are pancreatic insfficient and affects ~20% of patients. Treatment with repeated doses of laxative agents, sch as gastrograffin or a balanced intestinal lavage soltion are sally sccessfl [14]. Liver disease develops predominantly in childhood and is the case of death in ~2% of patients. Althogh biliary cirrhosis is a relatively common finding in CF, only ~5 % of patients progress to clinically significant disease and portal hypertension. Patients with evidence of liver disease are sally prescribed rsodeoxycholic acid, althogh its long-term efficacy in preventing the progression of liver disease in CF remains nproven [15]. Pnemothorax and haemoptyis both occr with increasing freqency as the disease progresses, adding to disease morbidity in affected individals. Allergic bronchoplmonary aspergillosis occrs in ~10% of patients and for some can be a recrrent problem reqiring repeated corses of steroids. The incidence of nontberclos mycobacterial infection seems to be increasing and while this does not always reqire treatment, some of these organisms can be associated with clinical decline and can be very difficlt to treat. Ultimately, most patients will progress to respiratory failre and when this occrs noninvasive ventilation is often sed, either to provide symptom relief or as a bridge to lng transplantation. Lng transplantation shold be considered for all patients with endstage lng disease. Sadly, many patients will die on the transplant waiting list becase of a shortage of donor organs. Srvival at a cost? Unfortnately, many of the treatments aimed at preventing or delaying disease progression in CF may in themselves case side-effects or longterm complications. Repeated corses of antibiotics, for instance, can lead to the development of mltiple drg allergies, ths limiting treatment options, as well as the emergence of drg-resistant organisms that are more difficlt to treat. Most clinicians wold advocate the se of an aminoglycoside antibiotic in combination with another antipsedomonal antibiotic when giving i.v. therapy, bt repeated corses of aminoglycosides can case significant hearing loss, vestiblar damage and renal failre, even when drg levels are therapetic. Prolonged se of azithromycin as an anti-inflammatory agent may predispose to antibiotic resistance, particlarly in nontberclos mycobacteria which are inherently difficlt to treat, and reports of resistance in S. ares and H. inflenzae following long-term azithromycin se are emerging. As patients live longer and are exposed to more treatment, it is increasingly important to assess the impact of treatments so that the potential benefits otweigh the risks of developing these and possibly other long-term complications. In addition, there is a significant financial cost to consider as many of the drgs sed to treat CF are expensive. Living with a chronic illness can pose other challenges for the individal. Life events that most of s take for granted, sch as seeking employment, obtaining insrance, secring a mortgage, forming long-term relationships and having families may not be straightforward. Having a chronic illness can also be very isolating, and nfortnately becase of the potential for cross-infection between individals with CF, patients are now advised to avoid contact with each other. For many this will take away an important spport network. Ftre developments Considerable efforts to increase or knowledge and nderstanding of the basic genetic defect and to develop new therapies aimed at improving long-term srvival and ltimately finding a cre are ongoing. Understanding of the effect of modifier genes may help to explain the variable clinical corse seen in CF even when controlling for genotype. New therapetic approaches are being developed to address all stages of the disease. Gene therapy, which aims to se a normal gene as a drg to override the falty version, is now a real possibility and the UK CF gene consortim will be begin a large gene therapy trial in A nmber of potential therapies designed to correct the fnction of the defective CFTR protein prodced by the CF gene and to correct disordered ion transport are being evalated. With these therapies, there is the real prospect of preventing the development of disease in individals with CF, frther improving srvival and decreasing the need for ardos daily therapy. In addition to treatments that target the nderlying defect, frther treatments are being Usefl weblinks UK CF Trst US CF Fondation Cystic Fibrosis mtation database Breathe September 2007 Volme 4 No 1 21

7 REVIEW The ftre for a child born with cystic fibrosis today Figre 6. A CF grandmother. This patient, with non-classic CF, was labelled a "difficlt asthmatic" for many years. developed and evalated to treat and prevent the progression of established disease. Clinical trials of new inhaled antibiotics are taking place and a nmber of anti-inflammatory agents are being assessed to see if they can redce inflammation in the CF lng. The introdction of newborn screening will also provide an opportnity to assess early intervention strategies. Conclsion There have been considerable advances in CF care and management since the disease was first recognised in 1938, with a dramatic improvement in life expectancy. A child born with CF today can now expect to live into their 6th decade (figre 6), bt we shold not forget that this improvement in srvival comes with a significant brden of treatment. As patients live longer, new challenges are emerging both as a conseqence of getting older with CF bt also as a reslt of the treatments that have led to this improved srvival. Ongoing research efforts contine to search for treatments that will prevent the development or progression of the disease and ltimately prodce a cre. Edcational qestions 1. Which of the following statement(s) is/are tre? a) The prevalence of CF is the same in all Cacasian poplations. b) A child born with CF today wold be expected to live into their 50s. c) All patients with CF present in early childhood. d) CF is always associated with pancreatic insfficiency. 2. Which of the following factors are associated with a worse prognosis in cystic fibrosis? a) A diagnosis of non-classic CF. b) Chronic infection with Psedomonas. c) Pancreatic sfficiency. d) Repeated lng infections. e) Poor ntritional stats. 3. Which of the following is/are tre with regards to treatment? a) Eradicating Psedomonas from the lngs can delay the onset of chronic infection. b) All infections shold be treated with i.v. antibiotics. c) Neblised antibiotics are prescribed from the age of diagnosis. d) Side-effects of long-term treatment are ncommon. 4. Which of the following complications are more likely to occr as patients get older? a) Liver disease. b) CF-related diabetes. c) Infection with Staphylococcs ares. d) Pnemothorax. 22 Breathe September 2007 Volme 4 No 1

8 The ftre for a child born with cystic fibrosis today REVIEW References 1. Hodson ME, Geddes DM, Bsh A, eds. Cystic Fibrosis. 3rd Edn. London, Chapman and Hall, Gibson LE, Cooke RE. A test for concentration of electrolytes in sweat in cystic fibrosis of the pancreas tilizing pilocarpine by iontophoresis. Pediatrics 1959; 23: Kerem B, Rommens JM, Bchanan JA, et al. Identification of the cystic fibrosis gene: genetic analysis. Science 1989; 245: Dodge JA, Lewis PA, Stanton M, Wilsher J. Cystic fibrosis mortality and srvival in the UK: Er Respir J 2007; 29: De Boeck K, Wilschanski M, Castellani C, et al. Cystic fibrosis: terminology and diagnostic algorithms. Thorax 2006; 61: Mahadeva R, Webb K, Westerbeek RC, et al. Clinical otcome in relation to care in centres specialising in cystic fibrosis: cross sectional stdy. BMJ 1998; 316: Smyth A. Update on treatment of plmonary exacerbations in cystic fibrosis. Crr Opin Plm Med 2006; 12: McCormack J, Bell S, Senini S, et al. Daily verss weekly azithromycin in cystic fibrosis patients. Er Respir J [Epb ahead of print. PMID: ] 9. Fchs HJ, Borowitz DS, Christiansen DH, et al. Effect of aerosolized recombinant hman DNase on exacerbations of respiratory symptoms and on plmonary fnction in patients with cystic fibrosis. The Plmozyme Stdy Grop. N Engl J Med 1994; 331: Elkins MR, Robinson M, Rose BR, et al. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med 2006; 354 : Corey M, McLaghlin FJ, Williams M, Levison H. A comparison of srvival, growth, and plmonary fnction in patients with cystic fibrosis in Boston and Toronto. J Clin Epidemiol 1988; 41: Haworth CS, Elkin SL. Diagnosis and management of cystic fibrosis related low bone mineral density. In: Webb AK, Ratjen FA. Cystic Fibrosis. Er Respir Mon 2006; 35: Brennan AL, Geddes DM, Gyi KM, Baker EH. Clinical importance of cystic fibrosis-related diabetes. J Cyst Fibros 2004; 3: Mascarenhas MR. Treatment of gastrointestinal problems in cystic fibrosis. Crr Treat Options Gastroenterol 2003; 6: Colombo C, Rsso MC, Zazzeron L, Romano G. Liver disease in cystic fibrosis. J Pediatr Gastroenterol Ntr 2006; 43: Sppl. 1, S49 S55. Sggested answers 1. b 2. b, d and e 3. a 4. b and d Frther reading Hodson ME, Geddes DM, Bsh A, eds. Cystic Fibrosis. 3rd Edn. London, Chapman and Hall, Accrso FJ. Update in cystic fibrosis Am J Respir Crit Care Med 2007; 175: Davis PB. Cystic fibrosis since Am J Respir Crit Care Med 2006; 173: Schechter MS. Non-genetic inflences on cystic fibrosis lng disease: the role of sociodemographic characteristics, environmental exposres, and healthcare interventions. Semin Respir Crit Care Med 2003; 24: Hadjiliadis D. Special considerations for patients with cystic fibrosis ndergoing lng transplantation. Chest 2007; 131: Breathe September 2007 Volme 4 No 1 23