Endemic pediatric fungal infections in India: clues to diagnosis.

This review is intended to familiarize readers with an emerging group of fungal infections that mostly manifest in immunocompetent individuals. This group was initially considered endemic to the tropics, but increasing worldwide prevalence has been reported. The organisms have been divided into dominant non-invasive forms and dominant invasive forms for ease of understanding. The non-invasive organisms include the group Entomophthoromycota, under which two genera Basidiobolus and Conidiobolus, have been identified as human pathogens. They present with plaques in the extremities and rhinofacial region, respectively. The invasive organisms are dematiaceous fungi (phaeohypomycosis), which includes Cladophialophora and Exophiala among others. They cause invasion of deep tissues, with the central nervous system being the most common target. The mycology, epidemiology, diagnosis, and treatment options have been summarized in brief. The clinical presentation, imaging manifestations, differentiation from other common infections and malignancies that show similar features have been detailed.

Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis.

BACKGROUND: Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level. METHODS: We systematically searched MEDLINE, Embase and Web of Science (1990-2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration-time curve from 0 to 24 h post-dose (AUC0-24) and peak plasma concentration (C max) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0-24 and C max were assessed with linear mixed-effects models. RESULTS: Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0-24 were summarised for isoniazid (18.7 (95% CI 15.5-22.6) h·mg·L-1), rifampicin (34.4 (95% CI 29.4-40.3) h·mg·L-1), pyrazinamide (375.0 (95% CI 339.9-413.7) h·mg·L-1) and ethambutol (8.0 (95% CI 6.4-10.0) h·mg·L-1). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC0-24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0-24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0-24 and slow acetylators had higher isoniazid AUC0-24 than intermediate acetylators. Determinants of C max were generally similar to those for AUC0-24. CONCLUSIONS: This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.

GeneXpert Ultra in Urine Samples for Diagnosis of Extra-Pulmonary Tuberculosis.

Extra-pulmonary tuberculosis (EPTB) continues to be difficult to diagnose. Novel biomarkers in biological specimens offer promise. Detection of Mycobacterium tuberculosis (Mtb) DNA in urine could prove useful in diagnosis of EPTB, possibly due to disseminated disease or micro-abscesses reported in kidneys. The current study was designed to detect Mtb DNA in stored urine samples from patients with EPTB. Diagnosis of EPTB was reached using Microbiological Reference Standards (MRS) on samples from the disease site using WHO Recommended Diagnostics (WRD), [smear microscopy, liquid culture (MGIT-960)] and GX (molecular WRD, mWRD) and Comprehensive reference standards [CRS, clinical presentation, microbiological reference standards, radiology, histopathology]. GX-Ultra was performed on urine samples stored in -80oC deep freezer, retrospectively. Of 70 patients, 51 (72.9%) were classified as confirmed TB, 11 (15.7%) unconfirmed TB, and 8 (11.4%) unlikely TB. GX-Ultra in urine samples demonstrated sensitivity of 52.9% and specificity of 57.9% against MRS, and higher sensitivity of 56.5% and specificity of 100% against CRS. The sensitivity and specificity of GX-Ultra in urine was 53.6% and 75% for pus sample subset and 52.2% and 53.3% for fluid sample subset. Urine being non-invasive and easy to collect, detection of Mtb DNA using mWRD in urine samples is promising for diagnosis of EPTB.

Efficacy of pulse dexamethasone in non-systemic juvenile idiopathic arthritis: a double-blind randomized controlled trial.

OBJECTIVE: Early aggressive therapy using biologicals is increasingly being used in JIA for early disease remission. Pulse steroids are used in induction regimes for rheumatic disorders such as SLE and systemic JIA; however, no controlled studies have demonstrated their use in non-systemic JIA. The objective of the present study was to evaluate the efficacy and safety of pulse dexamethasone therapy in children with treatment-naïve non-systemic JIA as early aggressive therapy in resource-limited settings. METHODS: Sixty treatment-naïve children with non-systemic JIA with an active joint count of ≥5 and/or involvement of hip or cervical joints were randomized to receive either pulse dexamethasone (3 mg/kg/day, max 100 mg/day) or placebo (normal saline) for three consecutive days during each visit at 0, 6 (±2) and 12 (±2) weeks; along with standard therapy (MTX and NSAIDs). The use of oral bridge steroids was permissible for persistent severe disease as per predefined criteria. The primary outcome was ACR-Pedi 70 response at 16 (±2) weeks after enrolment in the two groups. RESULTS: The proportion of children achieving ACR-Pedi 70 in the two groups at last follow-up was 11/30 (36.7%) in pulse dexamethasone arm vs 11/28 (39.3%) in the placebo arm (P-value 0.837, relative risk 0.93, 95% CI 0.48, 1.80). We did not observe any significant difference in the proportion of children requiring bridge steroids. Adverse events were comparable in the two groups. CONCLUSION: The addition of pulse dexamethasone to standard treatment may not add any advantage in improving ACR-Pedi 70 scores at medium-term follow-up. TRIAL REGISTRATION: Clinical Trial Registry-India; www.ctri.nic.in CTRI/2018/08/015151.

Intermittent versus daily regimen of prednisolone in ambulatory boys with Duchenne muscular dystrophy: A randomized, open-label trial.

INTRODUCTION/AIMS: Corticosteroids prolong ambulation and improve muscle power among boys with Duchenne muscular dystrophy (DMD). However, the optimal steroid regimen remains unclear. Hence, this study was undertaken to compare the efficacy of daily- versus intermittent-steroid regimens in ambulatory boys with DMD. METHODS: In this single-center, open-label randomized trial, 72 children were randomized to receive either daily prednisolone (0.75 mg/kg/day) or intermittent prednisolone (0.75 mg/kg/day, for first 10 days of every month). The primary outcome measure was the difference in average score on manual muscle testing (MMT) at baseline and after 6 mo of steroids. A difference of >0.2 was hypothesized to be significant. Secondary outcomes included changes in timed functions, muscular dystrophy-specific functional-rating scale score, peak torque, average power, and pulmonary function. RESULTS: In the intention-to-treat analysis, the mean (SD) change in MMT scores was 0.17 (0.15) and 0.08 (0.10) for the daily and intermittent steroid groups, respectively. The mean difference between the two interventions was 0.10 (95% confidence interval [CI] = 0.04-0.16; P = .003), which although significant was less than the predefined value of 0.2. Statistically significantly improvements were observed with daily-steroid regimen in the Gowers time (P = .01), nine-metre walk test (P = .02) and average power (P = .02) as compared to intermittent-steroid regimen. A total of 19/32 (52.8%) children in the daily-steroid group and 8/29 (27%) children in the intermittent-steroid group experienced some form of adverse effect (P = .02). DISCUSSION: Over a short-term period, the intermittent-steroid regimen was non-inferior to the daily-steroid regime in preserving muscle strength among children with DMD. However, better improvement of functional measures was observed with daily-steroid administration. The frequency of individual side effects was similar between the two groups.

A Novel Homozygous HAX1 Mutation in a Child With Cyclic Neutropenia: A Case Report and Review.

BACKGROUND: Cyclic neutropenia is a rare genetic disorder causing the arrest of neutrophil function and is characterized by periodic neutropenia and recurrent infections. Patients with cyclic neutropenia with autosomal dominant, sporadic, and X-linked may have mutations in the ELANE gene, and autosomal recessive cases have homozygous/compound heterozygous variants in the HAX1 gene primarily. OBSERVATION: The authors describe a novel variant in the HAX1 gene, which was detected by next-generation sequencing in an 8-year-old male child who presented with recurrent infections and neutropenia. CONCLUSION: The patient extends the clinical variability associated with HAX1 variants and highlights the importance of genetic investigations in patients with suspected cyclic neutropenia.

Role of computed tomography angiography in the evaluation of haemoptysis in children: Decoding the abnormal vessels.

Background & objectives: Haemoptysis in children is potentially life-threatening. In most cases, the bleeding arises from the systemic circulation, and in 5-10 per cent of cases, it arises from the pulmonary circulation. The role of computed tomography angiography (CTA) in this setting is important. This study was undertaken (i) to study the role of single-phase split-bolus dual energy contrast-enhanced multidetector row CTA (DECTA) in the evaluation of haemoptysis in children; (ii) to analyze the patterns of abnormal vascular supply in the various aetiologies encountered. Methods: A retrospective study of 86 patients who underwent split bolus DECTA for the evaluation of haemoptysis was performed. Final diagnoses were categorized as normal computed tomography, active tuberculosis (TB), post-infectious sequelae, non-TB active infection, cystic fibrosis (CF), non-CF bronchiectasis, congenital heart disease (CHD), interstitial lung disease, vasculitis, pulmonary thromboembolism and idiopathic pulmonary haemosiderosis. Abnormal bronchial arteries (BAs) and non-bronchial systemic collateral arteries (NBSCs) were assessed for number and site and their correlation with underlying aetiologies. Results: A total of 86 patients (45 males, age from 0.3 to 18 yr, mean 13.88 yr) were included in the study; among these only two patients were less than five years of age. The most common cause of haemoptysis was active infection (n=30), followed by bronchiectasis (n=18), post-infectious sequelae (n=17) and CHD (n=7). One hundred and sixty five abnormal arteries were identified (108 BA and 57 NBSC), and were more marked in bronchiectasis group. Interpretation & conclusions: Active infections and bronchiectasis are the most common causes of haemoptysis in children. While post-infectious sequelae are less common, in patients with haemoptysis, the presence of any abnormal arteries correlates with a more frequent diagnosis of bronchiectasis. NBSCs are more common in post-infectious sequelae and CHD.

Acute gastrointestinal injury in critically ill children: Impact on clinical outcome.

AIM: To estimate acute gastrointestinal injury (AGI) in critically ill children and association of its severity with mortality. METHODS: In a prospective cohort study, critically ill children (1 month-18 years) were enrolled. Gastrointestinal symptoms over the first week of admission were classified into AGI grades 1 through 4, using a paediatric adaptation of European Society of Intensive Care Medicine AGI definitions. Performance of AGI grades in predicting 28-day mortality was evaluated. RESULTS: Of 151 children enrolled, 71 (47%, 95% confidence interval (CI): 38.9-55.3%) developed AGI, with AGI grades 1, 2, 3 and 4 in 22.5%, 15.9%, 6.6% and 2%, respectively. The 28-day mortality progressively increased with AGI grade 0 (15%), 1 (35%), 2 (50%), 3 (70%), through 4 (100%), P < 0.001. Association of AGI grades with 28-day mortality was significant even after adjustment for disease severity, age and nutritional status (odds ratio (OR) = 2.152, 95% CI: 1.455, 3.184). Among AGI grades, and paediatric logistic organ dysfunction-2 score components, cardiovascular (OR = 1.525, 95% CI: 1.142, 2.037) and haematological (OR = 1.719, 95% CI: 1.067, 2.772) components of paediatric logistic organ dysfunction-2 score and AGI grades (OR = 1.565, 95% CI: 1.001, 2.449) showed significant association with 28-day mortality. CONCLUSIONS: Nearly half of the critically ill children developed AGI. AGI grades were independently associated with increased mortality, and mortality progressively increased with AGI grade.

Positive Expiratory Pressure Oxygen Therapy for Respiratory Distress: A Single-arm Feasibility Trial.

Background: Oxygen delivery devices with positive end-expiratory pressure (PEEP) valves have been described, but high inspiratory flows may lead to poor tolerance in tachypneic patients. Positive expiratory pressure oxygen therapy (PEP-OT) using an occlusive face mask, oxygen reservoir, and PEEP valve has not been evaluated in clinical settings. Materials and methods: In a single-arm intervention trial, patients aged 19-55 years admitted with acute respiratory illness with oxygen support were enrolled. PEP-OT trial was given with PEEP of 5 and 7 cm of water over 45 minutes. Feasibility was assessed as uninterrupted completion of the PEP-OT trial. The effects of PEP-OT on cardiopulmonary physiology and adverse effects of therapy were recorded. Results: Fifteen patients (6 males) were enrolled. Fourteen patients had pneumonia and one patient had pulmonary edema. Twelve patients (80%) completed the PEP-OT trial. There was significant improvement in respiratory rate (RR) and heart rate (HR) at the end of the 45-minute PEP-OT trial (p-values 0.048 and 0.003, respectively). There was a trend toward improved SpO2 and perceived dyspnea. None of the patients developed desaturation, shock, or air leaks. Positive expiratory pressure oxygen therapy is a feasible oxygen therapy in patients with acute hypoxia. Conclusion: Positive expiratory pressure oxygen therapy seems to be safe and has a positive impact on respiratory mechanics in parenchymal respiratory pathology. How to cite this article: Dhochak N, Ray A, Soneja M, Wig N, Kabra SK, Lodha R. Positive Expiratory Pressure Oxygen Therapy for Respiratory Distress: A Single-arm Feasibility Trial. Indian J Crit Care Med 2022;26(11):1169-1174.

Delayed Administration of Antibiotics Beyond the First Hour of Recognition Is Associated with Increased Mortality Rates in Children with Sepsis/Severe Sepsis and Septic Shock.

OBJECTIVE: To compare the risk of mortality and other clinical outcomes in children with sepsis, severe sepsis, or septic shock who received antibiotics within the first hour of recognition (early antibiotics group) with those who received antibiotics after the first hour (delayed antibiotics group). STUDY DESIGN: In this prospective cohort study, we enrolled children <17 years of age presenting to the pediatric emergency and diagnosed with sepsis or septic shock without prior antibiotic therapy. Primary outcome was mortality and the secondary outcomes were day 1 Pediatric Logistic Organ Dysfunction score, ventilator-free days, and hospital-free days. These outcomes were compared between the early and the delayed antibiotic groups. The reference point for defining early and delayed antibiotic groups was time 0, which was measured from the time the patient was diagnosed to have sepsis, severe sepsis, or septic shock to the time of administration of the first dose of antibiotics. RESULTS: About three-fourths (77%) of the 441 children enrolled had septic shock. A total of 241 (55%) and 200 (45%) children were in the delayed and early antibiotic groups, respectively. Children in the delayed group had significantly higher odds of mortality than those in the early group (29% vs 20%; aOR 1.83; 95% CI, 1.14-2.92; P = .01). The time to shock reversal was significantly shorter, and the ventilator-free days and hospital-free days were significantly greater, in the early antibiotic group. There was no difference between the groups with regard to any of the other clinical outcomes. CONCLUSIONS: Delayed administration of antibiotics beyond 1 hour of recognition was associated with higher mortality rates in children with sepsis, severe sepsis, and septic shock. Antibiotics should be administered within the first hour, along with other resuscitative measures, in these children.

Efficacy of vitamin D supplementation in asthmatic children with vitamin D deficiency: A randomized controlled trial (ESDAC trial).

BACKGROUND: Vitamin D supplementations for asthma control had shown inconsistent results. We aimed to study efficacy and safety of vitamin D supplementation in asthmatic children who were vitamin D deficient. METHODS: This double-blind, randomized controlled trial enrolled asthmatic children of 4-12 years of age who had 25-hydroxyvitamin D [25(OH)D] levels <20 ng/mL. The participants were randomized to receive either vitamin D orally 1000 IU/d for 9 months or similar-looking placebo. The primary outcomes were the proportion of children having the Childhood Asthma Control Test (CACT) score of ≥20 at the end of the treatment and adverse effects. RESULTS: The trial included 250 children (125 in each group) with a mean age of 8.1 ± 2.3 years and 180 boys. The baseline parameters were similar between the groups, including CACT score (21.7 ± 4.2 vs 21.9 ± 3.6, vitamin D vs placebo). At the end of the study, the proportion of asthmatic children who had CACT score ≥ 20 was similar between vitamin D and placebo group (93.6% vs 92.0%, P = .625). The number of exacerbations of asthma and side effect profile was also identical between the groups. 25(OH)D levels increased significantly in the vitamin D group (18.06 ± 7.11 vs 12.03 ± 5.98 ng/mL, P < .001). The results did not change when we did subgroup analysis for children with baseline CACT score < 20 and 25(OH)D levels at the end of the study ≥20 ng/mL. CONCLUSION: Vitamin D supplementation in asthmatic children with vitamin D deficiency did not improve control of asthma.

Cystic fibrosis in low and middle-income countries (LMIC): A view from four different regions of the world.

Cystic fibrosis (CF) has been shown to affect people all over the world. While life expectancy for people with CF has increased substantially, CF is still associated with death in infants and young children in many regions, particularly in low and middle-income countries (LMIC). These countries face significant challenges to promote CF diagnosis and improvements to CF care due to financial constraints and a significant burden of other diseases. In this review, we describe the status of CF diagnosis and care in different LMIC settings, from four different parts of the world (Brazil, South Africa, Israel and India). We highlight challenges and opportunities for CF practitioners in LMIC to improve CF care and outcomes. While early CF diagnosis is the key to optimising outcomes, newborn screening may not be feasible for countries with lower CF incidence and higher birth rates, such as India or South Africa. CF therapies and care in LMIC need to be adapted to available resources of these countries. Collaboration initiatives of the global CF community with LMIC may improve CF care in these countries. Most individuals with CF in LMIC are not benefiting from CFTR modulator treatments due to the prohibitive cost of these drugs.

Functional Outcomes at 1 Year After PICU Discharge in Critically Ill Children With Severe Sepsis.

OBJECTIVES: To evaluate the functional outcomes in critically ill children with severe sepsis using the Pediatric Overall Performance Category scale and Pediatric Cerebral Performance Category scale and to evaluate the risk factors for "worse outcomes." DESIGN: Prospective observational cohort study. SETTING: Tertiary care PICU from September 2017 to October 2019. PATIENTS: One hundred twenty-one children with severe sepsis, 2 months to 17 years old, admitted to PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Pediatric Overall Performance Category and Pediatric Cerebral Performance Category scores were recorded at admission, PICU discharge, at 3 months and 1 year after discharge. "New disability" was defined as Pediatric Overall Performance Category and Pediatric Cerebral Performance Category score change "from baseline score" by greater than or equal to 1 category. Risk factors for "worse outcomes" (defined as "death" or "new disability") were evaluated by univariate and multivariate analysis. At admission, 33% (n = 39) had mild to moderate "overall disability" (Pediatric Overall Performance Category) and 26% (n = 32) had mild to moderate "cognitive disability" (Pediatric Cerebral Performance Category). At PICU discharge (n = 89 children), 50.5% (n = 45) had "new disability" in overall function (Pediatric Overall Performance Category scores) and 28% (n = 25) had "new disability" in cognitive function (Pediatric Cerebral Performance Category scores). At 3 months follow-up (n = 85 children), "new disability" at PICU discharge improved in 65% (n = 28/43) and 50% (n = 12/24) of those with "overall disability" (Pediatric Overall Performance Category) and "cognitive disability" (Pediatric Cerebral Performance Category), respectively. At 1-year follow-up (n = 84 children), only 5% (n = 2/43) had residual "new disability" in overall function (Pediatric Overall Performance Category) and 14% (n = 3/21) had residual "new disability" in cognitive function. PICU mortality was 26% (n = 32). The proportion with "worse outcomes" was 64% (n = 77). Risk factors for worse outcomes on univariate analysis included higher Pediatric Index of Mortality-3 scores, day 1 pediatric Sequential Organ Failure Assessment score, receiving cardiopulmonary resuscitation during the ICU stay, and treatments received such as ventilation and Vasoactive-Inotrope Score. On multivariate analysis, only day 1 pediatric Sequential Organ Failure Assessment score and receiving cardiopulmonary resuscitation during the ICU stay were found to be statistically significant. CONCLUSIONS: Children with severe sepsis had significant "new onset" mild to moderate functional disability at PICU discharge, and most of these children recovered within 1 year after PICU discharge. Day 1 pediatric Sequential Organ Failure Assessment score and patient receiving cardiopulmonary resuscitation during the ICU stay were found to be the significant risk factors of "worse outcomes."

Use of Honey Versus Standard Care for Hospital-Acquired Pressure Injury in Critically Ill Children: A Multicenter Randomized Controlled Trial.

OBJECTIVES: To examine if the use of honey (medicated) for dressing is superior to standard care in terms of time to complete wound healing in stages 1-3 of pressure injuries in children admitted to the PICU. DESIGN: Multicenter, open-label, parallel-group, randomized trial. SETTING: Tertiary-care PICU from August 2017 to January 2019. PATIENTS: Critically ill children, 2 months to 17 years old, who developed pressure injury (stages 1-3) were included; those on more than two inotropes or with signs of acute wound infection or wounds with greater than 5 cm diameter or known allergy to honey were excluded. INTERVENTIONS: Children were randomized to receive either medicated honey dressing or standard (routine) wound care for the management of their pressure injury. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the time to complete wound healing. Manuka or active Leptospermum honey dressing/gel was used in the intervention group. Enrolled children were followed up until death or discharge from the hospital. A total of 99 children were enrolled: 51 in the intervention group and 48 in the standard care group. Baseline characteristics, including the nutritional status, were comparable between the groups. The most common sites of injury were bony prominences at face mask contact points. The median time to complete healing was 7 days (95% CI, 6-7 d) versus 9 days (7-10 d) in the intervention and standard care groups, respectively (p = 0.002; log-rank test). At any random time, children in the intervention group were about 1.9-fold more likely to have their pressure injury completely healed than those in the standard care group (hazard ratio 1.86; 95% CI, 1.21-2.87). There were no allergic reactions or secondary wound infections in the intervention group. CONCLUSIONS: The use of medicated honey dressings decreased the time to wound healing in critically ill children with pressure injuries. There were no allergic reactions or secondary bacterial infections in any of these children.

Twenty-Four-Hour Esophageal pH Measurement in Mechanically Ventilated Children: A Prospective Cohort Study.

OBJECTIVES: To assess the prevalence of gastroesophageal reflux in mechanically ventilated children using 24-hour esophageal pH-metry and its role as a risk factor for ventilator-associated pneumonia. DESIGN: Prospective cohort study. SETTING: PICU of a tertiary care hospital from North India. PATIENTS: Mechanically ventilated children 1-15 years old in PICU from July 2015 to June 2017, excluding those receiving acid suppressants, known cases of gastroesophageal reflux disease, having upper gastrointestinal bleed. INTERVENTION: Demographic details, baseline investigations, diagnosis, treatment details, and Pediatric Risk of Mortality III score were recorded at enrollment. Gastroesophageal reflux was evaluated using 24-hour esophageal pH-metry. Children were followed up for 7 days or 48 hours after extubation for development of ventilator-associated pneumonia using Centers for Disease Control and Prevention criteria. Pathologic acidic gastroesophageal reflux was defined as fall in esophageal pH less than 4 for more than 4% of total time, whereas pathologic alkaline gastroesophageal reflux as rise in esophageal pH greater than 7 for more than 17% of total time. MEASUREMENTS AND MAIN RESULTS: Sixty-one children (median [interquartile range], age 73 mo [30-132 mo]; 44 boys [72%]) were enrolled. Median Pediatric Risk of Mortality III score was 10.0 (3-16). Median duration of ventilation was 6 days (3-9 d). Pathologic gastroesophageal reflux (acidic or alkaline) was present in 47 children (77%). Twelve children (19.7%) met criteria for pathologic acidic gastroesophageal reflux, whereas 44 children (72.1%) had pathologic alkaline gastroesophageal reflux; nine children (14.7%) had both pathologic acidic and alkaline gastroesophageal reflux. Of the enrolled children, 17 (27.9 %) developed ventilator-associated pneumonia. No patient had both pathologic acidic gastroesophageal reflux and ventilator-associated pneumonia. Of 17 children who developed ventilator-associated pneumonia, 12 (70.5%) had pathologic alkaline gastroesophageal reflux as compared to 32 children (72.7%) among the 44 children who did not develop ventilator-associated pneumonia (p = 0.87). CONCLUSIONS: The current study shows high incidence of gastroesophageal reflux on 24-hour esophageal pH-metry in mechanically ventilated children with medical diagnoses. The significance of this finding and its impact on ventilator-associated pneumonia and other ventilator-associated events need to be examined in larger studies.

Viral Characteristics Associated with Maintenance of Elite Neutralizing Activity in Chronically HIV-1 Clade C-Infected Monozygotic Pediatric Twins.

Broad and potent neutralizing antibodies (bnAbs) with multiple epitope specificities evolve in HIV-1-infected children. Herein, we studied two antiretroviral-naive chronically HIV-1 clade C-infected monozygotic pediatric twins, AIIMS_329 and AIIMS_330, with potent plasma bnAbs. Elite plasma neutralizing activity was observed since the initial sampling at 78 months of age in AIIMS_330 and persisted throughout, while in AIIMS_329 it was seen at 90 months of age, after which the potency decreased over time. We evaluated potential viral characteristics associated with the varied immune profiles by generating single genome-amplified pseudoviruses. The AIIMS_329 viruses generated from the 90-month time point were neutralization sensitive to bnAbs and contemporaneous plasma antibodies, while viruses from the 112-month and 117-month time points were resistant to most bnAbs and contemporaneous plasma. AIIMS_329 viruses developed resistance to plasma neutralizing antibodies (nAbs) plausibly by N160 glycan loss and V1 and V4 loop lengthening. The viruses generated from AIIMS_330 (at 90 and 117 months) showed varied susceptibility to bnAbs and autologous contemporaneous plasma antibodies, while the viruses of the 112-month time point, at which the plasma nAb specificities mapped to the V2 glycan, V3 glycan, and CD4 binding site (CD4bs), were resistant to contemporaneous plasma antibodies as well as to most bnAbs. Chimeric viruses were constructed from 90-month-time-point PG9-sensitive AIIMS_329 and AIIMS_330 viruses with swapped V1V2 regions of their respective evolved viruses (at 112 and 117 months), which led to higher resistance to neutralization by PG9 and autologous plasma antibodies. We observed the evolution of a viral pool in the AIIMS_330 donor comprising plasma antibody neutralization-sensitive or -resistant diverse autologous viruses that may have contributed to the development and maintenance of elite neutralizing activity.IMPORTANCE Herein, we report the longitudinal development of bnAbs in a pair of chronically HIV-1 clade C-infected monozygotic pediatric twins, AIIMS_329 and AIIMS_330, who acquired the infection by vertical transmission. The plasma from both donors, sharing a similar genetic makeup and infecting virus, showed the evolvement of bnAbs targeting common epitopes in the V2 and V3 regions of the envelope, suggesting that bnAb development in these twins may perhaps be determined by specific sequences in the shared virus that can guide the development of immunogens aimed at eliciting V2 and V3 bNAbs. Characterization of the neutralization-sensitive and -resistant viruses coevolving with bNAbs in the contemporaneous AIIMS_330 plasma provides information toward understanding the viral alterations that may have contributed to the development of resistance to bnAbs. Further longitudinal studies in more monozygotic and dizygotic twin pairs will help in delineating the role of host and viral factors that may contribute to the development of bnAbs.

Prevalence and Risk Factors of Allergic Bronchopulmonary Aspergillosis and Aspergillus Sensitization in Children with Poorly Controlled Asthma.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) may be a risk factor for poorly controlled asthma in children. The studies regarding prevalence and risk factors of ABPA in children with poorly controlled asthma are limited in number. OBJECTIVES: To determine prevalence and risk factors of ABPA and aspergillus sensitization (AS) in children with poorly controlled asthma. METHODS: In this prospective cross-sectional study from a tertiary care center in India, we enrolled asthmatic children 5-15 years of age with poorly controlled asthma. We did the following investigations: spirometry, skin prick test, serum total immunoglobulin E (IgE), aspergillus-specific IgE and immunoglobulin G, serum precipitin for Aspergillus, absolute eosinophil count, chest X-ray and high-resolution computed tomography of the chest. ABPA and AS were diagnosed as per the recently proposed criteria. RESULTS: We enrolled 106 children [boys 72 (67.9%); mean age of 10.2 ± 2.6 years] with poorly controlled asthma. The prevalence of ABPA and AS were 11.3% (95% CI, 5.2-17.5%) and 61.3% (95% CI, 52.0-70.7%), respectively. The presence of brownish sputum was significantly more in ABPA compared with non-ABPA patients (33.3 vs. 4.2%, p = 0.002). The age, gender, allergic rhinitis and gastroesophageal reflux were not significantly different in ABPA compared with non-ABPA patients. CONCLUSION: The prevalence of ABPA and AS was 11.3 and 61.3%, respectively in children with poorly controlled asthma. We could not find any risk factors for ABPA except that the presence of brownish sputum was more in children with ABPA. Spirometry parameters were not significantly different in ABPA compared with non-ABPA patients.

Course of Illness after Viral Infection in Indian Children with Cystic Fibrosis.

OBJECTIVE: To study the clinical impact of respiratory viral infection in children with cystic fibrosis (CF). DESIGN: Retrospective cohort study. SETTING: Tertiary care referral centre for CF in India. PARTICIPANTS/PATIENTS: Children with CF attending a pediatric chest clinic. METHODS: Case records of the children with CF who had a pulmonary exacerbation with documented acute respiratory viral infection between October 2013 and December 2014 (Group I) and an equal number of controls (Group II) with pulmonary exacerbation in absence of acute respiratory viral infection were reviewed. OUTCOME MEASURES: The two groups were compared for the following outcomes over a period of 12-18 months: bacterial colonization, antibiotics usage, pulmonary exacerbations, numbers of outpatient visits, hospitalization and oxygen therapy and spirometric parameters. RESULTS: In total, 46 children [23 each with viral infection (Group I) and without viral infection (Group II)] of age 7-264 months were enrolled; baseline clinical status and pulmonary function tests were comparable. Mean (SD) follow-up duration in those who had viral infection and who had no viral infection was 15.7 (7.1) and 17.5 (5.4) months, respectively. On follow-up, children with viral infection (Group I) had adverse outcome in form of greater worsening of Shwachman clinical scores, number of pulmonary exacerbations requiring antibiotic usage [4 (2.1%)] and [2.8 (1.7%)], need for intravenous antibiotics 30.4% vs. 8.7%, hospitalization rates 31.8% vs. 4.3% and mortality 30.4% vs. 4.7%, respectively. CONCLUSION: Acute viral infection in children with CF affected course of illness on follow-up, including frequent and severe pulmonary exacerbations requiring hospitalization, intravenous antibiotics, decline in CF scores and increased mortality over next 12-18 months.

Impact of HIV infection and highly active antiretroviral therapy (HAART) on B cell subpopulations in children.

B-cells play an important role in defending children against various infections. In view of scare data, we undertook this prospective cohort study to describe B cell compartment in HIV infected children (<5 years of age) and the effect of HAART on B cell subpopulations. HIV infected children (<5 years) from Pediatric HIV services of the Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, were recruited (April 2012-December 2015). The enrolled HIV-1 infected children (n = 59) were followed up regularly for 12 months; healthy controls (n = 51) included HIV uninfected children with no major illness. Flow cytometry was performed on fresh EDTA-treated blood samples to characterize B cell subpopulations. In HIV-infected children, marked depletion of naive (P = 0.003), non-switched memory (P = 0.02), mature (P = 0.0005), resting memory (P < 0.0001) B cells, and expansion of double negative memory (P < 0.0001), activated memory (P < 0.0001) and tissue like memory (P < 0.0001) B cells were observed as compared to healthy controls. In children started on HAART, at the end of 12 months of therapy, frequencies of non-switched memory (P = 0.04), switched memory (P = 0.01), and resting memory (P = 0.003) B cells were lower; activated memory (P = 0.04), and tissue-like memory (P = 0.0001) B cells were still higher than healthy controls. HIV infection resulted in reduced memory B cells in HIV infected children. Following HAART, there was normalization of some B cell subpopulations. The study emphasizes the need of re-vaccination in HIV infected children to maintain the memory B cell pool and adequate humoral immune response against infections.

Evolution of cross-neutralizing antibodies and mapping epitope specificity in plasma of chronic HIV-1-infected antiretroviral therapy-naïve children from India.

Delineating the factors leading to the development of broadly neutralizing antibodies (bnAbs) during natural HIV-1 infection and dissecting their epitope specificities generates useful information for vaccine design. This is the first longitudinal study to assess the plasma-neutralizing antibody response and neutralizing determinants in HIV-1-infected children from India. We enrolled 26 and followed up 20 antiretroviral therapy (ART)-naïve, asymptomatic, chronic HIV-1-infected children. Five (19.2 %) baseline and 10 (50 %) follow-up plasma samples neutralized ≥50 % of subtypes A, B and C tier 2 viruses at an ID50 titre ≥150. A modest improvement in neutralization breadth and potency was observed with time. At baseline, subtype C-specific neutralization predominated (P=0.026); interestingly, follow-up samples exhibited cross-neutralizing activity. Epitope mapping revealed V3C reactive antibodies with significantly increased Max50 binding titres in follow-up samples from five infected children; patient #4's plasma antibodies exhibited V3-directed neutralization. A salient observation was the presence of CD4 binding site (CD4bs)-specific NAbs in patient #18 that improved with time (1.76-fold). The RSC3 wild-type (RSC3WT) protein-depleted plasma eluate of patient #18 demonstrated a more than 50% ID50 decrease in neutralization capacity against five HIV-1 pseudoviruses. Further, the presence of CD4bs-neutralizing determinants in patient #18's plasma was confirmed by the neutralizing activity demonstrated by the CD4bs-directed IgG fraction purified from this plasma, and competition with sCD4 against JRFLgp120, identifying this paediatric donor as a potential candidate for the isolation of CD4bs-directed bnAbs. Overall, we observed a relative increase in plasma-neutralizing activity with time in HIV-1-infected children, which suggests that the bnAbs evolve.