Evaluation of efficacy and safety of intradermal delivery of vaccines through microneedle(s) in human beings: a protocol for a systematic review.

BACKGROUND: Microneedles are defined as micron-sized projections with an insertion length ranging from 20 to 1500 µm and an external diameter up to 300 µm. Medications administered through microneedles diffuse through the deeper layers of the skin, into the systemic circulation, with minimal stimulation of pain-sensitive nerve endings. The rich presence of dendritic cells in the dermis makes microneedle-based vaccine delivery an attractive option. This systematic review will evaluate the efficacy and safety of intradermal delivery of vaccines using microneedles, in human beings. METHODS: We will search the following databases for studies reporting the efficacy and/or safety of intradermal delivery of vaccines using microneedles: Epistemonikos and the Cochrane Library for systematic reviews and MEDLINE (through PubMed), EMBASE, Cochrane CENTRAL, LIVIVO, Web of Science, Scopus and CINAHL databases for primary studies. We will also search grey literature databases and hand search reference lists of relevant studies. We will include randomised and quasi-randomised trials in human beings (any age), using microneedles (any material, length or bore) to deliver vaccines intradermally, wherein outcomes reflecting efficacy, safety, pain responses, participant satisfaction or cost are reported. We will additionally include non-randomised observational studies for long-term safety outcomes that are not reported in trials. Eligibility for inclusion will be independently determined by two reviewers. The risk of bias of the included studies will be assessed using the Cochrane RoB2 Tool (for randomised trials) and Newcastle-Ottawa Scale (for other study designs). Data on efficacy and safety will be pooled through meta-analysis (where feasible). We will explore the heterogeneity amongst randomised trials, using the Higgins and Thompson I2 method. We will undertake sensitivity analysis to explore the impact of study quality and subgroup analysis based on the age of participants, length of microneedle and vaccine dosage. The GRADE approach will be used to estimate the confidence in the evidence. RESULTS: This is a protocol for a systematic review; hence, there are no results at this stage. DISCUSSION: The proposed systematic review will provide evidence on efficacy, safety, pain responses, participant acceptability and cost in human beings (adults and children) for vaccines administered through the intradermal route using microneedles. Since intradermal injections using microneedles are associated with less pain due to their short lengths and narrow bores, we anticipate that delivery of vaccine antigens using this method could be a safe, efficacious and less painful alternative compared with conventional injections using hypodermic needles. The evidence in this review will be useful for policymakers, vaccine manufacturers and healthcare providers to consider this approach for the vaccination of infants and children in routine immunisation programmes. Therefore, we plan to disseminate the review through a peer-reviewed journal publication and will also provide data that cannot be included in the published version to anyone upon reasonable request. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020213608.

Therapeutic hypothermia in neonatal hypoxic encephalopathy: A systematic review and meta-analysis.

Background: Therapeutic hypothermia (TH) is regarded as the most efficacious therapy for neonatal hypoxic encephalopathy. However, limitations in previous systematic reviews and the publication of new data necessitate updating the evidence. We conducted this up-to-date systematic review to evaluate the effects of TH in neonatal encephalopathy on clinical outcomes. Methods: In this systematic review and meta-analysis, we searched Medline, Cochrane Library, Embase, LIVIVO, Web of Science, Scopus, CINAHL, major trial registries, and grey literature (from inception to October 31, 2021), for randomized controlled trials (RCT) comparing TH vs normothermia in neonatal encephalopathy. We included RCTs enrolling neonates (gestation ≥35 weeks) with perinatal asphyxia and encephalopathy, who received either TH (temperature ≤34°C) initiated within 6 hours of birth for ≥48 hours, vs no cooling. We excluded non-RCTs, those with delayed cooling, or cooling to >34°C. Two authors independently appraised risk-of-bias and extracted data on mortality and neurologic disability at four time points: neonatal (from randomization to discharge/death), infancy (18-24 months), childhood (5-10 years), and long-term (>10 years). Other outcomes included seizures, EEG abnormalities, and MRI findings. Summary data from published RCTs were pooled through fixed-effect meta-analysis. Results: We identified 36 863 citations and included 39 publications representing 29 RCTs with 2926 participants. Thirteen studies each had low, moderate, and high risk-of-bias. The pooled risk ratios (95% confidence interval, CI) were as follows: neonatal mortality: 0.87 (95% CI = 0.75, 1.00), n = 2434, I2 = 38%; mortality at 18-24 months: 0.88 (95% CI = 0.78, 1.01), n = 2042, I2 = 51%; mortality at 5-10 years: 0.81 (95% CI = 0.62, 1.04), n = 515, I2 = 59%; disability at 18-24 months: 0.62 (95% CI = 0.52, 0.75), n = 1440, I2 = 26%; disability at 5-10 years: 0.68 (95% CI = 0.52, 0.90), n = 442, I2 = 3%; mortality or disability at 18-24 months: 0.78 (95% CI = 0.72, 0.86), n = 1914, I2 = 54%; cerebral palsy at 18-24 months: 0.63 (95% CI = 0.50, 0.78), n = 1136, I2 = 39%; and childhood cerebral palsy: 0.63 (95% CI = 0.46, 0.85), n = 449, I2 = 0%. Some outcomes showed significant differences by study-setting; the risk ratio (95% CI) for mortality at 18-24 months was 0.79 (95% CI = 0.66,0.93), n = 1212, I2 = 7% in high-income countries, 0.67 (95% CI = 0.41, 1.09), n = 276, I2 = 0% in upper-middle-income countries, and 1.18 (95% CI = 0.94, 1.47), n = 554, I2 = 75% in lower-middle-income countries. The corresponding pooled risk ratios for 'mortality or disability at 18-24 months' were 0.77 (95% CI = 0.69, 0.86), n = 1089, I2 = 0%; 0.56 (95% CI = 0.41, 0.78), n = 276, I2 = 30%; and 0.92 (95% CI = 0.77, 1.09), n = 549, I2 = 86% respectively. Trials with low risk of bias showed risk ratio of 0.97 (95% CI = 0.80, 1.16, n = 1475, I2 = 62%) for neonatal mortality, whereas trials with higher risk of bias showed 0.71 (95% CI = 0.55, 0.91), n = 959, I2 = 0%. Likewise, risk ratio for mortality at 18-24 months was 0.96 (95% CI = 0.83, 1.13), n = 1336, I2 = 58% among low risk-of-bias trials, but 0.72 (95% CI = 0.56, 0.92), n = 706, I2 = 0%, among higher risk of bias trials. Conclusions: Therapeutic hypothermia for neonatal encephalopathy reduces neurologic disability and cerebral palsy, but its effect on neonatal, infantile and childhood mortality is uncertain. The setting where it is implemented affects the outcomes. Low(er) quality trials overestimated the potential benefit of TH.

Continuous positive airway pressure (CPAP) for acute bronchiolitis in children.

BACKGROUND: Acute bronchiolitis is one of the most frequent causes of emergency department visits and hospitalisation in children up to three years of age. There is no specific treatment for bronchiolitis except for supportive treatment, which includes ensuring adequate hydration and oxygen supplementation. Continuous positive airway pressure (CPAP) aims to widen the lungs' peripheral airways, enabling deflation of overdistended lungs in bronchiolitis. Increased airway pressure also prevents the collapse of poorly supported peripheral small airways during expiration. Observational studies report that CPAP is beneficial for children with acute bronchiolitis. This is an update of a review first published in 2015 and updated in 2019. OBJECTIVES: To assess the efficacy and safety of CPAP compared to no CPAP or sham CPAP in infants and children up to three years of age with acute bronchiolitis. SEARCH METHODS: We conducted searches of CENTRAL (2021, Issue 7), which includes the Cochrane Acute Respiratory Infections Group Specialised Register, MEDLINE (1946 to August 2021), Embase (1974 to August 2021), CINAHL (1981 to August 2021), and LILACS (1982 to August 2021) in August 2021. We also searched the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) for completed and ongoing trials on 26 October 2021. SELECTION CRITERIA: We considered randomised controlled trials (RCTs), quasi-RCTs, cross-over RCTs, and cluster-RCTs evaluating the effect of CPAP in children with acute bronchiolitis. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, extracted data using a structured pro forma, analysed data, and performed meta-analyses. We used the Cochrane risk of bias tool to assess risk of bias in the included studies. We created a summary of the findings table employing GRADEpro GDT software.  MAIN RESULTS: We included three studies with a total of 122 children (62/60 in intervention/control arms) aged up to 12 months investigating nasal CPAP compared with supportive (or 'standard') therapy. We included one new trial (72 children) in the 2019 update that contributed data to the assessment of respiratory rate and the need for mechanical ventilation for this update. We did not identify any new trials for inclusion in the current update. The included studies were single-centre trials conducted in France, the UK, and India. Two studies were parallel-group RCTs, and one study was a cross-over RCT. The evidence provided by the included studies was of low certainty; we made an assessment of high risk of bias for blinding, incomplete outcome data, and selective reporting, and confidence intervals were wide. The effect of CPAP on the need for mechanical ventilation in children with acute bronchiolitis was uncertain due to risk of bias and imprecision around the effect estimate (risk difference -0.01, 95% confidence interval (CI) -0.09 to 0.08; 3 RCTs, 122 children; low certainty evidence). None of the trials measured time to recovery. Limited, low certainty evidence indicated that CPAP decreased respiratory rate (decreased respiratory rate is better) (mean difference (MD) -3.81, 95% CI -5.78 to -1.84; 2 RCTs, 91 children; low certainty evidence). Only one trial measured change in arterial oxygen saturation (increased oxygen saturation is better), and the results were imprecise (MD -1.70%, 95% CI -3.76 to 0.36; 1 RCT, 19 children; low certainty evidence). The effect of CPAP on change in arterial partial carbon dioxide pressure (pCO2) (decrease in pCO2 is better) was imprecise (MD -2.62 mmHg, 95% CI -5.29 to 0.05; 2 RCTs, 50 children; low certainty evidence). Duration of hospital stay was similar in both the CPAP and supportive care groups (MD 0.07 days, 95% CI -0.36 to 0.50; 2 RCTs, 50 children; low certainty evidence). Two studies did not report pneumothorax, but pneumothorax did not occur in one study. No studies reported occurrences of deaths. Several outcomes (change in partial oxygen pressure, hospital admission rate (from the emergency department to hospital), duration of emergency department stay, and need for intensive care unit admission) were not reported in the included studies. AUTHORS' CONCLUSIONS: The use of CPAP did not reduce the need for mechanical ventilation in children with bronchiolitis, although the evidence was of low certainty. Limited, low certainty evidence suggests that breathing improved (a decreased respiratory rate) in children with bronchiolitis who received CPAP; this finding is unchanged from the 2015 review and 2019 update. Due to the limited available evidence, the effect of CPAP in children with acute bronchiolitis is uncertain for our other outcomes. Larger, adequately powered trials are needed to evaluate the effect of CPAP for children with acute bronchiolitis.

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 identified 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 identified. 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 different aspects of the guidelines, with very low quality in the critical domain of methodological rigor. There were no statistically significant differences 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 affecting their credibility, validity, and applicability. Urgent corrective strategies are presented for consideration.

Comparison of microbiota in the upper versus lower respiratory tract in children during health and respiratory disease: protocol for a systematic review.

BACKGROUND: The upper respiratory tract of children is colonized by various microbial species during the healthy state, whereas the lungs are believed to be sterile. In children with respiratory infections, micro-organisms can be recovered from the upper respiratory sites, as well as the lungs. However, the correlation of microbial yield between the two sites is unclear. This systematic review is designed to explore the microbial composition of the respiratory system in healthy children, comparing the organisms identified in the upper airways versus the lungs. We will also compare the prevalence and pattern of upper respiratory micro-organisms in healthy children versus those with various respiratory diseases. We will additionally compare the organisms identified in the upper airway versus the lungs in children with respiratory disease. METHODS: We will search the following electronic databases: Epistemonikos and Cochrane Library for systematic reviews and MEDLINE (through PubMed), EMBASE, Cochrane CENTRAL, LIVIVO, Web of Science, Scopus, and CINAHL databases for primary studies. Reference lists of relevant studies will be examined for links to potential related articles. Two reviewers will independently determine eligibility for inclusion. The methodological quality and risk of bias of the included observational studies will be scored using the Newcastle-Ottawa Scale tool, and JBI Critical Appraisal Checklist for case series. We will present the data with descriptive statistics and provide pooled estimates of outcomes, wherever it is feasible to perform a meta-analysis. Heterogeneity in studies will be explored by using the Higgins and Thompson I2 method. Sensitivity analysis will be done to explore the impact of study quality, and subgroup analysis will be done based on age, health condition, type of respiratory specimen, and method of identifying organisms. We will prepare a summary of findings' table and assess the confidence in the evidence using the GRADE methodology. RESULTS: This is a protocol; hence, there are no results at this stage. DISCUSSION: The proposed systematic review will provide comparisons of the microbiota in the upper respiratory tract versus the lungs, in children, during health as well as respiratory disease. Similarly, the site-specific yield will be compared between healthy children and those with respiratory disease. This will provide clinicians, microbiologists, and respiratory therapists a better understanding of the respiratory system microbiota, suitability (or otherwise) of upper airway specimens in various respiratory diseases, and the potential role of upper airway colonization on specific respiratory diseases. We will disseminate the review through a peer-reviewed journal publication. Data that cannot be included in the published version will be made available on request. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020202115 .