Efficiency, Economy and Excellence: Experimental Exploration of Evidence-based Guideline Development in Resource-Constrained Settings

Development of clinical practice guidelines is a scientific process based on a thorough review and appraisal of the global evidence, but factoring in local contextually relevant issues. It is highly resource intensive, demanding considerable time, human skills, and finances- making it challenging in resource-constrained settings. This article summarizes a unique attempt to develop evidence-based guidelines in such settings. This was made possible by mentoring and monitoring a group of committed healthcare professionals with limited prior expertise in evidence-based guideline development. The various steps included an online training workshop to build knowledge and skills. This was followed by a systematic process of identifying topics requiring evidence-based guidelines. Thereafter, the topics were prioritized through a Delphi process. Formal clinical questions were framed using the PICOTS (Patient/ Population, Intervention/ Exposure, Comparison, Outcome, Time-frame, Setting) format. The guideline development process was made time and resource efficient by starting with a formal search for existing guidelines whose recommendations could be adopted, adapted, or adoloped to the local setting. If such guidelines were unavailable, high quality secondary evidence (systemic reviews) was accessed to find answers to the clinical questions. If unavailable, de novo systematic reviews of primary research studies were undertaken. The evidence base was critically appraised and graded. Formal evidence-to-decision formats were used to enable translation of the evidence to recommendations implementable in the local setting. The entire guideline development process was completed with zero financial allocation. This model focusing on efficiency, economy, and excellence, can be emulated in diverse resource-constrained settings.

Serum Periostin Level in Children with Asthma

Objectives To determine the average serum periostin level in children with asthma between 6 and 16 y of age, and to fnd out if the levels correlated with markers of eosinophilic infammation, asthma control, and severity. Methods Children under follow-up at a tertiary care centre were enrolled. Children with conditions causing elevated serum periostin other than asthma, or history of systemic steroid use in the past 6 mo were excluded. Serum total IgE and periostin were estimated by ELISA. Results The median (IQR) serum periostin level was 52.6 (45.4, 58.3) ng/mL. Levels did not vary with age, gender, duration of symptoms, positive family history, or history of exacerbations in the last 6 mo. There was no signifcant correlation with anthropometric parameters or their z scores, or markers of eosinophilic infammation in blood including serum total IgE, eosinophil percentage or absolute eosinophil count. There was no diference in median periostin levels of children with diferent asthma symptom control or asthma severity. Conclusions In a group of 26 Indian children with physician-diagnosed asthma, serum periostin showed no signifcant correlation to markers of eosinophilic infammation.

Epidemiology, Clinical Profile, Intensive Care Needs and Outcome in Children with SARS-CoV-2 Infection Admitted to a Tertiary Hospital During the First and Second Waves of the COVID-19 Pandemic in India

Objectives To compare the epidemiological, clinical profle, intensive care needs and outcome of children hospitalized with SARS-CoV-2 infection during the frst and second waves of the pandemic. Methods This was a retrospective study of all children between 1 mo and 14 y, admitted to a dedicated COVID-19 hospital (DCH) during the frst (1st June to 31st December 2020) and second waves (1st March to 30th June 2021). Results Of 217 children, 104 (48%) and 113 (52%) were admitted during the frst and second waves respectively. One hundred ffty-two (70%) had incidentally detected SARS-CoV-2 infection, while 65 (30%) had symptomatic COVID-19. Comorbidities were noted in 137 (63%) children. Fifty-nine (27%) and 66 (30%) children required high-dependency unit (HDU) and ICU care respectively. Severity of infection and ICU needs were similar during both waves. High-fow oxygen (n=5, 2%), noninvasive ventilation [CPAP (n=34, 16%) and BiPAP (n=8, 5%)] and invasive ventilation (n=45, 21%) were respiratory support therapies needed. NIV use was more during the second wave (26% vs. 13%; p=0.02). The median (IQR) length (days) of DCH stay among survivors was longer during the frst wave [8 (6–10) vs. 5.5 (3–8); p=0.0001]. Conclusions Disease severity, associated comorbidities, PICU and organ support need and mortality were similar in the frst and second waves of the pandemic. Children admitted during the second wave were younger, had higher proportion of NIV use and shorter length of COVID-19 hospital stay.

Systematic Identification and Critical Appraisal of Pediatric COVID-19 Guidelines Applicable in India

Objective To systematically identify and critically appraise the methodological quality of pediatric guidelines applicable to management of COVID-19 in India. Methods Pediatric COVID-19 guidelines applicable to India, published until 30 April 2021, were identifed through a systematic search across ten databases. Each was critically appraised for methodological quality using the AGREE-II tool, by at least two appraisers. Median (interquartile range) of the total score and domain-wise scores were calculated, and compared for Indian vs. foreign guidelines, updated vs. original versions of guidelines, and those developed earlier vs. later in the pandemic. Results A total of 62 guidelines was identifed. Only 8 (12.9%) were published in India. The overall AGREE-II score ranged from 4.7% to 72.8%; with median (IQR) 37.9% (29.4, 48.6). This suggested overall low(er) methodological quality. The median (IQR) domain-wise scores were as follows: Scope and Purpose 66.7% (58.3, 83.3), Stakeholder Involvement 41.7% (30.6, 83.3), Rigor of Development 23.4% (14.8, 37.5), Clarity of Presentation 59.7% (50.0, 75.0), Applicability 27.1% (18.8, 33.3), and Editorial Independence 8.3% (0.0, 45.8). This suggested diversity in quality of diferent aspects of the guidelines, with very low quality in the critical domain of methodological rigor. There were no statistically signifcant diferences in the overall scores of Indian vs. foreign guidelines, updated versions vs. original versions, and those developed earlier vs. later in the pandemic. Conclusion The currently available pediatric COVID-19 guidelines have low methodological quality, adversely afecting their credibility, validity, and applicability. Urgent corrective strategies are presented for consideration.

Systematic Reviews and Meta-Analysis: A Guide for Beginners

Systematic reviews involve the application of scientific methods to reduce bias in review of literature. The key components of a systematic review are a well-defined research question, comprehensive literature search to identify all studies that potentially address the question, systematic assembly of the studies that answer the question, critical appraisal of the methodological quality of the included studies, data extraction and analysis (with and without statistics), and considerations towards applicability of the evidence generated in a systematic review. These key features can be remembered as six ‘A’; Ask, Access, Assimilate, Appraise, Analyze and Apply. Meta-analysis is a statistical tool that provides pooled estimates of effect from the data extracted from individual studies in the systematic review. The graphical output of meta-analysis is a forest plot which provides information on individual studies and the pooled effect. Systematic reviews of literature can be undertaken for all types of questions, and all types of study designs. This article highlights the key features of systematic reviews, and is designed to help readers understand and interpret them. It can also help to serve as a beginner’s guide for both users and producers of systematic reviews and to appreciate some of the methodological issues.

Efficacy and Safety of Pidotimod in Persistent Asthma: A Randomized Triple-Blinded Placebo-Controlled Trial

Objective: To study whether addition of pidotimod to inhaled corticosteroid (ICS) therapy enhances control in children with persistent asthma, as compared to ICS therapy alone. Design: Triple-blinded, randomized controlled trial. Setting: Allergy and Asthma Clinic, Department of Pediatrics, at a tertiary care hospital between May, 2018 and June, 2019. Patients: 79 children (5-12 years) with newly diagnosed persistent asthma as per Global Initiative for Asthma guidelines. Interventions: Children received 7 mL twice-a-day for 15 day, followed by 7 mL once-a-day for 45 days of either pidotimod (n=39) or placebo (n=40). In addition, both groups received inhaled budesonide via metered dose inhaler and spacer, throughout the study. Children were followed up every 4 weeks for a total of 12 weeks. At each follow-up visit, peak expiratory flow (PEF) and asthma symptom score and medicine adverse effects were recorded. Main outcome measures: Change in PEF at 12 weeks compared to baseline. Secondary outcomes were PEF at each follow-up visit, asthma symptom score at each visit, change in asthma symptom score at 12 weeks, and adverse event profile. Results: The median (IQR) change in PEF (from baseline to 12 weeks) was 13.0% (0.8%, 28.3%) in pidotimod group (n=35) vs 17.7% (4.3%, 35.2%) in placebo group (n=35) (P=0.69). All the secondary outcomes were also comparable between the two groups. There were no significant adverse effects observed. Conclusions: Addition of pidotimod for 8 weeks to standard ICS therapy did not enhance asthma control compared to placebo.

Does Normal Saline Have Clinical Effects in Infants with Bronchiolitis?

The objective of this systematic review and meta-analysis was to measure the short-term association of nebulizednormal saline with physiologic measures of respiratory status in children having bronchiolitis by comparingnebulized normal saline with the use of other placebos. Randomized clinical trials comparing children 2 years oryounger with bronchiolitis who were treated with nebulized normal saline were included. Studies enrolling atreatment group receiving an alternative placebo were included for comparison of normal saline with otherplacebos. Pooled estimates of the association with respiratory scores, respiratory rates, and oxygen saturationwithin 60 minutes of treatment were generated for nebulized NS vs another placebo and for change before and afterreceiving nebulized normal saline. A total of 29 studies including 1583 patients were included. Standardized meandifferences in respiratory scores for nebulized normal saline vs other placebo (3 studies) favored nebulized NS by –0.9 points (95% CI, –1.2 to –0.6 points) at 60 minutes after treatment (P<0.001). The standardized mean differencein respiratory score (25 studies) after nebulized NS was –0.7 (95% CI, –0.7 to –0.6; I2 = 62%). The weighted meandifference in respiratory scores using a consistent scale (13 studies) after nebulized NS was –1.6 points (95% CI, –1.9 to –1.3 points; I2 = 72%). The weighted mean difference in respiratory rate (17 studies) after nebulized NS was –5.5 breaths per minute (95%CI, –6.3 to –4.6 breaths per minute; I2 = 24%). The weighted mean difference in oxygensaturation (23 studies) after nebulized NS was –0.4% (95% CI, –0.6%to –0.2%; I2 = 79%). The authors concludedthat nebulized normal saline may be an active treatment for acute viral bronchiolitis and recommended that furtherevaluation should occur to establish whether it is a true placebo.

Tenofovir for Prevention of Mother-to-Child Transmission of Hepatitis B.

In this trial, 200 mothers, who were positive for hepatitis-B e antigen (HBeAg) and who had hepatitis-B virus (HBV) DNA level >200,000 IU/mL, were randomly assigned to receive usual care without antiviral therapy or to receive tenofovir (TDF) at an oral dose of 300 mg/d from 30 to 32 weeks of gestation until postpartum week 4; the participants were followed until postpartum week 28. All the infants received immunoprophylaxis. The primary outcomes were the rates of mother-to-child transmission and birth defects. The secondary outcomes were the safety of TDF, the percentage of mothers with an HBV DNA level of <200,000 IU/mL at delivery, and loss or seroconversion of HBeAg or hepatitis B surface antigen at postpartum week 28. At delivery, 68% of the mothers in the TDF group (66 of 97 women), as compared with 2% in the control group (2 of 100), had an HBV DNA level <200,000 IU/mL. At postpartum week 28, the rate of mother-to-child transmission was significantly lower in the TDF group than in the control group, both in the intention-to-treat analysis (5% vs. 18%, P=0.007) and the per-protocol analysis (0 vs. 7%, P=0.01). The maternal and infant safety profiles were similar in the TDF group and the control group, including birth defect rates (2% vs. 1%, P=1.00), although more mothers in the TDF group had an increase in the creatine kinase level. After the discontinuation of TDF, alanine aminotransferase elevations above the normal range occurred more frequently in mothers in the TDF group than in those in the control group (45% vs. 30%, P=0.03). The authors concluded that in HBeAg-positive mothers with an HBV DNA level >200,000 IU/mL during the third trimester, the rate of mother-to-child transmission was lower among those who received TDF therapy than among those who received usual care without antiviral therapy.

Can We Predict Antibiotic-resistance in Urinary Tract Infection.

In this study, 769 children (age 2-71 mo) enrolled in the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) or Careful Urinary Tract Infection Evaluation (CUTIE) studies were included to determine the risk factors of having pathogens resistant to narrow spectrum antimicrobials in urinary tract infection (UTI). The authors used logistic regression models to test the associations between demographic and clinical characteristics and resistance to narrow spectrum antimicrobials. Of the included patients, 91% were females, and 76% had vesicoureteral reflux. The odds of resistance to narrow-spectrum antibiotics in uncircumcised males were approximately 3 times that of females (OR 3.1; 95% CI 1.4, 6.7); in children with bladder bowel dysfunction, the odds were 2 times that of children with normal function (OR 2.2; 95% CI 1.2, 4.1). Children who had received one course of antibiotics during the past 6 months also had higher odds of harboring resistant organisms (OR 1.6; 95% CI 1.1, 2.3). Hispanic children had higher odds of harbouring pathogens resistant to some narrow-spectrum antimicrobials. The authors concluded that uncircumcised males, hispanic children, children with bladder bowel dysfunction, and children who received a course of antibiotics in the past 6 months were more likely to have a urinary tract infection caused by pathogens resistant to one or more narrow-spectrum antimicrobials.