Pediatric Pulmonology Training in India: Current Status and Future Directions

Respiratory illnesses are common causes of morbidity and mortality in children. Postgraduates in Pediatrics spent significant time in learning to manage respiratory disorders. Improved survival of preterm neonates, improved diagnosis and survival of chronic respiratory problems, and advances in diagnosis and therapeutics have increased the need for specialists trained in managing these patients. Training programs in Pediatric Pulmonology are evolving over the past few decades. In India, super-specialty training in Pediatric Pulmonology has grown over the past few years. There is a need to modify the training structure used in industrialized countries due to differences in patient population, priorities, and limited available resources and expertise. Formal training courses have been started in a limited number of institutions. There is a large gap between the need for a trained workforce and the available specialists in the limited number of institutions. The Indian Academy of Pediatrics National Respiratory Chapter (IAPNRC) has initiated a fellowship program to bridge the gap. Comprehensive training involving academic and hands-on training may go a long way to improve the care of children with acute and chronic respiratory problems. For sustainable development of the super specialty, there is a need to work towards creating Pediatric Pulmonology service departments in various institutions that may be responsible for comprehensive training and research activities to answer common research questions.

Management of Dengue: An Updated Review

Dengue is an important public health problem with a wide clinical spectrum. The World Health Organization classifes dengue into probable dengue, dengue with warning signs, and severe dengue. Severe dengue, characterized by plasma leakage, severe bleeding, or organ impairment, entails signifcant morbidity and mortality if not treated timely. There are no defnitive curative medications for dengue; management is supportive. Judicious fuid resuscitation during the critical phase of dengue is the cornerstone of management. Crystalloids are the initial fuid of choice. Prophylactic platelet transfusion is not recommended. Organ involvement in severe dengue should be carefully looked for and managed. Secondary hemophagocytic lymphohistiocytosis is a potentially fatal complication of dengue that needs to be recognized, as specifc management with steroids or intravenous immunoglobulin may improve outcomes. Several compounds with anti-dengue potential are being studied; no anti-dengue drug is available so far.

Initial Immunomodulation and Outcome of Children with Multisystem Inflammatory Syndrome Related to COVID-19: A Multisite Study from India

Objective To determine the outcomes in children with MIS-C receiving diferent immunomodulatory treatment. Methods In this multicentric, retrospective cohort study, data regarding treatment and outcomes of children meeting the WHO case defnition for MIS-C, were collected. The primary composite outcome was the requirement of vasoactive/inotropic support on day 2 or beyond or need of mechanical ventilation on day 2 or beyond after initiation of immunomodulatory treatment or death during hospitalization in the treatment groups. Logistic regression and propensity score matching analyses were used to compare the outcomes in diferent treatment arms based on the initial immunomodulation, i.e., IVIG alone, IVIG plus steroids, and steroids alone. Results The data of 368 children (diagnosed between April 2020 and June 2021) meeting the WHO case defnition for MIS-C, were analyzed. Of the 368 subjects, 28 received IVIG alone, 82 received steroids alone, 237 received IVIG and steroids, and 21 did not receive any immunomodulation. One hundred ffty-six (42.39%) children had the primary outcome. On logistic regression analysis, the treatment group was not associated with the primary outcome; only the children with shock at diagnosis had higher odds for the occurrence of the outcome [OR (95% CI): 11.4 (5.19–25.0), p<0.001]. On propensity score matching analysis, the primary outcome was comparable in steroid (n=45), and IVIG plus steroid (n=84) groups (p=0.515). Conclusion While no signifcant diference was observed in the frequency of occurrence of the primary outcome in diferent treatment groups, data from adequately powered RCTs are required for defnitive recommendations.

Application of real‑time quantitative polymerase chain reaction assay to detect Legionella pneumophila in patients of community‑acquired pneumonia in a tertiary care hospital.

Legionella pneumophila is one of the important pathogen responsible for community –acquired pneumonia attributing for 1-5% of cases. Since early and accurate therapy reduces mortality, rapid and reliable diagnostic methods are needed. A total of 134 samples of blood, urine and respiratory tract fluids were collected. Blood was tested for IgG, IgM and IgA antibodies using commercially available kits. A total of 8 (6%) samples were found to be positive for L. pneumophila by quantitative reverse transcription polymerase chain reaction (qRT‑PCR), compared to conventional PCR where 6 (4.4%) samples were positive. Serology was positive in a total of 32 (23%) cases though only 3 (2.2%) of the PCR‑positive cases were positive by serology as well. These results suggest that real‑time PCR can detect Legionella infection early in the course of the disease before serological response develops.

Coagulase‑negative staphylococci causing blood stream infection at an Indian tertiary care hospital: Prevalence, antimicrobial resistance and molecular characterisation.

Introduction: Recent years have seen a rise of coagulase‑negative staphylococci (CoNS) from common contaminants to agents of nosocomial blood stream infections (BSI’s). Molecular typing and establishing a correlation with antibiotic resistance is essential particularly in countries like India where genotyping studies for drug‑resistant CoNS are sparse. Methods: A prospective study was done over 18 months, wherein 42,693 blood samples were received, and 59 patients with BSI due to CoNS were evaluated. The isolates recovered were identified by a biochemical test panel and matrix‑assisted laser desorption ionization – time of flight mass spectrometry followed by antimicrobial susceptibility testing by Kirby–Baur disc diffusion method and E‑test strips. Staphylococcal chromosomal cassette mec (SCCmec) element was characterised by multiplex polymerase chain reaction for all methicillin‑resistant (MR) isolates. Results: The majority of CoNS isolated were constituted by Staphylococcus haemolyticus (47.5%) followed by Staphylococcus epidermidis (33.9%), Staphylococcus hominis (11.86%), Staphylococcus cohnii (5.08%) and Staphylococcus warneri (1.69%). Among all isolates 57.6% were MR with statistically significant higher resistance versus methicillin sensitive‑CoNS. This difference was significant for erythromycin (76% vs. 44%, P = 0.011), rifampicin (50% vs. 12%, P = 0.002) and amikacin (26.5% vs. 4%, P = 0.023), ciprofloxacin (64.7% vs. 20%, P = 0.001) and cotrimoxazole (55.9% vs. 20%, P = 0.006). SCCmec type I was predominant (61.8%, P = 0.028) and exhibited multidrug resistance (76.2%). Coexistence of SCCmec type I and III was seen in 8.82% MR isolates. Conclusion: CoNS exhibit high antimicrobial resistance thereby limiting treatment options. The presence of new variants of SCCmec type in hospital‑acquired CoNS may predict the antibiotic resistance pattern. This is the first evaluation of the molecular epidemiology of CoNS causing BSI from India and can serve as a guide in the formulation of hospital infection control and treatment guidelines.

Fractional Exhaled Nitric Oxide for Identification of Uncontrolled Asthma in Children.

Objectives: To determine the utility of Fractional Exhaled Nitric Oxide (FENO) in the identification of uncontrolled asthma in children on therapy, and to identify its cut-off value for determining asthma control. Methods: 207 children (age 5-15 y) with physician-diagnosed asthma on therapy with at least 12 months follow up were enrolled. Spirometry and FENO measurements were performed. Asthma control was assessed as per GINA guidelines. Sensitivity and specificity of various cut-off values of FENO (15 ppb, 20 ppb, 25 ppb, 30 ppb) for identification of status of control of asthma were calculated. Results: 156 (75%) children had uncontrolled or partly controlled asthma and 51 children were assessed to have controlled asthma. Median (IQR) FENO in children with controlled and uncontrolled asthma was 16 (11-23) ppb and 13 (11-25) ppb, respectively (P=0.26). No FENO cut-off had a reasonable combination of sensitivity and specificity to discriminate between controlled and uncontrolled asthma. Conclusion: FENO, in itself, does not have good discriminatory value in assessment of controlled and uncontrolled asthma in children on asthma therapy.

Non-Cystic Fibrosis Bronchiectasis in Children: Clinical Profile, Etiology and Outcome.

Objective: To describe clinical profile, etiology and outcome in children with non-cystic fibrosis bronchiectasis. Methods: A chart review of children diagnosed with non-cystic fibrosis bronchiectasis, attending pediatric chest clinic of tertiary care hospital. Results: The underlying cause was identified in 51 (63.8%) out of 80 children (mean age, 9.6 y). Common causes were post-infectious in 19 (23.8%), suspected primary ciliary dyskinesia in 12 (15%), and allergic bronchopulmonary aspergillosis in 6 (7.5%). One or more complications were observed in 76 (95%) patients; 14 (17.5%) children required surgery and 5 (11.1%) children died. Conclusions: Common causes of non-cystic fibrosis bronchiectasis are post infectious and primary ciliary dyskinesia. There is a need to create awareness about early diagnosis of bronchiectasis as it is often delayed.

Vitamin D levels in Indian children with intrathoracic tuberculosis.

Background & objectives: Deficiency of vitamin D, an immunomodulator agent, is associated with increased susceptibility to tuberculosis in adults, but only limited studies are available in the paediatric age group, especially regarding association of vitamin D with type and outcome of tuberculosis. We conducted this study to determine the baseline 25-hydroxy vitamin D levels in children suffering from intrathoracic tuberculosis and its association with type and outcome of tuberculosis. Methods: Children with intrathoracic tuberculosis, diagnosed on the basis of clinico-radiological criteria, were enrolled as part of a randomized controlled trial on micronutrient supplementation in paediatric tuberculosis patients. Levels of 25-hydroxy vitamin D were measured in serum samples collected prior to starting antitubercular therapy by chemiluminescent immunoassay technology. Results: Two hundred sixty six children (mean age of 106.9 ± 43.7 months; 57.1% girls) were enrolled. Chest X-ray was suggestive of primary pulmonary complex, progressive disease and pleural effusion in 81 (30.5%), 149 (56%) and 36 (13.5%) subjects, respectively. Median serum 25-hydroxy vitamin D level was 8 ng/ml (IQR 5, 12). One hundred and eighty six (69.9%) children were vitamin D deficient (serum 25-hydroxy vitamin D <12 ng/ml), 55 (20.7%) were insufficient (12 to <20 ng/ml) and 25 (9.4%) were vitamin D sufficient (≥ 20 ng/ml). lLevels of 25-hydroxy vitamin D were similar in all three types of intrathoracic tuberculosis, and in microbiologically confirmed and probable cases. Levels of 25-hydroxy vitamin D did not significantly affect outcome of the disease. Children who were deficient or insufficient were less likely to convert (become smear/culture negative) at two months as compared to those who were 25-hydroxy vitamin D sufficient (p<0.05). Interpretation & conclusions: Majority of Indian children with newly diagnosed intrathoracic tuberculosis were deficient in vitamin D. Type of disease or outcome was not affected by 25-hydroxy vitamin D levels in these children. However, children who did not demonstrate sputum conversion after intensive phase of antitubercular therapy had lower baseline 25-hydroxy vitamin D levels as compared to those who did.

Induction of resistant mutants of Salmonella enterica serotype Typhi under ciprofloxacin selective pressure.

Background & objectives: Infection with Salmonella enterica serovar Typhi (hereafter S. Typhi) is an important public health problem in India. There has been an increase in the number of reported clinical failures to ciprofloxacin treatment but the data on possible mechanism of failure are limited. One mechanism that has been widely reported and found associated with ciprofloxacin resistance, is the mutations in target genes in QRDR (quinolone resistance determining region). It is hypothesized that mutations in DNA gyrase or topoisomerase IV result in therapeutic failure under selective pressure of antibiotic while the patient is on treatment. We undertook in vitro sequential selection studies to expose the clinical isolates of S. Typhi to different concentration of ciprofloxacin to study the role of antibiotic selective pressure in the development of mutations in QRDR. Methods: Total 26 clinical isolates were divided in to two parts: part I included six isolates obtained from three patients with relapse of enteric fever and part II included 20 isolates with different ciprofloxacin MIC levels. For in vitro induction of mutation experiment, five S. Typhi isolates were selected which included three NAS (nalidixic acid sensitive) and 2 NAR (nalidixic acid resistant) S. Typhi. These isolates were grown under increasing concentrations of ciprofloxacin and mutations acquired in QRDR of DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC and parE) were investigated by sequencing. Results: For the isolates included in the part I of the study, it was found that the MIC to ciprofloxacin increased in the isolates obtained during the relapse of enteric fever as compare to the first isolate. All isolates had single mutation in gyrA gene at S83 without additional mutation in the second isolate. In the second part of the study, the nine isolates with varying MICs to ciprofloxacin also had single mutation in gyrA gene at S83 and another six had triple mutations, two mutations in gyrA gene (at S83 and D87) and one mutation in parC gene (at S80). In in vitro induction of mutation experiment, all mutated isolates showed triple mutation (two mutation in gyrA and one in parC gene) while no mutations were found in wild isolates. Interpretation & conclusions: Upon exposure to the step-wise increased concentration of ciprofloxacin, isolates become more tolerant to the ciprofloxacin and showed 2-4 fold higher MICs without new mutation after 8 μg/ml. So the accumulation of mutations under continuous ciprofloxacin pressure and tolerance of the mutant isolates led to the clinical failure. These results also suggested that there could be another mechanism responsible for resistance.

Prevalence and Risk Factors for Allergic Bronchopulmonary Aspergillosis in Indian Children with Cystic Fibrosis.

Objectives: Allergic bronchopulmonary aspergillosis (ABPA) is a common complication in patients with cystic fibrosis. This crosssectional study was planned to determine the prevalence and risk factors for ABPA in Indian children with cystic fibrosis. Methods: Clinical evaluation, spirometry, chest radiograph, sputum, total IgE, specific IgE for Aspergillus fumigatus, IgG precipitins and skin prick tests were done in 33 CF patients. Results: Prevalence of allergic bronchopulmonary aspergillosis was 18.2% (95% CI 6.9% - 35.4%): allergic bronchopulmonary aspergillosis was higher in patients with low cystic fibrosis score, age >12 years, atopy, and eosinophilia. Conclusion: Prevalence of ABPA is higher in Indian children with cystic fibrosis.

Pharmacokinetics of Nevirapine, Stavudine and Lamivudine in Indian HIV-infected Children Receiving Generic Fixed Dose Combinations.

Objective: To determine the trough and two hour plasma levels of nevirapine, stavudine, and lamivudine when administered in fixed dose combinations (FDC). Design: Cross sectional Setting: Tertiary care hospital in Northern India. Participants: 79 HIV-infected children receiving antiretroviral therapy with FDCs for more than month. Intervention: Two-point sampling (0 and 2 hours after the morning dose). Outcome measures: Plasma concentrations of all three drugs were simultaneously assayed by liquid chromatography/mass spectroscopy. Results: Majority (77%) of children were receiving fixed dose combination of stavudine, lamivudine, nevirapine in the ratio of 6:30:50mg. The median (IQR) trough and 2-hour plasma levels (µg/mL) of nevirapine, stavudine and lamivudine were 5.2 (4.0, 6.3) and 7.9 (6.0, 9.7); 0.1 (0.06, 0.16) and 1.1 (0.59, 1.6); 0.1 (0.02, 0.2) and 2.5 (1.4, 3.1), respectively. Very few children had sub-therapeutic plasma drug levels of stavudine (2.5%), lamivudine (7.6%) and nevirapine (10%). Inadequate viral suppression at 6 months follow up was significantly associated with initial high viral load, low CD4 percentage at the time of enrolment in study, and lower doses of lamivudine and stavudine. Conclusion: The currently available generic pediatric fixed dose antiretroviral combinations in India provide adequate drug exposure in majority of children.

Aeroallergen Sensitization in Childhood Asthmatics in Northern India.

Objective: To determine the prevalence of sensitization to common aeroallergens in asthmatic children and study the differences in characteristics of atopics and non atopics. Design: Analysis of data from a prospective cohort study. Setting: Pediatric Chest Clinic of tertiary care center in Northern India Patients: Asthmatic children from 5-18 year of age. Main outcome measures: Prevalence of sensitization to common aeroallergens. Results: Skin prick testing (SPT) was performed on 180 children above 5 years of age, with a mean (SD) age of 111.4 (34.2) months. 100 children (55.6%) were sensitized to at least one aeroallergen, suggesting atopy; 68 (37.8%) were sensitized to more than one allergen. 36.7% children were sensitized to housefly antigen; 31.1% to rice grain dust, 18.3% to cockroach, and 7.8% to house dust mite antigens. Atopic children had significantly higher median FENO during follow up than nonatopic children (17.5 ppb vs 13 ppb, P=0.002). There was a positive correlation between age and the number of allergens that an individual was sensitized to (r= 0.21; P=0.0049). Conclusions: More than half of asthmatic children in our cohort had sensitization to one or more aeroallergens suggesting atopy; sensitization was most commonly seen to housefly antigen and rice grain dust. Atopic children had significantly higher FENO measurements during follow up as compared to non-atopic children.

Prospective study estimating healthcare associated infections in a paediatric hemato-oncology unit of a tertiary care hospital in north India.

Background & objectives: Healthcare associated infections (HAIs) are responsible for morbidity and mortality among immunocompromised and critically ill patients. We undertook this study to estimate the burden of HAIs in the paediatric cancer patients in a tertiary care hospital in north India. Methods: This prospective, observational study, based on active surveillance for a period of 11 months was undertaken in a 4-bedded isolated, cubicle for paediatric cancer patients. Patients who stayed in the cubicle for ≥48 h, were followed prospectively for the development of HAIs. Results: Of the 138 patients, 13 developed 14 episodes of HAIs during the study period. Patient-days calculated were 1273 days. Crude infection rate (CIR) and incidence density (ID) of all HAIs were 9.4/100 patients and 11/1000 patient-days, respectively. Of the 14 episodes of HAIs, seven (50%) were of blood stream infections (HA-BSI), five (36%) of pneumonia (HAP) and two (14%) urinary tract infections (HA-UTI). The CIRs of HA-BSI, HAP and HA-UTI were 5.1, 3.6 and 1.4/100 patients, respectively. The corresponding IDs were 5.5, 3.9 and 1.6/1000 patient-days, respectively. Mean length of stay was significantly higher in patients who developed an HAI [13.8 (range 7-30), median (Interquartile range) 12 (11-14)] vs 7.5 days [range 2-28, median (interquartile range) 7 (5-9); P<0.0001]. Also mortality was significantly higher in patients who developed an HAI [23% (3/13) vs 3% (4/125), P<0.05]. Interpretation & conclusions: The incidence of HAIs in the paediatric cancer patients in the study was 11/1000 patient days, of which HA-BSIs were the commonest. HAIs were associated with an increase in morbidity and mortality amongst this high risk patient population.

Assessment of Bronchodilator Response in Preschool Children by Pulmonary Function Tests.

We performed pulmonary function test to document bronchodilator response by using tidal breathing flow volume loop (TBFVL), rapid thoracic compression (RTC), and raised volume rapid thoracic compression (RVRTC) techniques. Thirty-nine children (mean age 45.2 months) were evaluated. The parameters that showed significant improvement after bronchodilator administration included TEF10/ PTEF ratio in TBFVL, and FEF25-75%, FEV1and PEF in RVRTC. None of the parameters measured in RTC showed significant improvement. We conclude FEV1, PEF and FEF25-75% in RVRTC have greater sensitivity for detection of airways changes.

Recent Advances in Management of Bronchiolitis.

Background: Bronchiolitis is one of the major causes for hospital admissions in infants. Managing bronchiolitis, both in the outpatient and inpatient setting remains a challenge to the treating pediatrician. The effectiveness of various interventions used for infants with bronchiolitis remains unclear. Need and purpose: To evaluate the evidence supporting the use of currently available treatment and preventive strategies for infants with bronchiolitis and to provide practical guidelines to the practitioners managing children with bronchiolitis. Methods: A search of articles published on bronchiolitis was performed using PubMed. The areas of focus were diagnosis, treatment and prevention of bronchiolitis in children. Relevant information was extracted from English language studies published over the last 20 years. In addition, the Cochrane Database of Systematic Reviews was searched. Results and Conclusions: Supportive care, comprising of taking care of oxygenation and hydration, remains the corner-stone of therapy in bronchiolitis. Pulse oximetry helps in guiding the need for oxygen administration. Several recent evidence-based reviews have suggested that bronchodilators or corticosteroids lack efficacy in bronchiolitis and should not be routinely used. A number of other novel therapies (such as nebulized hypertonic saline, heliox, CPAP, montelukast, surfactant, and inhaled furosemide) have been evaluated in clinical trials, and although most of them did not show any beneficial results, some like hypertonic saline, surfactant, CPAP have shown promising results.

Multiple locus sequence typing of Salmonella Typhi, isolated in north India - a preliminary study.

Background & objectives: In India enteric fever is a major public health problem and Salmonella Typhi is the most common aetiologic agent. Any control strategy for such infections depends to a large extent on the understanding of the disease and relatedness of strains across the world. Multi locus sequence typing (MLST) is one such method of genotyping of bacteria based upon housekeeping genes of known function and chromosome position. MLST data of pathogens are important to determine the molecular evolution by a stable and reproducible method. This study was undertaken to determine the sequence types of representatives S. Typhi isolates obtained from enteric fever patients in a tertiary care centre in north India, over a period of 20 years (1990-2010). Methods: A total of 30 representative isolates of S. Typhi identified by biochemical and serological tests were subjected to multi locus sequence typing (MLST). Seven housekeeping genes of known function and chromosome position were used for the typing by MLST. Sequencing was carried out by using an automated DNA sequencer and results were analyzed to generate phylogenetic tree. Results: MLST pattern grouped S. Typhi into two sequence types- ST1 and ST2. ST1 was predominantly present followed by ST2. Interpretation & conclusions: By MLST the presence of both sequence types, ST1 and ST2, was found in S. Typhi isolates in our region. Predominately ST1 was present followed by ST2. These preliminary results corroborate the global distribution of both sequence types of S. Typhi and also emphasize for the continuous screening of S. Typhi.