Cystic fibrosis revisited

Introduction

Cystic fibrosis (CF) is characterized by a progressive decline in pulmonary function secondary to chronic lung infections, exocrine pancreatic insufficiency leading to malnutrition, liver disease, and growth impairment. Pathological, functional, and imaging studies all support the presence in early life of significant abnormalities in the small airways in individuals who have CF.[1] CF lung disease can vary widely in its severity and symptoms and can mimic other diseases such as asthma or bronchitis, making diagnosis and management challenging.[2] The natural history of CF lung disease is one of chronic progression with intermittent episodes of acute worsening or “pulmonary exacerbations.” These impact on survival in CF, reduce health-related quality of life due to hospitalization, and increase health costs.[3]

Clinical Manifestations

Phenotypic features consistent with a diagnosis of CF include the following:[4]

1. Chronic sinopulmonary disease manifested by:

   1. Persistent colonization/infection with typical CF pathogens including Staphylococcus aureus, nontypeable Haemophilus influenzae, mucoid and nonmucoid Pseudomonas aeruginosa, and Burkholderia cepacia
   2. Chronic cough and sputum production
   3. Persistent chest radiograph abnormalities (e.g., bronchiectasis, atelectasis, infiltrates, hyperinflation)
   4. Airway obstruction manifested by wheezing and air trapping
   5. Nasal polyps; radiographic or computed tomographic abnormalities of paranasal sinuses
   6. Digital clubbing.

2. Gastrointestinal and nutritional abnormalities including:

   1. Intestinal: meconium ileus, distal intestinal obstruction syndrome, rectal prolapse
   2. Pancreatic: pancreatic insufficiency, recurrent pancreatitis
   3. Hepatic: chronic hepatic disease manifested by clinical or histologic evidence of focal biliary cirrhosis or multilobular cirrhosis
   4. Nutritional: failure to thrive (protein-calorie malnutrition), hypoproteinemia and edema, complications secondary to fat-soluble vitamin deficiencies

3. Salt loss syndromes: acute salt depletion, chronic metabolic alkalosis (pseudo-Bartter's syndrome)

4. Male urogenital abnormalities (congenital bilateral absence of vas deferens) resulting in obstructive azoospermia.

Pathophysiology

Central to the abnormalities in CF is the defect in the function of the CF transmembrane conductance regulator (CFTR) protein. CFTR protein actively transports chloride and bicarbonate toward the airway surface, secondarily bringing water with these ions. CFTR also affects other ion channels, most notably blocking the influx of sodium into the cell through the epithelial sodium channel. This affects the balance of salt and fluids inside and outside of the cell. This imbalance leads to thick, sticky mucus in the lungs, pancreas, and other organs.[5]

While malabsorption and resulting failure to thrive were the main hallmarks of the disease when it was initially described, with advent of pancreatic enzyme replacement therapy, lung disease is now the most important predictor of survival. Forced expiratory volume in 1 second (FEV1) is the most studied measure of lung function and a key predictor of life expectancy in individuals with CF.[6]

Diagnosis and Screening

CF can be diagnosed based on the following:[7]

1. Positive test results in children with no symptoms, for example, infant screening [blood spot immunoreactive trypsinogen test (IRT)] followed by gene and sweat tests for confirmation or

2. Clinical manifestations, supported by sweat or gene test results for confirmation or

3. Clinical manifestations alone, in the rare case of people with symptoms who have normal sweat or gene test results.

Since 2003 in Scotland and 2007 in the rest of the United Kingdom, all babies born have been screened for CF using blood spot IRT followed by a screen for the four commonest mutations (F508del, G551D, 621+1G-NT, and G542X). As a result, most children with CF are diagnosed shortly after birth in the United Kingdom although diagnosis can be made later, and even in adult life.[6]

The diagnosis of CF is confirmed by measurement of sweat chloride concentration using quantitative pilocarpine iontophoresis, which measures chloride transport through CFTR channel. A positive result (sweat chloride of ≥60 mmol/L) should always be confirmed with a second sweat test on a different day and CFTR mutation analysis. Newborns greater than 36 weeks' gestation and >2 kg body weight with a positive CF newborn screen, or positive prenatal genetic test, should have sweat chloride testing performed between days 10 and 28 of age. Although it has been considered the best test for CF, the sweat test has been reported to have very high false-positive and false-negative rates. This can be due to inaccurate methodology, technical error, and patient physiology. Sweat chloride testing should be performed according to approved international published procedural guidelines such as Clinical and Laboratory Standards Institute 2009 Guidelines which describe appropriate methods of collection and analysis, quality control, and evaluation of results in sweat testing.[5]

Genetics of CF

Dorothy Andersen first described “CF of the pancreas” in 1939, but it was only in 1989 that the first gene causing CF was identified.[8,9] CF is a multisystem genetic disorder caused by mutations in the gene for CFTR protein on chromosome 7, which encodes an ion channel protein. More than 2000 mutations have been identified to date.[5] CF is autosomal recessive, so an affected individual inherits two copies of the abnormal gene, one copy from each parent. CF occurs in 1 in 2000–4000 whites, and about 1 in 25 people are heterozygous carriers. CF affects more than 80,000 people worldwide.[10] Once considered a disease of the Caucasian populations of Europe and America, it is now recognized that no ethnic group can be considered exempt from CF.[11] The UK CF registry shows that 90.8% of people with CF have one known genotype. Nearly 90% of the CF population have one or two copies of F508del mutation. However, 8.9% of people have at least one unknown genotype.[7] F508del homozygosity is far less common among south Asian patients.[12] F508del mutation has been reported in 19%–56% of Indian patients.[13] The largest series on mutation analysis in Indian patients found that delta F508 mutation accounted for 31.1% of mutations.[14]

Management

The primary aims of CF treatment include the following:[15]

• Maintaining and optimizing lung function as near to normal as possible by identifying, controlling, and aggressively treating respiratory infections. FEV1 is a key predictor of life expectancy in children with CF,[6] and optimizing lung function is a major goal of care using airway clearance techniques, that is, physiotherapy and inhalation with hypertonic saline and dornase alfa (DNase)

• Administering nutritional therapy (i.e., enzyme supplements, multivitamin, and mineral supplements) to ensure adequate growth

• Suppression of inflammation (e.g., steroids, high-dose ibuprofen)

• Identifying and managing complications, for example, intestinal obstruction, CF-related diabetes, CF liver disease, and respiratory failure.

Morbidity and Mortality

Death in childhood from CF is now rare in the western world, and children born today are likely to have a mean life expectancy of over 40–50 years. The majority of patients with CF die from their lung disease, and the median predicted survival is 39 years.[16] The improvement in survival is clearly multifactorial and complex, reflecting advances in antibiotic therapy, nutritional strategies, airway clearance techniques, newborn screening, lung imaging, genetics, the understanding of CFTR structure and function, and new medications that can augment CFTR function.[2] However, in low-income countries, mortality in childhood is still high.[6]

CF in India and Asia

CF was first described in an Indian patient in 1968.[17] Since then, the published data on Indian patients with CF, however, have been very limited. The precise incidence of CF in India is still not known, and the information on CF mutations is also very scarce.[13] Underdiagnosis in the Indian subcontinent remains a significant challenge, despite improvements over recent years, highlighting the need for more widespread understanding and greater disease awareness within the medical community.[18] Studies on migrant Indian population in the United States and United Kingdom estimate frequency of CF as 1:10,000–1:40,000.[19]

In a series of patients from a tertiary center in north India, around half of the cases were picked up during work-up for infertility. The remaining presented with fairly typical phenotypic features of CF.[20]

Ashavaid et al.[13] attempted to determine the frequency of six of the most common mutations of the world CF population including F508del, G542X, G551D, R553X, N1303K, and 621+1(G→T) mutations in 23 suspected Indian CF cases, by multiplex ARMS-PCR technique. F508del mutation, during this study, was observed to possess a frequency of 33%; however, none of the other common mutations was identified. However, the study identified a high percentage of rare and novel mutations.[13]

Patients with Asian roots represent less than 1% of the total patients on the UK and US CF registry. Bosch et al.[12] compared the diagnostic characteristics of Asian with non-Asian patients with CF and performed a retrospective analysis of CFTR2 (USA) and UK CF databases for clinical phenotype, sweat chloride values, and CFTR mutations and concluded that Asian patients with CF do not have a worse clinical phenotype. The repeatedly reported lower FEV1 of Asian patients with CF was attributed to the influence of ethnicity on lung function in general. However, pancreatic sufficiency was more common in Asian patients with CF. The mean sweat chloride values are lower and 14% had sweat chloride values below 60 mmol/L (versus 6% in non-Asians). In addition, CFTR mutations differed from those in Caucasians: 55% of British Asian patients with CF did not have one mutation included in the routine newborn screening panel.[12]

Ashavaid et al.[13] report that sweat testing facilities are not available in most centers in India. The high initial and recurring cost of this test probably makes it less suitable for use in all centers. This poor availability of facilities for CF diagnosis may also be responsible for the underdiagnosis and low incidence of CF in India.[13]

In the absence of a screening program in India, the emphasis should be on a high index of suspicion and availability of diagnostic and management facilities. There is need to create awareness among pediatricians, develop diagnostic facilities, and manage protocols based on locally available resources.[21] Since the total number of CF-causing mutations in the Indian patients is likely to be very large, a DNA-based population screening in India is likely to be complicated. Ashavaid et al. suggest that an indirect genetic screening of the entire gene by single-strand conformation polymorphism, denaturing gradient gel electrophoresis, DNA sequencing, and so on may be necessary to characterize all the CFTR mutations in Indian patients.[13]

Recent Updates and New Developments

In 2017, CF diagnostic consensus guidelines were published, encompassing research advances in newborn screening outcomes, genetics, and advanced diagnostic techniques.[22] These guidelines emphasize that sweat chloride levels are essential as a marker of abnormal CFTR function. They also suggest that nasal potential difference and intestinal current measurements may be alternatives when diagnosis is elusive and when performed at an expert referral center. The latest classifications of mutation disease liability identified in the Clinical and Functional Translation of CFTR project (http://www.cftr2.org/index.php) should be used to aid CF diagnosis.[22,23]

Methods to study lung disease and its progression in young children continue to evolve in clinical practice. Evaluation of patients' pulmonary state is made by a combination of monitoring of lung function and more directly by assessing the lung structure in imaging studies. Computed tomography (CT) of the chest can identify a wide range of morphological abnormalities in patients with CF, such as bronchiectasis (which may be progressive, irreversible, and probably the most relevant structural change in CF), peribronchial thickening, mucous plugging, and many other disorders that occur in the course of the disease. CT of the chest has played a crucial role in the assessment of pulmonary damage over time, detecting complications and monitoring treatment effects in patients with CF and has been the gold standard for the identification of airways and lung parenchymal structural changes in CF.[24,25] Magnetic resonance imaging (MRI) especially hyperpolarized gas MRI appears promising in imaging CF lungs with the advantage that it does not expose patients to radiation. However, the availability of this technique remains limited.[26]

Unfortunately, gene therapy has progressed little in 20 years. However, there have been rapid advances in the discovery and clinical application of small molecules called CFTR modulators.[7] CFTR modulators are a family of new compounds that target specific defects caused by mutations in CFTR and thereby treat the underlying cause of CF. Ivacaftor and lumacaftor are first-generation modulators. Ivacaftor has now been commissioned to treat all patients in England who are 2 years of age and older with CF and have at least one copy of the specified gating mutations: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, and G1349D.[7] A recent phase 3 trial of tezacaftor–ivacaftor combination involved patients 12 years of age or older with CF who were homozygous for the most common F508del CFTR mutation. The results have been promising with significantly lower rate of pulmonary exacerbations than placebo.[16] Although CFTR modulator therapy is promising, prompt treatment to combat infections, steps to improve pulmonary health, and treat complications optimally remain indispensable.

Scope for Development

Presently, few centers are providing specialized pediatric pulmonology services in India. To be able to diagnose and manage CF, there is a need to develop more tertiary centers to enhance services including provision of resources to undertake assessment of respiratory condition (culture of respiratory secretions for CF-associated pathogens, age-appropriate respiratory function testing and imaging), improve diagnostic and therapeutic role of bronchoscopy and bronchoalveolar lavage, noninvasive evaluation of exocrine pancreatic function (e.g., estimating faecal elastase), along with dietetic, psychology, and physiotherapy support.[7,27]

End-of-life care and transplant remain important as CF remains a progressive disease despite advancing life expectancy. Evaluation for lung transplantation should be offered to patients with end-stage lung disease, and clinicians need a better understanding of who and when to refer.[22,23]

Considerable work is still needed in the areas of establishing and maintaining CF patient registries, universal access to neonatal screening, sweat chloride testing availability, modern diagnostic facilities, multidisciplinary specialist input, infection control, and improvements in the provisions for transition to adult respiratory services.[7,11]