Clinico-Epidemiological Characteristics of Children with Cystic Fibrosis: A Tertiary Care Experience

Background: Cystic brosis (CF) is considered to be rare among individuals from Bangladesh. The objective of the study was to delineate the clinico-epidemiological characteristics of pediatric cystic brosis cases. Method: This observational study included pediatric patients (up to 14 years of age) with a clinical diagnosis of CF. Data were collected within the period from February 2021 and October 2021. Written informed consent was obtained from the accompanying parent. Clinical and epidemiological characteristics were analyzed on the basis of demographic data, medical history, laboratory tests, and outcome information. Data analysis was done with SPSS 26. Result: A total of 50 patients (66% male) with a mean age of 39.7 ±30.75 (SD) months were included. Twenty-eight patients (57.14%) had siblings with CF, and 41.67% of parents had a history of consanguineous marriage. The majority of them were stunted (86%) and underweight (86%), and half of them had wasting (54%). Median disease duration was 12 months (range: 2 – 72). Cough (100%) and purulent sputum (100%) were the predominant respiratory symptoms, while failure to thrive (98%) and bulky offensive stools (86%) were prime gastrointestinal symptoms. Among the signs, malnutrition (94%), short stature (72%), digital clubbing (64%), and bronchiectasis (40%) were most frequent. Pulmonary hypertension n=24) was most common comorbidity identied in the study participants. In hospital, mortality was 16% (n=8). Digital clubbing, bronchiectasis, pancreatic insuciency, and abnormal liver function tests were signicantly higher in the patient who died. Conclusion: Children with cystic brosis most present with undernutrition and respiratory symptoms. global Pulmonary hypertension


Background
Cystic brosis (CF) is a life-limiting classic Mendelian autosomal recessive genetic disorder involving multiple organs, particularly the lungs and digestive system [1]. According to the Cystic Fibrosis According to history, the median life expectancy for patients with CF was only a few months in the 1950s [6], while during the past six decades, the median age of survival has increased progressively and is now more than 40 years in developed countries [7]. In Asian countries, the majority of them expired within the rst 5 years of their life [7][8][9]. However, understanding the disease process, early identi cation, treatment of infection, pancreatic enzyme replacement, correction of nutritional de ciency, innovative and transformational therapies targeting basic defects in CF are considered the highest longevity of these children worldwide [10,11]. In Bangladesh, genetic diagnosis of CF patients is still challenging, and diagnosis depends on the high level of clinical suspicion as well as supportive evidence. Knowing the clinico-epidemiological characteristics is therefore thought to be useful for clinicians to understand the natural history, disease process, sociodemographic pattern, and short-term outcome of these patient groups. With regard to the scarcity of information on epidemiological aspects of this disease in Bangladesh, this observational study was designed to summarize the clinic-epidemiological characteristics of pediatric cystic brosis attending Dhaka Sishu (children) Hospital, Bangladesh.

Patients And Methods
Patients and study settings: Patients with CF living in Bangladesh and attending the CF clinic in Dhaka Sishu (children) Hospital (DSH), Dhaka, Bangladesh in the period February 2021 and October 2021 were selected for the study. Dhaka Sishu (children) Hospital is the largest tertiary level hospital that serves dedicated to children and deals thousands of cases each year. The hospital provides for various pediatric health problems. It operates a CF clinic equipped with a multidisciplinary team specialized in the management of CF. Hence, it receives referrals and admissions from nearby districts and cities. During the study period, a total of 181 suspected cases were examined and investigated. Finally, a total of 50 cases of CF (46 con rmed cases and 4 possible cases) were included in this study. Details about the patient selection are described in supplementary gure 1.
Diagnosis of the children: A total of 50 individuals aged less than 14 with a clinical diagnosis of CF were included in the study. Diagnosis was con rmed by characteristic symptoms of CF and/or a positive family history of CF and/or a positive sweat chloride test for two separate samples. A chloride concentration of more than and above 90 mmol/L in sweat was considered positive for CF, and 60-89 mmol/L was considered a possible case [12]. Patients were excluded if CF was ruled out in further followups. SANASOL (SM-01) sweat analyzer (Country of origin: Sanasol Ltd. Hungary) was used to determine the total ion quality. As facilities for genetic testing are sparse in the country, we were able to conduct genetic studies for 2 children only. All patients were managed according to the hospital protocol and were observed up to discharge.
Clinical case management protocol: This was prepared in line of therapeutic management. Treatment included counseling about the disease, airway clearance therapy, antibiotics both systemic and inhalational, anti-in ammatory agents, mucolytics, pancreatic enzyme replacement, calcium, multivitamins and nutritional support.
Data gathering: Data were collected in a structured case record form. Demographic information was obtained from interviews with parents of children with CF. It included age of the child, gender, family history, and consanguinity of parents. Clinical information obtained from the children included the nutritional status of the child, clinical manifestation at the time of the interview, and laboratory investigations. All patients were subjected to thorough physical examination, and the ndings were recorded in the case record form. Height and weight were measured for all children. Nutritional status was de ned as underweight (<2 SD of weight for age), wasting (<2 SD for weight for height), and stunting (<2 SD of height for age) using WHO growth charts. Laboratory pro les and other investigations, such as complete blood count (CBC), random blood sugar (RBS), liver enzymes [serum alanine aminotransferase (ALT)], stool for occult blood, fat globules and occult parasites, chest radiograph, and echocardiography results, were also assessed. In addition, comorbidities of the children with CF were also recorded. The outcome was de ned as 'alive' in cases of discharge from the hospital and 'died' in cases of in-hospital deaths. Data collection was performed by study research physicians under the supervision of the investigator team.
Ethics statement: Informed written consent was ensured before participation in the study and was obtained from parents or their legal representatives after disclosing the full purpose of the study. The institutional review board (IRB) of Bangladesh Institute of Child Health, Bangladesh [ethical approval no.

Statistical analyses:
Data were analyzed using SPSS Version 26. Descriptive statistics were used to describe the sociodemographic distribution, clinical pro le and comorbidities of the admitted children. Chi-square tests, Fisher's exact tests, and Student's t tests were used as appropriate. A nonparametric test (Mann-Whitney U test) was used in the relevant case. Statistical signi cance was determined at p ≤ 0.05.

Results:
The mean and median age of the 50 children included in this study was 39.70 months and 30 months, respectively. The age ranged from 6 to 120 months, and the majority were aged between >1 and 5 years (60%). Most of the children were male (66%) except the infants who were predominantly female (66.7% of infants). Of all, 57.14% of children had a family history of cystic brosis, 41.67% of children's parents had consanguinity of marriage, 86% were underweight, 54% had wasting and 86% had stunting. All these characteristics were statistically similar across age groups ( Table 1). Out of all, 16% died, and 84% were discharged after improvement ( Figure 1). There was no signi cant difference between those who improved and those who died in relation to age, sex, family history, and nutritional status (Supplementary Table 1). The median duration of disease was 12 months (range 2 to 72 months). Cough and purulent sputum or hemoptysis was the most prevalent symptom being present in 100% of cases. Additionally, failure to thrive and bulky offensive stool were present in 98% and 86% of cases, respectively. The most frequent sign was malnutrition (94%), followed by short stature (72%), digital clubbing (64%), and bronchiectasis (40%). All the symptoms and signs were present in a similar proportion in all age groups except bronchiectasis which was signi cantly more frequent among the children age ≥5 years (Table 2). Additionally, all the symptoms including duration of disease were present in statistically similar proportion in both live and dead children except digital clubbing, bronchiectasis, pancreatic insu ciency, and abnormal liver function tests, which were present in a signi cantly higher proportion among those who died (Supplementary Table 2). The most common complication among children was pulmonary hypertension (48%). In addition, asthma, meconium ileus, allergic bronchopulmonary aspergillosis, and neonatal hepatitis syndrome were present in 12%, 6.52%, 2%, and 2%, respectively. There was no age-related difference in the distribution of complications (Table 3). However, pulmonary hypertension and allergic bronchopulmonary aspergillosis were present in a statistically signi cantly higher proportion in children who died than in those who were alive (Supplementary Table 3). The median hemoglobin level, WBC count, platelet count, RBS and ALT were 10.7 g/dl, 13.85 x 103/mm3, 3.00 x 106/mm3, 4.7 mmol/l and 55 u/l, respectively. On chest X-ray, 66% had bilateral patchy opacity, 40% hyperin ation of the lung, 16% had consolidation or inhomogeneous opacity, and 10% had a honeycomb appearance. Older children were signi cantly more likely to have lower median lymphocyte count than infants (Table 4). In addition, children who died had signi cantly higher ALT levels and a CF was a relatively overlooked problem in Bangladesh. Only recently was a multicenter study of 94 cases over a period of 17 years between 2000 and 2017 published by Kabir et al [13] in 2020. Given the scarcity of information regarding children with CF in the country, it was reasonable to continue the exploration of demographic and clinical features of CF patients. Additionally, an examination of the patients' characteristics across outcomes would identify important conditions to be addressed during management. Hence, this study was aimed.
The average age at diagnosis of our participants was lower than that found by Kabir et al [13] in Bangladesh, Kabra et al [15] in India, and Aziz et al [16] in Pakistan. Increased availability of diagnostic facilities might have lowered the age of diagnosis of CF. We found a slightly higher proportion of males, in conformity with previous studies [13,15,16]. However, unlike previous studies [17], we did not note any increased risk of case fatality among female patients.
Out of 50 children with CF included in the study, 16% died. This is higher than the previous nding by Kabir et al [13], who reported 11 deaths out of 95 patients (case fatality 11.5%). Additionally, this gure of childhood case fatality is much higher than in Western countries equipped with better management resources [14].
As an autosomal recessive genetic disorder [3], a family history of CF and consanguinity of marriage between parents are common ndings in CF patients. We noted a family history in nearly three-fths (57.1%) of patients and consanguinity of marriage in more than two-fths (41.7%). In contrast, consanguinity was found in 22%, 55.8%, and 15% of cases by Kabir et al [13], Aziz et al [16], and Kabra et al [15], respectively. These differences in distribution agree with the global distribution of consanguinity, where an important cluster of countries shows a high level of consanguinity and includes mostly Muslim majority areas [18]. However, the distribution might vary due to other factors, including religion, race, ethnicity, and sociocultural factors.
We noted a very high prevalence of malnutrition in the form of underweight, stunting, and wasting among our children with CF, which conforms with other studies [15,16]. All age groups and both alive and dead children shared a statistically similar proportion of malnutrition. Malnutrition is common in cystic brosis, and the cause of growth failure and malnutrition is multifactorial, including chronic in ammation [3].
The most frequent clinical features were cough with purulent sputum or hemoptysis and failure to thrive among the study participants. Additionally, malnutrition, short stature, digital clubbing, and bronchiectasis were predominant signs. Cough occurs mainly due to repeated infection of the airway. Hence, recurrent respiratory infections and failure to thrive are the most commonly reported symptoms in studies involving CF [15,16,[19][20][21]. Children with CF frequently pass bulky offensive stools due to fat malabsorption from the gut, and malnutrition occurs due to inadequate absorption of proteins, fats, and fat-soluble vitamins because of pancreatic insu ciency [22]. All the symptoms occur across all age groups. Interestingly, however, we noted an association of case fatality with the presence of digital clubbing, bronchiectasis, pulmonary hypertension, allergic bronchopulmonary aspergillosis, pancreatic insu ciency, abnormal liver tests, and honeycomb appearance on chest X-ray. All these features are suggestive of advanced disease [23]. In particular, the presence of bronchiectasis and honeycombing indicates underlying chronic in ammation and repeated infection. Management of pancreatic insu ciency requires multidisciplinary, carefully tailored strategies [3], which are often not possible in resource-poor settings. Hence, a combination of explored and unexplored factors might be responsible for premature deaths in CF among children in our setting.
Our study was limited by the fact that it was a single-center study with a small sample of cases. Genetic studies were not available for most of the patients due to economic problems or a lack of adequate facilities. Long-term follow-up of the patients was beyond the scope of the study. However, the study presented a detailed examination of sociodemographic and clinical features of children with CF in the country with a comparison across different outcomes, which will aid in the diagnosis and management of CF cases.

Conclusion
Cough, purulent sputum, and bulky offensive were the prominent presenting symptoms of children with CF. Failure to thrive is a global feature. Laboratory, radiographic and echocardiographic assessments support several abnormalities linked with the disease. To yield more reliable epidemiological information of these patients, a single prospective nationally representative database is therefore warranted.

Declarations
Ethics approval and consent to participate: The study protocol was approved by the institutional