Assembling a global database of child pneumonia studies to inform WHO pneumonia management algorithm: Methodology and applications.

Background: The existing World Health Organization (WHO) pneumonia case management guidelines rely on clinical symptoms and signs for identifying, classifying, and treating pneumonia in children up to 5 years old. We aimed to collate an individual patient-level data set from large, high-quality pre-existing studies on pneumonia in children to identify a set of signs and symptoms with greater validity in the diagnosis, prognosis, and possible treatment of childhood pneumonia for the improvement of current pneumonia case management guidelines. Methods: Using data from a published systematic review and expert knowledge, we identified studies meeting our eligibility criteria and invited investigators to share individual-level patient data. We collected data on demographic information, general medical history, and current illness episode, including history, clinical presentation, chest radiograph findings when available, treatment, and outcome. Data were gathered separately from hospital-based and community-based cases. We performed a narrative synthesis to describe the final data set. Results: Forty-one separate data sets were included in the Pneumonia Research Partnership to Assess WHO Recommendations (PREPARE) database, 26 of which were hospital-based and 15 were community-based. The PREPARE database includes 285 839 children with pneumonia (244 323 in the hospital and 41 516 in the community), with detailed descriptions of clinical presentation, clinical progression, and outcome. Of 9185 pneumonia-related deaths, 6836 (74%) occurred in children <1 year of age and 1317 (14%) in children aged 1-2 years. Of the 285 839 episodes, 280 998 occurred in children 0-59 months old, of which 129 584 (46%) were 2-11 months of age and 152 730 (54%) were males. Conclusions: This data set could identify an improved specific, sensitive set of criteria for diagnosing clinical pneumonia and help identify sick children in need of referral to a higher level of care or a change of therapy. Field studies could be designed based on insights from PREPARE analyses to validate a potential revised pneumonia algorithm. The PREPARE methodology can also act as a model for disease database assembly.

External validation of the RISC, RISC-Malawi, and PERCH clinical prediction rules to identify risk of death in children hospitalized with pneumonia.

BACKGROUND: Existing scores to identify children at risk of hospitalized pneumonia-related mortality lack broad external validation. Our objective was to externally validate three such risk scores. METHODS: We applied the Respiratory Index of Severity in Children (RISC) for HIV-negative children, the RISC-Malawi, and the Pneumonia Etiology Research for Child Health (PERCH) scores to hospitalized children in the Pneumonia REsearch Partnerships to Assess WHO REcommendations (PREPARE) data set. The PREPARE data set includes pooled data from 41 studies on pediatric pneumonia from across the world. We calculated test characteristics and the area under the curve (AUC) for each of these clinical prediction rules. RESULTS: The RISC score for HIV-negative children was applied to 3574 children 0-24 months and demonstrated poor discriminatory ability (AUC = 0.66, 95% confidence interval (CI) = 0.58-0.73) in the identification of children at risk of hospitalized pneumonia-related mortality. The RISC-Malawi score had fair discriminatory value (AUC = 0.75, 95% CI = 0.74-0.77) among 17 864 children 2-59 months. The PERCH score was applied to 732 children 1-59 months and also demonstrated poor discriminatory value (AUC = 0.55, 95% CI = 0.37-0.73). CONCLUSIONS: In a large external application of the RISC, RISC-Malawi, and PERCH scores, a substantial number of children were misclassified for their risk of hospitalized pneumonia-related mortality. Although pneumonia risk scores have performed well among the cohorts in which they were derived, their performance diminished when externally applied. A generalizable risk assessment tool with higher sensitivity and specificity to identify children at risk of hospitalized pneumonia-related mortality may be needed. Such a generalizable risk assessment tool would need context-specific validation prior to implementation in that setting.

A living WHO guideline on drugs to prevent covid-19.

CLINICAL QUESTION: What is the role of drugs in preventing covid-19? WHY DOES THIS MATTER?: There is widespread interest in whether drug interventions can be used for the prevention of covid-19, but there is uncertainty about which drugs, if any, are effective. The first version of this living guideline focuses on the evidence for hydroxychloroquine. Subsequent updates will cover other drugs being investigated for their role in the prevention of covid-19. RECOMMENDATION: The guideline development panel made a strong recommendation against the use of hydroxychloroquine for individuals who do not have covid-19 (high certainty). HOW THIS GUIDELINE WAS CREATED: This living guideline is from the World Health Organization (WHO) and provides up to date covid-19 guidance to inform policy and practice worldwide. Magic Evidence Ecosystem Foundation (MAGIC) provided methodological support. A living systematic review with network analysis informed the recommendations. An international guideline development panel of content experts, clinicians, patients, an ethicist and methodologists produced recommendations following standards for trustworthy guideline development using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. UNDERSTANDING THE NEW RECOMMENDATION: The linked systematic review and network meta-analysis (6 trials and 6059 participants) found that hydroxychloroquine had a small or no effect on mortality and admission to hospital (high certainty evidence). There was a small or no effect on laboratory confirmed SARS-CoV-2 infection (moderate certainty evidence) but probably increased adverse events leading to discontinuation (moderate certainty evidence). The panel judged that almost all people would not consider this drug worthwhile. In addition, the panel decided that contextual factors such as resources, feasibility, acceptability, and equity for countries and healthcare systems were unlikely to alter the recommendation. The panel considers that this drug is no longer a research priority and that resources should rather be oriented to evaluate other more promising drugs to prevent covid-19. UPDATES: This is a living guideline. New recommendations will be published in this article and signposted by update notices to this guideline. READERS NOTE: This is the first version of the living guideline for drugs to prevent covid-19. It complements the WHO living guideline on drugs to treat covid-19. When citing this article, please consider adding the update number and date of access for clarity.

A living WHO guideline on drugs to prevent COVID-19

Clinical question What is the role of drugs in preventing covid-19? Why does this matter?There is widespread interest in whether drug interventions can be used for the prevention of covid-19, but there is uncertainty about which drugs, if any, are effective. The first version of this living guideline focuses on the evidence for hydroxychloroquine. Subsequent updates will cover other drugs being investigated for their role in the prevention of covid-19. The guideline development panel made a strong recommendation against the use of hydroxychloroquine for individuals who do not have covid-19 (high certainty). How this guideline was created This living guideline is from the World Health Organization (WHO) and provides up to date covid-19 guidance to inform policy and practice worldwide. Magic Evidence Ecosystem Foundation (MAGIC) provided methodological support. A living systematic review with network analysis informed the recommendations. An international guideline development panel of content experts, clinicians, patients, an ethicist and methodologists produced recommendations following standards for trustworthy guideline development using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Understanding the new recommendation The linked systematic review and network meta-analysis (6 trials and 6059 participants) found that hydroxychloroquine had a small or no effect on mortality and admission to hospital (high certainty evidence). There was a small or no effect on laboratory confirmed SARS-CoV-2 infection (moderate certainty evidence) but probably increased adverse events leading to discontinuation (moderate certainty evidence). The panel judged that almost all people would not consider this drug worthwhile. In addition, the panel decided that contextual factors such as resources, feasibility, acceptability, and equity for countries and healthcare systems were unlikely to alter the recommendation. The panel considers that this drug is no longer a research priority and that resources should rather be oriented to evaluate other more promising drugs to prevent covid-19. Updates This is a living guideline. New recommendations will be published in this article and signposted by update notices to this guideline.

Kawasaki disease presenting with hoarseness: A multinational study of the REKAMLATINA network.

BACKGROUND: Recently, hoarseness affecting the supraglottic structure has been reported in Kawasaki disease (KD). The objective of this study was to characterize the frequency of hoarseness in acute KD patients in Latin America. METHODS: We used prospective data from the multinational Red de Enfermedad de Kawasaki en America Latina (REKAMLATINA) network. A total of 865 patients from 20 countries were enrolled during the 3 year study period. Data on hoarseness were available in 858 (99.2%) patients. The clinical and laboratory characteristics between hoarse and non-hoarse KD were compared. RESULTS: Hoarseness was documented in 100 (11.6%) patients. Hoarse patients were younger than those with KD without hoarseness (median age 18 vs 26 months; P = 0.002) and presented with lower hemoglobin (10.7 g/dL vs 11.3 g/dL; P = 0.040) and hematocrit levels (32% vs 33%, P = 0.048). CONCLUSIONS: Hoarseness was found to be prevalent as a presenting sign of acute KD in younger children. Anemia may indicate the presence of active inflammation.

A living WHO guideline on drugs for COVID-19

What is the role of drug interventions in the treatment of patients with covid-19? The latest version of this WHO living guidance focuses on remdesivir, following the 15 October 2020 preprint publication of results from the WHO SOLIDARITY trial. It contains a weak or conditional recommendation against the use of remdesivir in hospitalised patients with covid-19 The first version on this living guidance focused on corticosteroids. The strong recommendation for systemic corticosteroids in patients with severe and critical covid-19, and a weak or conditional recommendation against systemic corticosteroids in patients with non-severe covid-19 are unchanged.

Stunting is associated with poor outcomes in childhood pneumonia.

OBJECTIVE: Stunting affects 26.7% of children worldwide, and little is known about its effects on the outcomes of childhood pneumonia. We evaluated the effect of stunting on the outcomes of pneumonia among children enrolled in two large clinical trials. METHODS: We analysed data from two WHO and USAID-sponsored inpatient treatment trials, the Severe Pneumonia Evaluation Antimicrobial Research study (n = 958) and the Amoxicillin Penicillin Pneumonia International Study (n = 1702), which enrolled children aged 2-59 months across 16 sites in LMICs. We assessed the effect of stunting (height-for-age Z score < -2) on treatment outcome and time to resolution of hypoxaemic pneumonia. RESULTS: Among 2542 (96%) children with valid data for height, 28% were stunted and 12.8% failed treatment by 5 days. The failure rate among stunted patients was 16.0% vs. 11.5% among non-stunted patients [unadjusted RR = 1.24 (95% CI 1.08, 1.41); adjusted RR = 1.28 (95% CI 1.10, 1.48)]. An inverse relationship was observed between height and failure rates, even among non-stunted children. Among 845 patients with hypoxaemic pneumonia, stunting was associated with a lower probability of normalisation of respiratory rate [HR = 0.63 (95% CI 0.52, 0.75)] and oxygen saturation [HR = 0.74 (95% CI 0.61, 0.89)]. CONCLUSIONS: Stunting increases the risk of treatment failure and is associated with a longer course of recovery in children with pneumonia. Strategies to decrease stunting may decrease the burden of adverse outcomes in childhood pneumonia in low-resource settings.

Childhood anemia at high altitude: risk factors for poor outcomes in severe pneumonia.

BACKGROUND: Pneumonia is the leading cause of mortality in young children globally, and factors that affect tissue delivery of oxygen may affect outcomes of pneumonia. We studied whether altitude and anemia influence disease severity and outcomes in young children with World Health Organization-defined severe pneumonia. METHODS: We analyzed data from the SPEAR (Severe Pneumonia Evaluation Antimicrobial Research) study, a World Health Organization- and USAID-sponsored multinational randomized controlled trial of antibiotics for severe pneumonia among children aged 2 to 59 months in resource-poor settings. The trial enrolled 958 children in 8 sites at varying elevations, classified as high (≥ 2000 m) or low (<2000 m) altitude. We compared illness severity and assessed the effect of anemia on treatment outcome at high and low altitudes, adjusting for potential confounders and study site. RESULTS: Children at high altitudes had significantly lower oxygen saturation on presentation, more cyanosis, lower systolic blood pressure, and higher hemoglobin. After adjusting for potential confounders, anemia predicted treatment failure in children living at high altitude (relative risk: 4.07; 95% confidence interval: 2.60-6.38) but not at low altitude (relative risk: 1.12; 95% confidence interval: 0.96-1.30). Children at high altitude took longer to reach normoxemia than did children at lower altitudes (5.25 vs 0.75 days; P < .0001). CONCLUSIONS: Children at high altitude present with more severe disease, and children with anemia at high altitude are at greater risk of poor outcome when being treated for severe pneumonia. Given the high global prevalence of anemia among young children, prevention and treatment of anemia should be a priority in children living at high altitude and could improve outcomes of pneumonia.

Vaccine-preventable diseases and their impact on Latin American children.

A joint meeting of the Latin American Society of Pediatric Infectious Diseases, the Dominican Society of Pediatrics and the Dominican Society of Vaccinology was held in the Dominican Republic. This report highlights the most relevant issues that were presented and discussed about vaccine-preventable diseases, their epidemiology and impact in Latin American children, the need to move forward and expand national immunization programs and the economical and political obstacles to introduce 'new' vaccines. These include those against Streptococcus pneumoniae, rotavirus, hepatitis A, varicella, Neisseria meningitidis, Bordetella pertussis, influenza and human papillomavirus, among others.

Hearing impairment in childhood bacterial meningitis is little relieved by dexamethasone or glycerol.

OBJECTIVE: Several studies have evaluated dexamethasone for prevention of hearing loss in childhood bacterial meningitis, but results have varied. We compared dexamethasone and/or glycerol recipients with placebo recipients, and measured hearing at 3 threshold levels. METHODS: Children aged 2 months to 16 years with meningitis were treated with ceftriaxone but were double-blindly randomly assigned to receive adjuvant dexamethasone intravenously, glycerol orally, both agents, or neither agent. We used the Glasgow coma scale to grade the presenting status. The end points were the better ear's ability to detect sounds of >40 dB, >or=60 dB, and >or=80 dB, with these thresholds indicating any, moderate-to-severe, or severe impairment, respectively. All tests were interpreted by an external audiologist. Influence of covariates in the treatment groups was examined by binary logistic regression. RESULTS: Of the 383 children, mostly with meningitis caused by Haemophilus influenzae type b or Streptococcus pneumoniae, 101 received dexamethasone, 95 received dexamethasone and glycerol, 92 received glycerol, and 95 received placebo. Only the presenting condition and young age predicted impairment independently through all threshold levels. Each lowering point in the Glasgow scale increased the risk by 15% to 21% (odds ratio: 1.20, 1.21, and 1.15 [95% confidence interval: 1.06-1.35, 1.07-1.37, and 1.01-1.31]; P = .005, .003, and .039) for any, moderate-to-severe, or severe impairment, respectively. Each increasing month of age decreased the risk by 2% to 6% (P = .0001, .0007, and .041, respectively). Neither dexamethasone nor glycerol prevented hearing loss at these levels regardless of the causative agent or timing of antimicrobial agent. CONCLUSIONS: With bacterial meningitis, the child's presenting status and young age are the most important predictors of hearing impairment. Little relief is obtained from current adjuvant medications.

Influence of admission findings on death and neurological outcome from childhood bacterial meningitis.

A post hoc analysis of 654 children with bacterial meningitis showed that the level of consciousness is the most important predictor of death and/or neurological sequelae, more than is etiology per se. This finding emphasizes the need of including a measurement of the presenting status in all studies examining treatment efficacy.

Chloramphenicol versus ampicillin plus gentamicin for community acquired very severe pneumonia among children aged 2-59 months in low resource settings: multicentre randomised controlled trial (SPEAR study).

OBJECTIVE: To evaluate whether five days' treatment with injectable ampicillin plus gentamicin compared with chloramphenicol reduces treatment failure in children aged 2-59 months with community acquired very severe pneumonia in low resource settings. DESIGN: Open label randomised controlled trial. SETTING: Inpatient wards within tertiary care hospitals in Bangladesh, Ecuador, India, Mexico, Pakistan, Yemen, and Zambia. PARTICIPANTS: Children aged 2-59 months with WHO defined very severe pneumonia. INTERVENTION: Chloramphenicol versus a combination of ampicillin plus gentamicin. MAIN OUTCOME MEASURES: Primary outcome measure was treatment failure at five days. Secondary outcomes were treatment failure defined similarly among all participants evaluated at 48 hours and at 10 and 21 days. RESULTS: More children failed treatment with chloramphenicol at day 5 (16% v 11%; relative risk 1.43, 95% confidence interval 1.03 to 1.97) and also by days 10 and 21. Overall, 112 bacterial isolates were obtained from blood and lung aspirates in 110 children (11.5%), with the most common organisms being Staphylococcus aureus (n=47) and Streptococcus pneumoniae (n=22). In subgroup analysis, bacteraemia with any organism increased the risk of treatment failure at 21 days in the chloramphenicol group (2.09, 1.41 to 3.10) but not in the ampicillin plus gentamicin group (1.12, 0.59 to 2.13). Similarly, isolation of S pneumoniae increased the risk of treatment failure at day 21 (4.06, 2.73 to 6.03) and death (5.80, 2.62 to 12.85) in the chloramphenicol group but not in the ampicillin plus gentamicin group. No difference was found in treatment failure for children with S aureus bacteraemia in the two groups, but the power to detect a difference in this subgroup analysis was low. Independent predictors of treatment failure by multivariate analysis were hypoxaemia (oxygen saturation <90%), receiving chloramphenicol, being female, and poor immunisation status. CONCLUSION: Injectable ampicillin plus gentamicin is superior to injectable chloramphenicol for the treatment of community acquired very severe pneumonia in children aged 2-59 months in low resource settings. TRIAL REGISTRATION: Current Controlled Trials ISRCTN39543942.

Adjuvant glycerol and/or dexamethasone to improve the outcomes of childhood bacterial meningitis: a prospective, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Despite favorable meta-analyses, no study involving third-generation cephalosporins for the treatment of childhood bacterial meningitis has documented a benefit of adjuvant dexamethasone therapy if the outcomes are examined individually. METHODS: We conducted a prospective, randomized, double-blind trial comparing adjuvant dexamethasone or glycerol with placebo in children aged from 2 months through 16 years in Latin America. Ceftriaxone was administered to all children; children were randomized to also receive dexamethasone intravenously, glycerol orally, both agents, or neither agent. Primary end points were death, severe neurological sequelae, or deafness, with the first 2 end points forming a composite end point. A subgroup analysis for Haemophilus influenzae type b meningitis was undertaken. Intention-to-treat analysis was performed using binary logistic regression models. RESULTS: H. influenzae type b, pneumococci, and meningococci were the main agents found among 654 patients; dexamethasone was given to 166, dexamethasone and glycerol were given to 159, glycerol was given to 166, and placebo was given to 163. No adjuvant therapy significantly affected death or deafness. In contrast, glycerol and dexamethasone plus glycerol reduced severe neurological sequelae, compared with placebo; the odds ratios were 0.31 (95% confidence interval [95% CI], 0.13-0.76; P=.010) and 0.39 (95% CI, 0.17-0.93; P=.033), respectively. For neurological sequelae and death, the odds ratios were 0.44 (95% CI, 0.25-0.76; P=.003) and 0.55 (95% CI, 0.32-0.93; P=.027), respectively. Dexamethasone therapy prevented deafness in patients with H. influenzae type b meningitis only if patients were divided grossly into dexamethasone recipients and nonrecipients and if timing between dexamethasone and ceftriaxone administration was not taken into account (odds ratio, 0.27; 95% CI, 0.09-0.77; P=.014). CONCLUSION: Oral glycerol therapy prevents severe neurological sequelae in patients with childhood meningitis. Safety, availability, low cost, and oral administration also add to its usefulness, especially in resource-limited settings.

A quick and cost-effective method for diagnosing disseminated histoplasmosis in children.

The examination of fecal mucus for detecting yeast cells of Histoplasma capsulatum has proved to be a useful tool for diagnosing disseminated histoplasmosis in paediatric patients in a study of 13 cases carried out in Ecuador.