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Editorial Indian Pediatrics 2002; 39:813-818 |
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Cystic Fibrosis: Indian Experience |
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Cystic fibrosis was thought to be extremely rare in India. However published reports, reviews and comments indicate that CF is probably far more common in people of Indian origin than previously thought but is under diagnosed or missed in the majority of cases (4–25)(Table I). The precise incidence of CF among Indians is unknown. The incidence in migrant Indian populations in the USA has been estimated to be 1 in 40000(8), and in the UK between 1 in 10000 to 12000 (9,10). As a result of the widespread belief that CF does not occur in Indians, the disease is rarely suspected and even if it is suspected the diagnosis is rarely confirmed due to the poor availability of facilities for diagnosis. The median age of diagnosis among Indian Americans is 12 months compared with 6 months among Caucasian American children and reflects a low index of suspicion for the disease even among Indians in western countries(8). Recent reports suggest that genetic and clinical profile of Indian children with CF may be different(7-9). These reports suggest that the diagnosis of CF is delayed in Indian children which may result in severe malnutrition by the time the condition is eventually diagnosed — one of the bad prognostic indicators for survival(12). Molecular genetics of Cystic Fibrosis The CF gene was identified in 1989 and is located on the long arm of chromosome 7 at position 7ql3(26-27). More than 1000 mutations in the gene have been recognized (www.genet.sickkids.on.ca).The basic defect in CF is a mutation in the gene for chloride conductance channel i.e. cystic fibrosis transmembrane conductance regulator (CFTR). This results in an abnormality of cAMP regulated chloride conductance by epithelial cells on mucosal surface. The failure of chloride conductance by epithelial cells leads to dehydration of secretions that are too viscid and difficult to clear(28). The prevalence of genetic mutations varies from one population to other. The commonest mutation is DF508, which constitutes about 70% of the total cases(29). The frequency of this mutation in Indian children has been reported between 19 to 44% (4,7-9). According to UK CF database, out of 5274 children with CF, 196 (3.75%) were of Non Caucasian origin. Of these 88 were from the Indian Subcontinent (ISC). Sixty-three were Pakistani, 12 Indian, 7 Bangladeshi and six from other Asian regions. Of the ISC Group, genotype is available on 78 patients — 24.7% were homozygous for DF508 and 4.7% were heterozygous. Other mutations were reported in 38.8% and these were not identified in 27% (personal communication). There were similar lower rate of DF508 mutation compared to the Caucasian population, reported from other Asian countries. Desgeorges et al(30) have identified 20 families living in Lebanon for several generations, who have had at least one child with CF. They showed that 10 different DNA alterations-including two novel mutations-accounted for 88% of the CF alleles. DF508 was found in 37.5% of alleles. TABLE I– Summary of reported cases of cystic fibrosis in patients from Indian subcontinent
Clinical manifestations The clinical features of CF are variable. The clinical features depend on age of diagnosis, supportive care and treatment. The common clinical presentation includes meconium ileus in neonatal period, recurrent bronchiolitis in infancy and early childhood, recurrent lower respiratory tract infections, chronic lung disease, bronchiectasis, failure to thrive, steatorrhoea and rectal prolapse. In older patients pancreatitis or male infertility due to azoospermia may be the presenting features(31). Pancreatic insufficiency is present in over 90% of people with cystic fibrosis. It has been reported that the condition may be more severe in patients of Indian origin(9,11). However this may be due to delayed diagnosis and treatment. Diagnosis The diagnosis of CF is suspected by the presence of typical clinical features such as meconium ileus at birth, recurrent or persistent pneumonia, malabsorption causing failure to gain weight and growth problems, salt-losing syndromes or obstructive azoospermia(32). Pneumonia and gastroenteritis due to acute infections are common causes of morbidity and mortality among children aged less than 5 years in India. Recurrent pneumonia or unusually prolonged episodes of pneumonia should arouse suspicion. Pneumonia associated with chronic bowel symptoms, such as steatorrhoea or other signs of malabsorption despite a good appetite, is strongly suggestive. Dehydration secondary to gastroenteritis is common in India. However dehydration without significant diarrhea during summer months, suggests a possibility of cystic fibrosis. Between 10 and 20% of children with CF present with meconium ileus and all newborns with intestinal obstruction should undergo further investigation for CF which will be present in over 95% of cases. Similarly obstructive azoospermia in post pubertal boys and exocrine pancreatic insufficiency below 20 years of age is very likely to be due to cystic fibrosis(33). Diagnosis of CF in Indian reports has been made by sweat test or by histopathology. The diagnosis of CF should be suspected by the presence of a typical phenotype or family history and confirmed by the demonstration of a high sweat chloride (>60 mEq/L) on repeated measurements and/or by identifying two CF mutations. Ideally evidence of intestinal malabsorption and pancreatic insufficiency should be sought. Nasal potential difference measurements can be used as an adjunct to sweat test but is not widely available (34). Sweat test Conventionally the diagnosis of CF is confirmed by a typical phenotype and increased sweat chloride measurements on repeat testing. Sweat chloride values of more than 60 mEq/L are considered abnormal although some authors suggest lower cut off values in younger children(35). Normal values are <40 mEq/L. Values between 40-60 mEq/L are indeterminate. Such borderline sweat chloride values in the presence of a typical phenotype should be investigated by repeat sweat testing and ancillary diagnostic tests. Average sweat chloride values in CF patients are around 100 mEq/L. In a recent study of Indian children the mean sweat chloride was 99 mEq/L (36). Genotypically confirmed CF with normal sweat chloride levels has been reported but is extremely rare. Such patients manifest milder symptoms and may first present in adult life (37). Mutation analysis The gene for cystic fibrosis has been identified on chromosome 7 (26-27). Among Caucasian populations the commonest mutation is DF508 and accounts for approximately 70% of all CF genes (29). Over 90% of CF mutations can be identified if a patient’s blood is tested for a panel of 70 mutations in the general population of the United States(29). The panel of most common mutations for Indian patients is not yet known. Small studies indicate that the proportion of patients with DF508 may be 19-44%(4,7-9) but there are no comprehensive studies investigating the wider mutation profile. In a study on 24 patients it was observed that DF508 was present in 40% and the remaining mutations were multiple in accordance with the multiethnic background of patient population (4). A larger study is required to compile a panel of common mutations that can be used for confirmatory diagnosis of patients with CF in India. Facilities for identification of CF mutations are not readily available in India. Hence sweat test remains the first line diagnostic test. However attempts should be made to identify mutations by sending the patient or a blood sample to centers carrying out CF mutation testing for further evaluation where appropriate. Supportive laboratory tests In the absence of sweat chloride estimation and mutation analysis, CF may be suspected in most centers in India on the presence of supportive investigations. These are as follows: Abnormality in blood biochemistry and acid base status Patients with CF may have low or low normal serum sodium. There may be metabolic alkalosis and hypochloremia. Presence of these in a patient with typical phenotype suggests a possibility of cystic fibrosis(31). Anemia can occur along with hypoalbuminemia and ascites as a result of vitamin E deficiency and protein malabsorption. Also the routine blood count may show signs suggestive of bacterial infection. Airway bacterial colonization and infection Children with cystic fibrosis may be infected with Pseudomonas aeruginosa, Staphylococcus aureus or non-typable Haemophilus influenzae.The isolation of P. aeruginosa or Burkholdelia cepacia from sputum or cough swabs is suggestive of a CF diagnosis(3). All children suspected of having CF should have specimens sent for microbiological culture to identify and treat infecting respiratory pathogens. Older children should have sputum specimens sent regularly for culture. Young children and infants are often unable to expectorate and secretions from the airways obtained after saline inhalation and physiotherapy or a cough swab should therefore be cultured. Pancreatic function tests Cystic fibrosis is the commonest cause of exocrine pancreatic deficiency below 20 years of age(33). Direct assessment of pancreatic function is difficult, but more recently measurement of stool pancreatic elastase-1 has been reported as a sensitive and specific test(38). Semi quantitative estimates of intestinal fat malabsorption can be made using either faecal microscopy or faecal steatocrit(39). Obstructive azoospermia In post pubertal boys, a semen analysis for azoospermia can be carried out. Sperms are absent in up to 98% of men with cystic fibrosis(33). Radiological imaging X-ray film of the chest, sinuses and computerized axial tomography(CT) scan of chest may show findings suggestive of CF although these are non-specific. These investigations are more useful for monitoring diagnosed patients. X-ray films of chest may show hyperinflation, peribronchial thickening, cystic changes and lobar or segmental collapse. The findings on CT include cystic or varicose bronchiectasis, peribronchial thickening, segmental collapse, mucus impaction and sub pleural bullae formation. The imaging studies of sinuses may show delayed pneumatization or mucosal thickening. Conclusion Although CF may be relatively rare in India, if the possibility is kept in mind in the clinical circumstances described above it is likely that more patients will be identified at an early stage when treatment is likely to be more effective. The availability of mutation analysis, searching for mutations appropriate for the population, permits the investigation to be performed on blood specimens sent to distant laboratories although the inability to demonstrate mutations does not entirely rule out the condition. The final opinion must include full clinical evaluation, a reliable sweat test and ancillary investigations as described. Acknowledgement We are very thankful to Dr J.M. Littlewood OBE, Chairman, Research and Medical Advisory Committee, Cystic Fibrosis Trust UK for going through the manuscript and for his useful suggestions. Funding: None. Competing interests: None stated. A. S. Ahuja. Consultant Pediatrician Royal Albert Edward Infirmary Wigan, Lancs., UK S. K. Kabra , Additional Professor, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi. E-mail: [email protected]
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