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.

The epidemiology of all-cause and rotavirus acute gastroenteritis and the characteristics of rotavirus circulating strains before and after rotavirus vaccine introduction in Yemen: analysis of hospital-based surveillance data.

BACKGROUND: Rotavirus (RV) vaccine was added to Yemen's childhood vaccination schedule in late 2012. We evaluated the effect of vaccination on the epidemiology of acute gastroenteritis (AGE) and the characteristics of circulating RV strains. METHODS: Surveillance data was obtained at two sentinel hospitals from 5,691 children with acute gastroenteritis (AGE) who were under 5 years of age. Data collected before (2007-2011) and after (2013-2014) RV vaccine introduction were retrospectively analyzed. Treatment outcome, presence of severe dehydration, and the proportion of all-cause AGE due to RV-antigen positive AGE were calculated for each period and compared. Binominal generalized linear models were used to calculate adjusted odds ratios (ORs) and 95 % confidence intervals (CIs). We also compared severe RVAGE and severe dehydration proportions in hospitalized children with severe AGE and characterized RV circulating strains in available specimens from the two periods. RESULTS: Before RV vaccination, mean RVAGE prevalence peaked in October (58.8 %), November (69.5 %), and December (56.4 %). In 2013-2014, the variation became less defined, with only a few RVAGE cases. The average annual prevalence of severe RVAGE needing hospitalization was 42.9 % in 2007-2011, decreased to 21.1 % in 2013, and to 18.5 % in 2014, representing declines of 50.8 % (95 % CI: 36.4-65.0) and 56.9 % (95 % CI: 42.1-70.5). The proportion of children <12 months of age with all-cause AGE decreased significantly after introduction of RV vaccination (58.7 % vs. 62.3 %; p = 0.042), severe dehydration decreased by 50 % (14.7 % vs. 21.7 %; OR = 0.501, p < 0.0001), and RVAGE proportion decreased by 48 % (19.9 % vs. 41.6 %; OR = 0.52, p < 0.0001). The proportion of severe RVAGE in hospitalized patients decreased by 67 % (20.1 % vs. 43.5 %; OR = 0.33, p < 0.0001), and severe dehydration decreased by 58 % (17.2 % vs. 33.1 %; OR = 0.42, p < 0.0001). Non-RV AGE prevalence significantly increased, with ORs of 2.8-3.1 in favor of non-RV AGE in 2013-2014. Analysis of 128 available stool specimens revealed that circulation of the G1 genotype did not change following vaccination (33.3 % vs. 41.3 %; p = 0.366). G2 significantly decreased in 2013-2014 (4.2 % vs. 42.5 % p = 0.0001), and G9 increased (29.2 % vs. 6.3 %; p = 0.001). G1P[8] and G2P[4] remained prevalent, and G9P[8] and G9P[4], which were not detected in the pre-vaccine period appeared in 2013-2014. G and [P] mixed genotypes became more prevalent in 2013-2014. It is not known if this predominance is related to the vaccine introduction or attributable to normal genotype fluctuations. CONCLUSIONS: Rotarix substantially reduced the prevalence of RVAGE, with a 67 % reduction of severe RVAGE hospitalizations, and over 50 % reduction of diarrhea with severe dehydration. Circulation of RV G and [P] mix strains was significantly increased in 2013-2014 and needs continuous monitoring.

In-hospital mortality risk stratification in children aged under 5 years with pneumonia with or without pulse oximetry: A secondary analysis of the Pneumonia REsearch Partnership to Assess WHO REcommendations (PREPARE) dataset.

OBJECTIVES: We determined the pulse oximetry benefit in pediatric pneumonia mortality risk stratification and chest-indrawing pneumonia in-hospital mortality risk factors. METHODS: We report the characteristics and in-hospital pneumonia-related mortality of children aged 2-59 months who were included in the Pneumonia Research Partnership to Assess WHO Recommendations dataset. We developed multivariable logistic regression models of chest-indrawing pneumonia to identify mortality risk factors. RESULTS: Among 285,839 children, 164,244 (57.5%) from hospital-based studies were included. Pneumonia case fatality risk (CFR) without pulse oximetry measurement was higher than with measurement (5.8%, 95% confidence interval [CI] 5.6-5.9% vs 2.1%, 95% CI 1.9-2.4%). One in five children with chest-indrawing pneumonia was hypoxemic (19.7%, 95% CI 19.0-20.4%), and the hypoxemic CFR was 10.3% (95% CI 9.1-11.5%). Other mortality risk factors were younger age (either 2-5 months [adjusted odds ratio (aOR) 9.94, 95% CI 6.67-14.84] or 6-11 months [aOR 2.67, 95% CI 1.71-4.16]), moderate malnutrition (aOR 2.41, 95% CI 1.87-3.09), and female sex (aOR 1.82, 95% CI 1.43-2.32). CONCLUSION: Children with a pulse oximetry measurement had a lower CFR. Many children hospitalized with chest-indrawing pneumonia were hypoxemic and one in 10 died. Young age and moderate malnutrition were risk factors for in-hospital chest-indrawing pneumonia-related mortality. Pulse oximetry should be integrated in pneumonia hospital care for children under 5 years.

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.

Derivation and validation of a novel risk assessment tool to identify children aged 2-59 months at risk of hospitalised pneumonia-related mortality in 20 countries.

INTRODUCTION: Existing risk assessment tools to identify children at risk of hospitalised pneumonia-related mortality have shown suboptimal discriminatory value during external validation. Our objective was to derive and validate a novel risk assessment tool to identify children aged 2-59 months at risk of hospitalised pneumonia-related mortality across various settings. METHODS: We used primary, baseline, patient-level data from 11 studies, including children evaluated for pneumonia in 20 low-income and middle-income countries. Patients with complete data were included in a logistic regression model to assess the association of candidate variables with the outcome hospitalised pneumonia-related mortality. Adjusted log coefficients were calculated for each candidate variable and assigned weighted points to derive the Pneumonia Research Partnership to Assess WHO Recommendations (PREPARE) risk assessment tool. We used bootstrapped selection with 200 repetitions to internally validate the PREPARE risk assessment tool. RESULTS: A total of 27 388 children were included in the analysis (mean age 14.0 months, pneumonia-related case fatality ratio 3.1%). The PREPARE risk assessment tool included patient age, sex, weight-for-age z-score, body temperature, respiratory rate, unconsciousness or decreased level of consciousness, convulsions, cyanosis and hypoxaemia at baseline. The PREPARE risk assessment tool had good discriminatory value when internally validated (area under the curve 0.83, 95% CI 0.81 to 0.84). CONCLUSIONS: The PREPARE risk assessment tool had good discriminatory ability for identifying children at risk of hospitalised pneumonia-related mortality in a large, geographically diverse dataset. After external validation, this tool may be implemented in various settings to identify children at risk of hospitalised pneumonia-related mortality.

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.

Respiratory syncytial virus and human metapneumovirus in children with acute respiratory infections in Yemen.

A survey of 604 Yemeni children younger than 2 years with acute respiratory infections identified respiratory syncytial virus (RSV) in 244 (40%), human metapneumovirus (HMPV) in 41 (7%) and RSV/HMPV coinfection in 25 (4%) children. RSV infections occurred in younger children and were associated with more severe hypoxia than observed with HMPV. Both viruses are important causes of severe acute respiratory infection in Yemen.

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.

Nutritional rickets and vitamin D deficiency--association with the outcomes of childhood very severe pneumonia: a prospective cohort study.

BACKGROUND: The association of rickets and vitamin D deficiency (VDD) with pneumonia is well documented, but not with its outcomes. OBJECTIVES: To investigate whether rickets and VDD predict the outcomes in very severe pneumonia (VSP). DESIGN: A prospective cohort study conducted at Al-Sabeen hospital in Sana'a, Yemen. A total of 152 children aged 2-59 months with WHO-defined VSP were enrolled, managed, and followed for up to 30 days. Treatment outcome was either successful or failure (antibiotic modification for clinical worsening, death, relapse after 10-day antibiotics, or development of complications). Serum vitamin D (25OHD) was measured in 79 cases. A concentration of

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.

Bacterial profile and clinical outcome of childhood meningitis in rural Yemen: a 2-year hospital-based study.

BACKGROUND: Childhood acute bacterial meningitis (ABM) is an important cause of death and long-term neurological disability in Yemen, the only low income-high mortality country in the Arabian Peninsula. The objective of this study was to document the microbial characteristics, the antibacterial sensitivity pattern, and the outcome for children hospitalized with ABM, prior to the introduction of Haemophilus influenzae type b (Hib) vaccine in Yemen. PATIENTS AND METHODS: The study was retrospective, conducted at a rural district hospital, serving the rural population of the northern parts of Yemen. All patients aged 1 month-15 years admitted between May 1999 and June 2001, with clinical evidence of meningitis and cerebrospinal fluid (CSF) cultured, were included in the study. Clinical information from case notes, including CSF result and the outcome on discharge, were obtained. Analysis of extracted data was performed using Epi Info software. RESULTS: During the 2-year study period, 160 study patients met the inclusion criteria, and 7 (4.4%) were negative for bacterial growth. In the 153 positive cultures there were 46 (30.1%) Streptococcus pneumoniae (SP), 23 (15%) H. influenzae (HI), 81 (52.9) Neisseria meningitidis (NM), 2 (1.3%) Staphylococcus aureus (S. aureus), and 1 (0.7%) Escherichia coli. Sixteen study patients died (overall case fatality rate (CFR) 10%), 7 aged under 12 months, 6 aged 12-60 months, and 3 more than 60 months. Ten deaths were due to SP meningitis, 2 HI meningitis, 3 NM meningitis, and 1 had S. aureus. Of the 144 survivors, 28 (19.4%) developed permanent neurological complications, 17 aged less than 12 months, 6 aged 12-60 months, and 5 more than 60 months. SP meningitis accounted for 57.1% (16/28), and 6 (21.4%) had HI meningitis. Among the 89 aged 1-60 months, 13 died (CFR 14.6%), and 23 (30.3%) of the 76 survivors developed permanent complications. Of those tested 20% and 35% of the 20 HI tested isolates and 9.5% and 14.3% of the 42 SP isolates, were resistant to ampicillin and penicillin G, respectively, and the majority of the 81 NM isolates were sensitive to both. The 3 pathogens were largely resistant to gentamicin, and almost all were susceptible to chloramphenicol and cefotaxime. CONCLUSION: In contrast to the studies from the low-mortality countries of the region, our study showed that the predominant pathogens of childhood ABM were SP and NM. SP meningitis was associated with increased mortality and permanent disability.