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Optimizing respiratory health in children with cystic fibrosis
SYMPOSIUM: RESPIRATORY MEDICINE
Optimizing respiratory health in children with cystic fibrosis
manifest disease. Forty years ago, few children survived beyond infancy however improvements in management have led to dramatic changes in the life expectancy for patients with CF. The mean life expectancy for a baby born in 2003 was 42 years for a boy and 36 years for a girl. The aim of current research and clinical care is to increase this to beyond 50 years. Traditionally the survival for girls with CF appeared to be worse than that of their male counterparts, however this may not necessarily be universal. There are numerous gene mutations that effect a change in the presence or function of the cystic fibrosis transmembrane regulator (CFTR). This cell membrane protein acts directly as a chloride channel but is also responsible for regulating the epithelial sodium channel (ENaC). The net result being impaired chloride transport and excess sodium loss resulting in a depletion of the airway surface liquid, thickening mucus that entraps cell surface cilia. CFTR mutations also may be responsible for facilitating infection with early non-mucoid Pseudomonas aeruginosa and reducing the efficacy of the adaptive immune response to later mucoid P. aeruginosa. The effects upon the function of CFTR are not restricted to the lungs, resulting in the complications of pancreatic exocrine and eventual endocrine insufficiency, abnormal intestinal function and poor nutrition, skin salt loss, metabolic abnormalities and biliary fibrosis. Nasal polyps, congenital absence of the vas deferens and CF related arthritis further add to the effect the disease has on quality of life.
Matthew N Hurley Alan R Smyth
Abstract Cystic fibrosis is a multi-system genetic disorder causing thick secretions, lung infection and pancreatic insufficiency. Optimizing respiratory health in children with cystic fibrosis depends upon meticulous attention to maintaining general health, in addition to preserving lung health. Maximizing nutrition and growth are essential as these are independent predictors of lung function and survival. Neonatal screening has enabled an earlier, more proactive approach to optimizing health. However the primary predictor of deterioration is the acquisition of the opportunistic bacterium Pseudomonas aeruginosa. Eradication of chronic infection with this organism is impossible, leading to lung destruction and shortened life expectancy for individuals with CF. The optimal strategies for managing this critical complication of cystic fibrosis are the subject of ongoing research, however these strategies may depend upon antibiotic regimens to which the bacteria may gain resistance. Novel strategies, adopted alongside continued improvements in care, are needed to further defer the complications and deterioration experienced by patients with cystic fibrosis, enhance quality of life and extend survival.
Inflammation and infection Those with cystic fibrosis have an up-regulated inflammatory cascade, however it has been contentious whether this is due to an intrinsic pro-inflammatory state, disproportionate inflammation in result to infection or a proportionate immune response. In studies aimed at answering this question extensive examination of bronchoalveolar lavage (BAL) fluid suggests that those with infection have significantly increased levels of inflammatory mediators compared to those without. Attempts at ameliorating the lung damage with oral corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) have demonstrated improvements in lung function. Concerns regarding side effects have however, prevented the routine use of oral corticosteroids.
Keywords cystic fibrosis; infection; Pseudomonas
Introduction Cystic fibrosis (CF) is a multi-organ disease with recurrent and chronic lung infection being the critical life-limiting feature. The subsequent lung destruction, accompanied by pancreatic insufficiency, alongside increased metabolic demands, adversely affects growth and leads to respiratory failure, a reduced quality of life and premature death. In infants, treatment focuses on early aggressive management of lung infection and optimization of nutritional status. This continues alongside treatment of complications in later childhood. Cystic fibrosis is the commonest life-limiting autosomal recessive condition; in the UK approximately 8000 people have
Early care Age at diagnosis is significantly associated with survival. For each year increase in age at diagnosis there is an accompanied increase in the acquisition of P. aeruginosa, reduced lung function and survival.
Matthew N Hurley BSc (Hons) MBBCh MRCPCH is a Clinical Research Fellow in the Academic Department of Child Health, University of Nottingham, Queens Medical Centre, Nottingham, UK. Conflicts of interest: none.
Diagnosis The diagnosis of cystic fibrosis depends upon the presence of one or more characteristic phenotypic features, a positive newborn screening test result or a history of CF in a sibling and laboratory evidence of a CFTR abnormality. CFTR abnormality may be demonstrated by elevated sweat chloride concentration, identification of mutations in each CFTR gene known to cause CF or in vivo demonstration of characteristic abnormalities in ion transport across the nasal epithelium. In the UK however since the
Alan R Smyth MA MBBS MCRP MD FRCPCH is a Professor in Child Health at the School of Clinical Sciences, University of Nottingham, Director of Trent Local Children’s Research Network (TLC-RN) and Co-ordinating Editor of Cochrane Cystic Fibrosis & Genetic Disorders Group, UK. Conflicts of interest: none.
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SYMPOSIUM: RESPIRATORY MEDICINE
introduction of universal neonatal screening, the vast majority of diagnoses are made via this route. The justification for neonatal screening revolves around recent improvements in outcome that have been attributed to improvements in intervention. The natural suggestion is that if these improvements are instituted earlier, before lung damage and nutritional status is impaired, that clinical status will improve. There are obvious confounders in outcomes of screening, an intervention that was instituted at the same time as other improvements in management. However US CF Registry data strongly suggest that screening confers a survival advantage. Superficially, the early clinical course of children with CF can be split e those diagnosed through screening and those diagnosed prior to the neonatal screening procedure due to an early complication. This group of patients largely present due to meconium ileus.
likely that in future BAL will become a more common undertaking and treatment, as a result, will become more targeted. Infections of the CF lung The altered lung environment in those with CF provides an ideal niche for bacterial growth. There appears to be a recognizable sequence of escalation in the organisms isolated from children with CF (Figure 1). One can speculate that this progression represents a change in competitive advantage between species. In infancy Staphylococcus aureus predominates as the most common organism isolated (50%) with the prevalence peaking in the 6e10 age group. Haemophilus influenzae and P. aeruginosa are similarly prevalent until about age 5 (30e35% prevalence) when the prevalence of P. aeruginosa increases such that it is the most common organism isolated in the 11e17 age group with a prevalence increasing to the 80% level in the late-teens. The opportunist P. aeruginosa eventually establishes a chronic infection causing reduced growth, faster deterioration of lung function and progression to end-stage lung disease as evidenced by lung transplantation or death. Decline in lung function is largely responsible for the morbidity and mortality in CF and over the last two decades more efficient treatment of pulmonary infections has accompanied the increase in life expectancy. Burkholderia cepacia is a similar opportunist although the prevalence has reduced over time.
The effect of meconium ileus The influence that meconium ileus has on outcomes for children with CF has been controversial. A large study including the 27 703 patients on the cystic fibrosis registry between 1986 and 2000 (including the pre-screening era) concluded that the risk of acquiring P. aeruginosa and mortality was significantly higher in those who presented with meconium ileus compared to those identified through screening. In the pre-screening era it is possible that the disadvantage conferred by having meconium ileus was reduced by the advantage of earlier diagnosis such that there were no differences in lung function, weight and height and acquisition of P. aeruginosa in those early studies. Now we have entered the screening era this ‘advantage’ may have disappeared. An Australian head-to-head comparison with 39 children in each group of those diagnosed through screening or through presentation with meconium ileus demonstrated that whilst having meconium ileus appeared not to affect nutritional status, or predispose to other complications of CF, lung function and Schwachman scores were significantly worse in those who had presented with meconium ileus.
Prevention of lung infection Immunization is at the forefront of attempts to prevent infection in all children and this is as important in those with CF. Immunization has also been recommended for the prevention of viruses that may provoke an exacerbation or respiratory deterioration. This includes an annual influenza vaccination although
100
80
Lung infection Patients (%)
Whilst accounting for the effect of age of diagnosis upon outcome, acquisition of P. aeruginosa is independently responsible for deterioration. It is therefore a priority to aim to defer and even eradicate lung infection in those with CF. Identification of infection Identification of infection so that treatment may be given for lung infection is therefore crucial. Respiratory cultures are recommended at each medical contact. However, as infants cannot expectorate, microbiological evidence of infection depends on oropharyngeal (OP) cultures which, whilst having good specificity (95%), have poor sensitivity (44%) resulting in antibiotics being withheld in circumstances where a positive culture would be accompanied by the prescription of antibiotics. The presence of symptoms is also a poor predictor of lung infection as up to 20% of asymptomatic infants have pathogens identified at BAL. Currently most patients have treatment guided by regular OP cultures. With evidence that in children younger than 6 years BAL is well tolerated, with only 3% of procedures being associated with a clinically significant adverse effect related to the procedure; it is
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40
20
0 0–1
2–5
6–10
11–17
18–24
25–34
35–44
45+
Age (years) P. aeruginosa 52.5% S. aureus 50.9% Any Staph 65.3% H. influenza 16.3%
S. maltophilia 12.5% B. cepacia complex 2.8% MRSA 22.6%
Figure 1 Respiratory infections versus age (Cystic Fibrosis Foundation Patient Registry 2008 Annual Data Report, Bethesda, Maryland Ó 2009 Cystic Fibrosis Foundation: Cystic Fibrosis Foundation, 2008. pp. 12.).
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the evidence to support this is lacking. Similarly there is little evidence to support the use of palivizimab to prevent respiratory syncytial virus (RSV). P. aeruginosa is comprised of many highly immunogenic proteins and therefore the search for a vaccine and antibodies to prevent infection is closely pursued. However at present there are no available vaccines or antibodies that can be recommended. S. aureus is the predominant infection in early life and is associated with inflammation and clinical deterioration. Antibiotics given prophylactically for the first 3 years to prevent S. aureus infection is effective in reducing the isolation of the organism, however this has not demonstrated an improvement in clinical outcome. However there is an argument that prophylactic antibiotics provide an advantage to other competing organisms and concern that P. aeruginosa gains such an advantage. This remains debatable with a Cochrane review metaanalysis identified that prophylaxis tended to benefit at least up to the age of 3 years and the UK CF Trust recommends that flucloxacillin be instituted from diagnosis until 3 years of age. If breakthrough infection occurs this is treated in a step-wise manner up to the administration of intravenous antibiotics. However the Cystic Fibrosis Foundation (CFF) remains concerned regarding P. aeruginosa infection and so recommends against the use of prophylactic antistaphylococcal antibiotics. The guidelines from both agencies are summarized (Table 1). As the acquisition of P. aeruginosa is specifically associated with deterioration in clinical status and increased mortality, it appears rational that early treatment of lung infection and prevention of chronic colonization should result in improved clinical outcomes. Indeed, eradication of P. aeruginosa infection is possible if instituted early and reduces the sequelae of lung
deterioration and the emergence of antibiotic resistant strains. This has been taken further and the question of whether it is most effective to prevent or treat early P. aeruginosa is being asked in a randomized trial of prophylactic cycled therapy versus culture-based therapy (the EPIC trial). The clinical sequelae of each approach will thereafter be available. Various strategies are used in eradication including ciprofloxacin, colistin and tobramycin, usually in combination, however there is insufficient evidence regarding which is the optimal strategy. Many units use a combination of colistin and ciprofloxacin for three months. If early re-growth is identified inhaled tobramycin is recommended. The clarification of the optimal treatment strategy to eradicate P. aeruginosa in early infection is being sought through the TORPEDO randomized trial where the effect of 3 months colistin accompanied by either 10 days intravenous ceftazidime and tobramycin or 3 months ciprofloxacin is being sought. For those that favour tobramycin, the ELITE study (EarLy Inhaled Tobramycin for Eradication) has recently demonstrated equivalence between a short (28 days) and long (56 days) duration of inhaled tobramycin therapy. The timing of treatment is critical however as eradication of P. aeruginosa once conversion to a mucoid phenotype is difficult, if not impossible. Trials of azithromycin in those uninfected with P. aeruginosa have not yielded an improvement in lung function, but have reduced the number of exacerbations in this group over a sixmonth period. Patient segregation Segregation of patients with P. aeruginosa is by its nature divisive and interferes with the support network that would be available otherwise. Some question the utility of segregation, not least
Comparison of recommendations from the Cystic Fibrosis Trust and Cystic Fibrosis Foundation UK e Cystic Fibrosis Trust
USA e Cystic Fibrosis Foundation
Antistaphylococcal antibiotic prophylaxis (flucloxacillin) (should be commenced upon diagnosis and continued until the age of 3 years). Sputum samples or cough swabs should be sent for culture at every medical contact. The culture of P. aeruginosa in a patient who was previously free of P. aeruginosa should prompt the administration of an appropriate eradication regimen in a timely fashion. All patients with chronic P. aeruginosa infection should have long term nebulized anti-pseudomonal therapy, unless contra-indicated. Pulmonary exacerbations should be treated promptly with oral or intravenous antibiotics e intravenous if the patient’s condition does not improve with oral treatment. A six-month trial of azithromycin should be considered in those who are deteriorating on conventional therapy regardless of infection status.
Recommends against the use of oral prophylactic antistaphylococcal antibiotics.
Nutrition and physiotherapy support should be intensified during exacerbations.
It is recommended that those of 6 years and older with chronic P. aeruginosa infection receive long-term nebulized tobramycin. There is insufficient evidence to recommend the use of single antibiotics instead of antibiotics given in combination. For patients of 6 years and older with chronic P. aeruginosa infection, the chronic use of azithromycin is recommended. It is recommended that patients of 6 years and older receive chronic dornase alpha. It is recommended that all patients of 6 years and older receive chronic inhaled hypertonic saline. Recommends that airway clearance therapy be increased as part of treatment of an acute exacerbation.
Table 1
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because the origin of most patients’ P. aeruginosa is the environment. However the absence of such segregation policies have resulted in the dissemination of virulent epidemic strains and significantly increased acquisition among patients in clinics with a considerable difference identified once a segregation policy had been adopted. The segregation policy requires complete separation in time and space such that common areas are not used by multiple patients.
duration of a treatment course. The only firm recommendation is that where aminoglycosides are used tobramycin, in once-daily dosing, is preferred. There is an option on an individual patient basis to opt for home intravenous antibiotic administration. The evidence base again is limited however there appears to be unique benefits and disadvantages to this approach which need to be assessed in the context of the individual patient and family.
Multidisciplinary management Treatment of established infection In terms of treatment of established infection in CF the poor quality of the current evidence base makes determining the optimal treatment strategy impossible. There is a consensus that treatment of S. aureus and H. influenzae should, a breakthrough infection become established, be treated with appropriate antibiotics in a step-wise approach with efficacy of treatment being confirmed with follow-up respiratory cultures. Treatment should be escalated up to intravenous antibiotics should the attempts at eradication not be successful. However following a controlled trial of long-term cephalexin demonstrating a significant increase in isolates of P. aeruginosa, it is advised that cephalosporins should be avoided. Treatment of those with chronic P. aeruginosa infection may be split into maintenance phase chronic treatment and treatment of exacerbations.
CF should continuously be regarded a multi-system disease. A variety of specialists should be available to offer support to the care of such children. The optimal CF team would consist of nurse specialists and physicians, physiotherapists, dieticians, pharmacists, social workers and psychologists, with access to specialist microbiology advice and investigation, an endocrinologist, a gastroenterologist and other tertiary specialists when required. This is largely achieved either by patients attending specialist tertiary centres or attending their local hospital with care shared with a specialist centre. Airway clearance Physiotherapy is effective in increasing clearance of mucus, at least in the short term. As with much of the CF literature, the effect upon long-term benefit and the optimal approach is unclear but suggest that positive expiratory pressure (PEP), non-invasive ventilation (NIV) for patients with respiratory failure and additional physical training are likely to confer benefit. Adjuncts to optimize the effectiveness of mucus clearance by physiotherapy (or vice versa) include recombinant human DNase, hypertonic saline and N-acetylcysteine (NAC). DNase reduces the viscosity of mucus by digesting the DNA released from neutrophils and while expensive, significantly improves lung function. Nebulized hypertonic saline can improve mucus clearance by reducing viscosity by breaking ionic bonds within the mucus, restoring airway surface liquid volume, enhancing mucociliary clearance and hydrating the airway. While this may not have a sustained effect on lung function, quality of life is much improved in those taking hypertonic saline and they suffer less pulmonary exacerbations. Both DNase and hypertonic saline are recommended by the Cystic Fibrosis Foundation for all those above 6 years with CF. The evidence base supporting the routine use of NAC is less robust however and, whilst the irritant effect promoting cough may not harm, there appears to be a need for more research before this can be recommended.
Treatment of Chronic P. aeruginosa Chronic P. aeruginosa infection may be defined as the isolation of P. aeruginosa in more than half of samples taken that year. For those chronically infected with P. aeruginosa, it is recommended that regular nebulized anti-pseudomonals be instituted, initially with nebulized colistin. Thereafter nebulized tobramycin should be considered, given for 28 days followed by a 28-day break and then repeated. In patients who appear to be deteriorating, a trial of azithromycin is recommended as this may provide improvement in some patients. There may also be benefits of long-term azithromycin use for those not yet infected with P. aeruginosa. Treatment of infective exacerbations in those with P. aeruginosa For those chronically infected with P. aeruginosa an ‘infective exacerbation’ essentially refers to a period of increased symptoms that would include at least four of: increased productive cough or breathlessness decreased exercise tolerance absence from school or work changes in the appearance or volume of sputum new signs on auscultation new chest radiograph signs loss of appetite fall in respiratory function fever requiring treatment with intravenous antibiotics. UK Cystic Fibrosis Trust Antibiotic Working Group
Nutrition Pancreatic insufficiency and related malabsorption, cystic fibrosis-related diabetes mellitus (CFRD), anorexia due to chronic ill health and increased energy demands make optimization of nutrition critical to the management of children with CF. The aim is to maintain normal growth velocity for age. Those patients with nutritional optimization have better weight, height and survival. Lung function is intimately related to BMI, with an almost linear association (Figure 2) with FEV1 being most conserved in those with BMI values greater than the 50% centile. To achieve optimal growth, the effect of pancreatic insufficiency is reduced by pancreatic enzyme replacement therapy being administered from diagnosis. Pancreatic insufficiency should be confirmed by measuring pancreatic elastase in stool.
Initially a trial of oral antibiotics may be reasonable however if these are unsuccessful, then a course of intravenous antibiotics is recommended. Committing to a prolonged course of antibiotics is a significant undertaking and is associated with adverse effects from the drug regime itself and impact on family life. However due to the lack of a quality evidence base, it is not possible to determine the optimal combinations of antibiotics or
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ability to adapt during a single antibiotic treatment course. Antibiotic resistance is widespread and there are no new antibiotics on the horizon that exert a novel mechanism of action. In the absence of new antibiotics, focus turns to ways in which our existing armoury of antibiotics may be made more effective. The aim is to achieve an adequate concentration of antibiotic at the site of infection. Administration is achieved via the oral, intravenous or inhalation routes. The difficulty is that in the CF lung plugs of mucus block the free passage of nebulized molecules and systemically administered agents may not reach the biofilm which ‘float’ on the damaged epithelial surface, away from the circulation. Even if the agent does get to the site of infection, penetrating the biofilm to reach the protected bacteria within is a challenge. If the antibiotic reaches the bacterial cell the concentration of antibiotic within the cell needs to exceed the minimum inhibitory concentration (MIC) in order to kill the organism. P. aeruginosa however hosts efflux pumps that act to remove toxic substances from within the cell. Additionally it may upregulate the expression of these efflux pumps to increase its virulence. This is particularly the case with epidemic strains.
100
FEV1 predicted (%)
90
80
70
Males Females
Goal 50th percentile 60 <5
10
20
30
40
50
60
70
80
90
BMI percentiles Figure 2 FEV1 percent predicted versus BMI percentile in children 6e20 years (Cystic Fibrosis Foundation Patient Registry. 2008 Annual Data Report: Bethesda, Maryland Ó 2009 Cystic Fibrosis Foundation. Cystic Fibrosis Foundation, 2008. pp. 8.).
Drug delivery mechanisms Manipulation of antibiotics to increase delivery through the biofilm is of therefore of interest. Liposomal preparations, polymerbased nanoparticles and ultrasound enhancement of passage of drug across the biofilm are under investigation. Aerosolized antibiotics including inhaled dry powder formulations of common antibiotics are under development and trials including tobramycin, ciprofloxacin and nebulized levofloxacin are underway.
The diet may need supplementation with fat-soluble vitamins, and multivitamins. To optimize calorie intake aiming for 110e200% of that of the healthy population, if oral feeding is insufficient patients should be provided with enteral (either by nasogastric or gastrostomy) or parenteral nutrition. Surveillance is important not only of nutritional state but also of sequelae including puberty, and bone density. Cystic Fibrosis Foundation guidelines on nutrition recommend: From age 2 years, energy intakes greater than the standard for the general population. For children with growth deficits nutritional supplements in addition to usual dietary intake (although a Cochrane review found no evidence of this recommendation). Maintenance of normal ranges of weight for height e using age-appropriate BMI in older children. That children diagnosed before the age of 2 years, reach a weight for length status of 50th centile by age of 2 years. Pancreatic enzyme supplementation appropriate for weight.
Antibiotic adjuvants Antibiotic adjuvants are agents that themselves may not exhibit bactericidal activity, but act to potentiate the activity of a coadministered antibiotic. Bacteriophages, quorum sensing inhibitors and vitamins may exert a beneficial effect over and above the effect of the antibiotic, however many of these studies are in their infancy. A recent Cochrane review demonstrated that these antibiotic adjuvant strategies remain novel with few being examined in the context of a rigorous clinical trial and so cannot be recommended currently. It is likely that improvements in the future however will be dependent upon these, or similar novel interventions.
Summary
In addition the UK CF Trust nutrition working group recommend: Monitoring of bone mineral density by DEXA scan in those over 10 years of age. Supplemental vitamins A, D and E in those pancreatic insufficient. Invasive nutritional support should commence when oral methods of maintaining an adequate nutritional status have failed. A combination of the CF and diabetes diet in those with CF related diabetes mellitus.
Cystic fibrosis is a multi-system disorder mediated by a gene mutation that causes an error of electrolyte and water transport across epithelia. This leads to dry epithelial surfaces that in the lungs predispose to infection and inflammation. It is infection, often with P. aeruginosa, that is the primary predictor of clinical deterioration. At present acquisition of this devastating bacteria is not predictable, is challenging to detect at an early stage before chronic infection is established, at which point the bacteria can no longer be eradicated. Optimizing the well-being of children from early diagnosis is essential to maintain lung function, quality of life and improve long-term survival. Improvements over recent years have led to maintaining lung function over a longer period and deferring the morbidity associated with CF into the late-teens and third decade of life. Comprehensive proactive management using the
Future directions It is clear that infection and inflammation are the primary influencing factors of lung function and survival with the acquisition of P. aeruginosa being uniquely responsible for clinical deterioration. The difficulty posed by P. aeruginosa is its inherent diversity and
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Langton Hewer SC, Smyth AR. Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis. Cochrane Database Syst Rev 2009(4): CD004197. O’Sullivan BP, Freedman SD. Cystic fibrosis. Lancet 2009; 373: 1891e904. Sagel S, Gibson R, Emerson J, et al. Impact of Pseudomonas and Staphylococcus infection on inflammation and clinical status in young children with cystic fibrosis. J Pediatr 2009; 154: 183e8. UK Cystic Fibrosis Nutrition Working Group. Nutritional management of cystic fibrosis. Cystic Fibrosis Trust, 2002.
biopsychosocial model within a multidisciplinary team is essential to improving quality of life and survival such that, even when facing a seemingly well child in clinic, there is no room for complacency. A
FURTHER READING CF Trust. Standards for the clinical care of children and adults with cystic fibrosis in the UK. Cystic Fibrosis Trust, 2001. Emerson J, Rosenfeld M, McNamara S, Ramsey B, Gibson RL. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatr Pulmonol 2002; 34: 91e100. Flume P, O’Sullivan B, Robinson K, et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med 2007; 176: 957e69. Flume PA, Mogayzel Jr PJ, Robinson KA, et al. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Respir Crit Care Med 2009; 180: 802e8. Kerem E, Conway S, Elborn S, Heijerman H. Standards of care for patients with cystic fibrosis: an European consensus. J Cyst Fibros 2005; 4: 7e26. Lai HJ, Cheng Y, Cho H, Kosorok MR, Farrell PM. Association between initial disease presentation, lung disease outcomes, and survival in patients with cystic fibrosis. Am J Epidemiol 2004; 159: 537e46.
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Practice points C
C
C
C
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Early diagnosis of cystic fibrosis through screening enables a proactive management strategy and family education. Optimizing nutrition and airway clearance defers clinical deterioration. Eradicating early Pseudomonas aeruginosa infection and deferring chronic colonization postpones the adverse sequelae of reduced lung function and quality of life. Retrieving representative microbiological samples from the lungs depends on bronchoalveolar lavage. When this is not practicable clinicians should be aware that upper respiratory specimens may fail to detect lower respiratory infection.
Ó 2010 Elsevier Ltd. All rights reserved.
Optimizing respiratory health in children with cystic fibrosis
manifest disease. Forty years ago, few children survived beyond infancy however improvements in management have led to dramatic changes in the life expectancy for patients with CF. The mean life expectancy for a baby born in 2003 was 42 years for a boy and 36 years for a girl. The aim of current research and clinical care is to increase this to beyond 50 years. Traditionally the survival for girls with CF appeared to be worse than that of their male counterparts, however this may not necessarily be universal. There are numerous gene mutations that effect a change in the presence or function of the cystic fibrosis transmembrane regulator (CFTR). This cell membrane protein acts directly as a chloride channel but is also responsible for regulating the epithelial sodium channel (ENaC). The net result being impaired chloride transport and excess sodium loss resulting in a depletion of the airway surface liquid, thickening mucus that entraps cell surface cilia. CFTR mutations also may be responsible for facilitating infection with early non-mucoid Pseudomonas aeruginosa and reducing the efficacy of the adaptive immune response to later mucoid P. aeruginosa. The effects upon the function of CFTR are not restricted to the lungs, resulting in the complications of pancreatic exocrine and eventual endocrine insufficiency, abnormal intestinal function and poor nutrition, skin salt loss, metabolic abnormalities and biliary fibrosis. Nasal polyps, congenital absence of the vas deferens and CF related arthritis further add to the effect the disease has on quality of life.
Matthew N Hurley Alan R Smyth
Abstract Cystic fibrosis is a multi-system genetic disorder causing thick secretions, lung infection and pancreatic insufficiency. Optimizing respiratory health in children with cystic fibrosis depends upon meticulous attention to maintaining general health, in addition to preserving lung health. Maximizing nutrition and growth are essential as these are independent predictors of lung function and survival. Neonatal screening has enabled an earlier, more proactive approach to optimizing health. However the primary predictor of deterioration is the acquisition of the opportunistic bacterium Pseudomonas aeruginosa. Eradication of chronic infection with this organism is impossible, leading to lung destruction and shortened life expectancy for individuals with CF. The optimal strategies for managing this critical complication of cystic fibrosis are the subject of ongoing research, however these strategies may depend upon antibiotic regimens to which the bacteria may gain resistance. Novel strategies, adopted alongside continued improvements in care, are needed to further defer the complications and deterioration experienced by patients with cystic fibrosis, enhance quality of life and extend survival.
Inflammation and infection Those with cystic fibrosis have an up-regulated inflammatory cascade, however it has been contentious whether this is due to an intrinsic pro-inflammatory state, disproportionate inflammation in result to infection or a proportionate immune response. In studies aimed at answering this question extensive examination of bronchoalveolar lavage (BAL) fluid suggests that those with infection have significantly increased levels of inflammatory mediators compared to those without. Attempts at ameliorating the lung damage with oral corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) have demonstrated improvements in lung function. Concerns regarding side effects have however, prevented the routine use of oral corticosteroids.
Keywords cystic fibrosis; infection; Pseudomonas
Introduction Cystic fibrosis (CF) is a multi-organ disease with recurrent and chronic lung infection being the critical life-limiting feature. The subsequent lung destruction, accompanied by pancreatic insufficiency, alongside increased metabolic demands, adversely affects growth and leads to respiratory failure, a reduced quality of life and premature death. In infants, treatment focuses on early aggressive management of lung infection and optimization of nutritional status. This continues alongside treatment of complications in later childhood. Cystic fibrosis is the commonest life-limiting autosomal recessive condition; in the UK approximately 8000 people have
Early care Age at diagnosis is significantly associated with survival. For each year increase in age at diagnosis there is an accompanied increase in the acquisition of P. aeruginosa, reduced lung function and survival.
Matthew N Hurley BSc (Hons) MBBCh MRCPCH is a Clinical Research Fellow in the Academic Department of Child Health, University of Nottingham, Queens Medical Centre, Nottingham, UK. Conflicts of interest: none.
Diagnosis The diagnosis of cystic fibrosis depends upon the presence of one or more characteristic phenotypic features, a positive newborn screening test result or a history of CF in a sibling and laboratory evidence of a CFTR abnormality. CFTR abnormality may be demonstrated by elevated sweat chloride concentration, identification of mutations in each CFTR gene known to cause CF or in vivo demonstration of characteristic abnormalities in ion transport across the nasal epithelium. In the UK however since the
Alan R Smyth MA MBBS MCRP MD FRCPCH is a Professor in Child Health at the School of Clinical Sciences, University of Nottingham, Director of Trent Local Children’s Research Network (TLC-RN) and Co-ordinating Editor of Cochrane Cystic Fibrosis & Genetic Disorders Group, UK. Conflicts of interest: none.
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Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: RESPIRATORY MEDICINE
introduction of universal neonatal screening, the vast majority of diagnoses are made via this route. The justification for neonatal screening revolves around recent improvements in outcome that have been attributed to improvements in intervention. The natural suggestion is that if these improvements are instituted earlier, before lung damage and nutritional status is impaired, that clinical status will improve. There are obvious confounders in outcomes of screening, an intervention that was instituted at the same time as other improvements in management. However US CF Registry data strongly suggest that screening confers a survival advantage. Superficially, the early clinical course of children with CF can be split e those diagnosed through screening and those diagnosed prior to the neonatal screening procedure due to an early complication. This group of patients largely present due to meconium ileus.
likely that in future BAL will become a more common undertaking and treatment, as a result, will become more targeted. Infections of the CF lung The altered lung environment in those with CF provides an ideal niche for bacterial growth. There appears to be a recognizable sequence of escalation in the organisms isolated from children with CF (Figure 1). One can speculate that this progression represents a change in competitive advantage between species. In infancy Staphylococcus aureus predominates as the most common organism isolated (50%) with the prevalence peaking in the 6e10 age group. Haemophilus influenzae and P. aeruginosa are similarly prevalent until about age 5 (30e35% prevalence) when the prevalence of P. aeruginosa increases such that it is the most common organism isolated in the 11e17 age group with a prevalence increasing to the 80% level in the late-teens. The opportunist P. aeruginosa eventually establishes a chronic infection causing reduced growth, faster deterioration of lung function and progression to end-stage lung disease as evidenced by lung transplantation or death. Decline in lung function is largely responsible for the morbidity and mortality in CF and over the last two decades more efficient treatment of pulmonary infections has accompanied the increase in life expectancy. Burkholderia cepacia is a similar opportunist although the prevalence has reduced over time.
The effect of meconium ileus The influence that meconium ileus has on outcomes for children with CF has been controversial. A large study including the 27 703 patients on the cystic fibrosis registry between 1986 and 2000 (including the pre-screening era) concluded that the risk of acquiring P. aeruginosa and mortality was significantly higher in those who presented with meconium ileus compared to those identified through screening. In the pre-screening era it is possible that the disadvantage conferred by having meconium ileus was reduced by the advantage of earlier diagnosis such that there were no differences in lung function, weight and height and acquisition of P. aeruginosa in those early studies. Now we have entered the screening era this ‘advantage’ may have disappeared. An Australian head-to-head comparison with 39 children in each group of those diagnosed through screening or through presentation with meconium ileus demonstrated that whilst having meconium ileus appeared not to affect nutritional status, or predispose to other complications of CF, lung function and Schwachman scores were significantly worse in those who had presented with meconium ileus.
Prevention of lung infection Immunization is at the forefront of attempts to prevent infection in all children and this is as important in those with CF. Immunization has also been recommended for the prevention of viruses that may provoke an exacerbation or respiratory deterioration. This includes an annual influenza vaccination although
100
80
Lung infection Patients (%)
Whilst accounting for the effect of age of diagnosis upon outcome, acquisition of P. aeruginosa is independently responsible for deterioration. It is therefore a priority to aim to defer and even eradicate lung infection in those with CF. Identification of infection Identification of infection so that treatment may be given for lung infection is therefore crucial. Respiratory cultures are recommended at each medical contact. However, as infants cannot expectorate, microbiological evidence of infection depends on oropharyngeal (OP) cultures which, whilst having good specificity (95%), have poor sensitivity (44%) resulting in antibiotics being withheld in circumstances where a positive culture would be accompanied by the prescription of antibiotics. The presence of symptoms is also a poor predictor of lung infection as up to 20% of asymptomatic infants have pathogens identified at BAL. Currently most patients have treatment guided by regular OP cultures. With evidence that in children younger than 6 years BAL is well tolerated, with only 3% of procedures being associated with a clinically significant adverse effect related to the procedure; it is
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Age (years) P. aeruginosa 52.5% S. aureus 50.9% Any Staph 65.3% H. influenza 16.3%
S. maltophilia 12.5% B. cepacia complex 2.8% MRSA 22.6%
Figure 1 Respiratory infections versus age (Cystic Fibrosis Foundation Patient Registry 2008 Annual Data Report, Bethesda, Maryland Ó 2009 Cystic Fibrosis Foundation: Cystic Fibrosis Foundation, 2008. pp. 12.).
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the evidence to support this is lacking. Similarly there is little evidence to support the use of palivizimab to prevent respiratory syncytial virus (RSV). P. aeruginosa is comprised of many highly immunogenic proteins and therefore the search for a vaccine and antibodies to prevent infection is closely pursued. However at present there are no available vaccines or antibodies that can be recommended. S. aureus is the predominant infection in early life and is associated with inflammation and clinical deterioration. Antibiotics given prophylactically for the first 3 years to prevent S. aureus infection is effective in reducing the isolation of the organism, however this has not demonstrated an improvement in clinical outcome. However there is an argument that prophylactic antibiotics provide an advantage to other competing organisms and concern that P. aeruginosa gains such an advantage. This remains debatable with a Cochrane review metaanalysis identified that prophylaxis tended to benefit at least up to the age of 3 years and the UK CF Trust recommends that flucloxacillin be instituted from diagnosis until 3 years of age. If breakthrough infection occurs this is treated in a step-wise manner up to the administration of intravenous antibiotics. However the Cystic Fibrosis Foundation (CFF) remains concerned regarding P. aeruginosa infection and so recommends against the use of prophylactic antistaphylococcal antibiotics. The guidelines from both agencies are summarized (Table 1). As the acquisition of P. aeruginosa is specifically associated with deterioration in clinical status and increased mortality, it appears rational that early treatment of lung infection and prevention of chronic colonization should result in improved clinical outcomes. Indeed, eradication of P. aeruginosa infection is possible if instituted early and reduces the sequelae of lung
deterioration and the emergence of antibiotic resistant strains. This has been taken further and the question of whether it is most effective to prevent or treat early P. aeruginosa is being asked in a randomized trial of prophylactic cycled therapy versus culture-based therapy (the EPIC trial). The clinical sequelae of each approach will thereafter be available. Various strategies are used in eradication including ciprofloxacin, colistin and tobramycin, usually in combination, however there is insufficient evidence regarding which is the optimal strategy. Many units use a combination of colistin and ciprofloxacin for three months. If early re-growth is identified inhaled tobramycin is recommended. The clarification of the optimal treatment strategy to eradicate P. aeruginosa in early infection is being sought through the TORPEDO randomized trial where the effect of 3 months colistin accompanied by either 10 days intravenous ceftazidime and tobramycin or 3 months ciprofloxacin is being sought. For those that favour tobramycin, the ELITE study (EarLy Inhaled Tobramycin for Eradication) has recently demonstrated equivalence between a short (28 days) and long (56 days) duration of inhaled tobramycin therapy. The timing of treatment is critical however as eradication of P. aeruginosa once conversion to a mucoid phenotype is difficult, if not impossible. Trials of azithromycin in those uninfected with P. aeruginosa have not yielded an improvement in lung function, but have reduced the number of exacerbations in this group over a sixmonth period. Patient segregation Segregation of patients with P. aeruginosa is by its nature divisive and interferes with the support network that would be available otherwise. Some question the utility of segregation, not least
Comparison of recommendations from the Cystic Fibrosis Trust and Cystic Fibrosis Foundation UK e Cystic Fibrosis Trust
USA e Cystic Fibrosis Foundation
Antistaphylococcal antibiotic prophylaxis (flucloxacillin) (should be commenced upon diagnosis and continued until the age of 3 years). Sputum samples or cough swabs should be sent for culture at every medical contact. The culture of P. aeruginosa in a patient who was previously free of P. aeruginosa should prompt the administration of an appropriate eradication regimen in a timely fashion. All patients with chronic P. aeruginosa infection should have long term nebulized anti-pseudomonal therapy, unless contra-indicated. Pulmonary exacerbations should be treated promptly with oral or intravenous antibiotics e intravenous if the patient’s condition does not improve with oral treatment. A six-month trial of azithromycin should be considered in those who are deteriorating on conventional therapy regardless of infection status.
Recommends against the use of oral prophylactic antistaphylococcal antibiotics.
Nutrition and physiotherapy support should be intensified during exacerbations.
It is recommended that those of 6 years and older with chronic P. aeruginosa infection receive long-term nebulized tobramycin. There is insufficient evidence to recommend the use of single antibiotics instead of antibiotics given in combination. For patients of 6 years and older with chronic P. aeruginosa infection, the chronic use of azithromycin is recommended. It is recommended that patients of 6 years and older receive chronic dornase alpha. It is recommended that all patients of 6 years and older receive chronic inhaled hypertonic saline. Recommends that airway clearance therapy be increased as part of treatment of an acute exacerbation.
Table 1
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because the origin of most patients’ P. aeruginosa is the environment. However the absence of such segregation policies have resulted in the dissemination of virulent epidemic strains and significantly increased acquisition among patients in clinics with a considerable difference identified once a segregation policy had been adopted. The segregation policy requires complete separation in time and space such that common areas are not used by multiple patients.
duration of a treatment course. The only firm recommendation is that where aminoglycosides are used tobramycin, in once-daily dosing, is preferred. There is an option on an individual patient basis to opt for home intravenous antibiotic administration. The evidence base again is limited however there appears to be unique benefits and disadvantages to this approach which need to be assessed in the context of the individual patient and family.
Multidisciplinary management Treatment of established infection In terms of treatment of established infection in CF the poor quality of the current evidence base makes determining the optimal treatment strategy impossible. There is a consensus that treatment of S. aureus and H. influenzae should, a breakthrough infection become established, be treated with appropriate antibiotics in a step-wise approach with efficacy of treatment being confirmed with follow-up respiratory cultures. Treatment should be escalated up to intravenous antibiotics should the attempts at eradication not be successful. However following a controlled trial of long-term cephalexin demonstrating a significant increase in isolates of P. aeruginosa, it is advised that cephalosporins should be avoided. Treatment of those with chronic P. aeruginosa infection may be split into maintenance phase chronic treatment and treatment of exacerbations.
CF should continuously be regarded a multi-system disease. A variety of specialists should be available to offer support to the care of such children. The optimal CF team would consist of nurse specialists and physicians, physiotherapists, dieticians, pharmacists, social workers and psychologists, with access to specialist microbiology advice and investigation, an endocrinologist, a gastroenterologist and other tertiary specialists when required. This is largely achieved either by patients attending specialist tertiary centres or attending their local hospital with care shared with a specialist centre. Airway clearance Physiotherapy is effective in increasing clearance of mucus, at least in the short term. As with much of the CF literature, the effect upon long-term benefit and the optimal approach is unclear but suggest that positive expiratory pressure (PEP), non-invasive ventilation (NIV) for patients with respiratory failure and additional physical training are likely to confer benefit. Adjuncts to optimize the effectiveness of mucus clearance by physiotherapy (or vice versa) include recombinant human DNase, hypertonic saline and N-acetylcysteine (NAC). DNase reduces the viscosity of mucus by digesting the DNA released from neutrophils and while expensive, significantly improves lung function. Nebulized hypertonic saline can improve mucus clearance by reducing viscosity by breaking ionic bonds within the mucus, restoring airway surface liquid volume, enhancing mucociliary clearance and hydrating the airway. While this may not have a sustained effect on lung function, quality of life is much improved in those taking hypertonic saline and they suffer less pulmonary exacerbations. Both DNase and hypertonic saline are recommended by the Cystic Fibrosis Foundation for all those above 6 years with CF. The evidence base supporting the routine use of NAC is less robust however and, whilst the irritant effect promoting cough may not harm, there appears to be a need for more research before this can be recommended.
Treatment of Chronic P. aeruginosa Chronic P. aeruginosa infection may be defined as the isolation of P. aeruginosa in more than half of samples taken that year. For those chronically infected with P. aeruginosa, it is recommended that regular nebulized anti-pseudomonals be instituted, initially with nebulized colistin. Thereafter nebulized tobramycin should be considered, given for 28 days followed by a 28-day break and then repeated. In patients who appear to be deteriorating, a trial of azithromycin is recommended as this may provide improvement in some patients. There may also be benefits of long-term azithromycin use for those not yet infected with P. aeruginosa. Treatment of infective exacerbations in those with P. aeruginosa For those chronically infected with P. aeruginosa an ‘infective exacerbation’ essentially refers to a period of increased symptoms that would include at least four of: increased productive cough or breathlessness decreased exercise tolerance absence from school or work changes in the appearance or volume of sputum new signs on auscultation new chest radiograph signs loss of appetite fall in respiratory function fever requiring treatment with intravenous antibiotics. UK Cystic Fibrosis Trust Antibiotic Working Group
Nutrition Pancreatic insufficiency and related malabsorption, cystic fibrosis-related diabetes mellitus (CFRD), anorexia due to chronic ill health and increased energy demands make optimization of nutrition critical to the management of children with CF. The aim is to maintain normal growth velocity for age. Those patients with nutritional optimization have better weight, height and survival. Lung function is intimately related to BMI, with an almost linear association (Figure 2) with FEV1 being most conserved in those with BMI values greater than the 50% centile. To achieve optimal growth, the effect of pancreatic insufficiency is reduced by pancreatic enzyme replacement therapy being administered from diagnosis. Pancreatic insufficiency should be confirmed by measuring pancreatic elastase in stool.
Initially a trial of oral antibiotics may be reasonable however if these are unsuccessful, then a course of intravenous antibiotics is recommended. Committing to a prolonged course of antibiotics is a significant undertaking and is associated with adverse effects from the drug regime itself and impact on family life. However due to the lack of a quality evidence base, it is not possible to determine the optimal combinations of antibiotics or
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ability to adapt during a single antibiotic treatment course. Antibiotic resistance is widespread and there are no new antibiotics on the horizon that exert a novel mechanism of action. In the absence of new antibiotics, focus turns to ways in which our existing armoury of antibiotics may be made more effective. The aim is to achieve an adequate concentration of antibiotic at the site of infection. Administration is achieved via the oral, intravenous or inhalation routes. The difficulty is that in the CF lung plugs of mucus block the free passage of nebulized molecules and systemically administered agents may not reach the biofilm which ‘float’ on the damaged epithelial surface, away from the circulation. Even if the agent does get to the site of infection, penetrating the biofilm to reach the protected bacteria within is a challenge. If the antibiotic reaches the bacterial cell the concentration of antibiotic within the cell needs to exceed the minimum inhibitory concentration (MIC) in order to kill the organism. P. aeruginosa however hosts efflux pumps that act to remove toxic substances from within the cell. Additionally it may upregulate the expression of these efflux pumps to increase its virulence. This is particularly the case with epidemic strains.
100
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Goal 50th percentile 60 <5
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BMI percentiles Figure 2 FEV1 percent predicted versus BMI percentile in children 6e20 years (Cystic Fibrosis Foundation Patient Registry. 2008 Annual Data Report: Bethesda, Maryland Ó 2009 Cystic Fibrosis Foundation. Cystic Fibrosis Foundation, 2008. pp. 8.).
Drug delivery mechanisms Manipulation of antibiotics to increase delivery through the biofilm is of therefore of interest. Liposomal preparations, polymerbased nanoparticles and ultrasound enhancement of passage of drug across the biofilm are under investigation. Aerosolized antibiotics including inhaled dry powder formulations of common antibiotics are under development and trials including tobramycin, ciprofloxacin and nebulized levofloxacin are underway.
The diet may need supplementation with fat-soluble vitamins, and multivitamins. To optimize calorie intake aiming for 110e200% of that of the healthy population, if oral feeding is insufficient patients should be provided with enteral (either by nasogastric or gastrostomy) or parenteral nutrition. Surveillance is important not only of nutritional state but also of sequelae including puberty, and bone density. Cystic Fibrosis Foundation guidelines on nutrition recommend: From age 2 years, energy intakes greater than the standard for the general population. For children with growth deficits nutritional supplements in addition to usual dietary intake (although a Cochrane review found no evidence of this recommendation). Maintenance of normal ranges of weight for height e using age-appropriate BMI in older children. That children diagnosed before the age of 2 years, reach a weight for length status of 50th centile by age of 2 years. Pancreatic enzyme supplementation appropriate for weight.
Antibiotic adjuvants Antibiotic adjuvants are agents that themselves may not exhibit bactericidal activity, but act to potentiate the activity of a coadministered antibiotic. Bacteriophages, quorum sensing inhibitors and vitamins may exert a beneficial effect over and above the effect of the antibiotic, however many of these studies are in their infancy. A recent Cochrane review demonstrated that these antibiotic adjuvant strategies remain novel with few being examined in the context of a rigorous clinical trial and so cannot be recommended currently. It is likely that improvements in the future however will be dependent upon these, or similar novel interventions.
Summary
In addition the UK CF Trust nutrition working group recommend: Monitoring of bone mineral density by DEXA scan in those over 10 years of age. Supplemental vitamins A, D and E in those pancreatic insufficient. Invasive nutritional support should commence when oral methods of maintaining an adequate nutritional status have failed. A combination of the CF and diabetes diet in those with CF related diabetes mellitus.
Cystic fibrosis is a multi-system disorder mediated by a gene mutation that causes an error of electrolyte and water transport across epithelia. This leads to dry epithelial surfaces that in the lungs predispose to infection and inflammation. It is infection, often with P. aeruginosa, that is the primary predictor of clinical deterioration. At present acquisition of this devastating bacteria is not predictable, is challenging to detect at an early stage before chronic infection is established, at which point the bacteria can no longer be eradicated. Optimizing the well-being of children from early diagnosis is essential to maintain lung function, quality of life and improve long-term survival. Improvements over recent years have led to maintaining lung function over a longer period and deferring the morbidity associated with CF into the late-teens and third decade of life. Comprehensive proactive management using the
Future directions It is clear that infection and inflammation are the primary influencing factors of lung function and survival with the acquisition of P. aeruginosa being uniquely responsible for clinical deterioration. The difficulty posed by P. aeruginosa is its inherent diversity and
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Langton Hewer SC, Smyth AR. Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis. Cochrane Database Syst Rev 2009(4): CD004197. O’Sullivan BP, Freedman SD. Cystic fibrosis. Lancet 2009; 373: 1891e904. Sagel S, Gibson R, Emerson J, et al. Impact of Pseudomonas and Staphylococcus infection on inflammation and clinical status in young children with cystic fibrosis. J Pediatr 2009; 154: 183e8. UK Cystic Fibrosis Nutrition Working Group. Nutritional management of cystic fibrosis. Cystic Fibrosis Trust, 2002.
biopsychosocial model within a multidisciplinary team is essential to improving quality of life and survival such that, even when facing a seemingly well child in clinic, there is no room for complacency. A
FURTHER READING CF Trust. Standards for the clinical care of children and adults with cystic fibrosis in the UK. Cystic Fibrosis Trust, 2001. Emerson J, Rosenfeld M, McNamara S, Ramsey B, Gibson RL. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatr Pulmonol 2002; 34: 91e100. Flume P, O’Sullivan B, Robinson K, et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med 2007; 176: 957e69. Flume PA, Mogayzel Jr PJ, Robinson KA, et al. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Respir Crit Care Med 2009; 180: 802e8. Kerem E, Conway S, Elborn S, Heijerman H. Standards of care for patients with cystic fibrosis: an European consensus. J Cyst Fibros 2005; 4: 7e26. Lai HJ, Cheng Y, Cho H, Kosorok MR, Farrell PM. Association between initial disease presentation, lung disease outcomes, and survival in patients with cystic fibrosis. Am J Epidemiol 2004; 159: 537e46.
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Early diagnosis of cystic fibrosis through screening enables a proactive management strategy and family education. Optimizing nutrition and airway clearance defers clinical deterioration. Eradicating early Pseudomonas aeruginosa infection and deferring chronic colonization postpones the adverse sequelae of reduced lung function and quality of life. Retrieving representative microbiological samples from the lungs depends on bronchoalveolar lavage. When this is not practicable clinicians should be aware that upper respiratory specimens may fail to detect lower respiratory infection.
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