Factors predicting mortality in hospitalised HIV-negative children with lower-chest-wall indrawing pneumonia and implications for management.

INTRODUCTION: In 2012, the World Health Organization revised treatment guidelines for childhood pneumonia with lower chest wall indrawing (LCWI) but no 'danger signs', to recommend home-based treatment. We analysed data from children hospitalized with LCWI pneumonia in the Pneumonia Etiology Research for Child Health (PERCH) study to identify sub-groups with high odds of mortality, who might continue to benefit from hospital management but may not be admitted by staff implementing the 2012 guidelines. We compare the proportion of deaths identified using the criteria in the 2012 guidelines, and the proportion of deaths identified using an alternative set of criteria from our model. METHODS: PERCH enrolled a cohort of 2189 HIV-negative children aged 2-59 months who were admitted to hospital with LCWI pneumonia (without obvious cyanosis, inability to feed, vomiting, convulsions, lethargy or head nodding) between 2011-2014 in Kenya, Zambia, South Africa, Mali, The Gambia, Bangladesh, and Thailand. We analysed risk factors for mortality among these cases using predictive logistic regression. Malnutrition was defined as mid-upper-arm circumference <125mm or weight-for-age z-score <-2. RESULTS: Among 2189 cases, 76 (3·6%) died. Mortality was associated with oxygen saturation <92% (aOR 3·33, 1·99-5·99), HIV negative but exposed status (4·59, 1·81-11·7), moderate or severe malnutrition (6·85, 3·22-14·6) and younger age (infants compared to children 12-59 months old, OR 2·03, 95%CI 1·05-3·93). At least one of three risk factors: hypoxaemia, HIV exposure, or malnutrition identified 807 children in this population, 40% of LCWI pneumonia cases and identified 86% of the children who died in hospital (65/76). Risk factors identified using the 2012 WHO treatment guidelines identified 66% of the children who died in hospital (n = 50/76). CONCLUSIONS: Although it focuses on treatment failure in hospital, this study supports the proposal for better risk stratification of children with LCWI pneumonia. Those who have hypoxaemia, any malnutrition or those who were born to HIV positive mothers, experience poorer outcomes than other children with LCWI pneumonia. Consistent identification of these risk factors should be prioritised and children with at least one of these risk factors should not be managed in the community.

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.

Study protocol: A randomised trial of the effectiveness of the Common Elements Treatment Approach (CETA) for improving HIV treatment outcomes among women experiencing intimate partner violence in South Africa.

INTRODUCTION: Intimate partner violence (IPV) is a barrier to consistent HIV treatment in South Africa. Previous trials have established that the Common Elements Treatment Approach (CETA), a cognitive-behavioural-based intervention, is effective in reducing mental and behavioural health problems but has not been trialled for effectiveness in improving HIV outcomes. This paper describes the protocol for a randomised trial that is testing the effectiveness of CETA in improving HIV treatment outcomes among women experiencing IPV in South Africa. METHODS AND ANALYSIS: We are conducting a randomised trial among HIV-infected women on antiretroviral therapy, who have experienced sexual and/or physical IPV, to test the effect of CETA on increasing retention and viral suppression and reducing IPV. Women living with HIV who have an unsuppressed viral load or are at high risk for poor adherence and report experiencing recent IPV, defined as at least once within in the last 12 months, will be recruited from HIV clinics and randomised 1:1 to receive CETA or an active attention control (text message reminders). All participants will be followed for 24 months. Follow-up HIV data will be collected passively using routinely collected medical records. HIV outcomes will be assessed at 12 and 24 months post-baseline. Questionnaires on violence, substance use and mental health will be administered at baseline, post-CETA completion and at 12 months post-baseline. Our primary outcome is retention and viral suppression (<50 copies/mL) by 12 months post-baseline. We will include 400 women which will give us 80% power to detect an absolute 21% difference between arms. Our primary analysis will be an intention-to-treat comparison of intervention and control by risk differences with 95% CIs. ETHICS AND DISSEMINATION: Ethics approval provided by University of the Witwatersrand Human Research Ethics Committee (Medical), Boston University Institutional Review Board and Johns Hopkins School Institutional Review Board. Results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04242992.

Microbiologic and virulence characteristics of Moraxella catarrhalis isolates from Zambian children presenting with acute pneumonia.

BACKGROUND: Moraxella catarrhalis is one of the bacterial pathogens associated with childhood pneumonia, but its clinical importance is not clearly defined. OBJECTIVE: This study aimed to investigate the microbiologic and virulence characteristics of M. catarrhalis isolates obtained from children with pneumonia in Lusaka, Zambia. METHODS: This retrospective, cross-sectional study analyzed 91 M. catarrhalis isolates from induced sputum samples of children less than 5 years of age with pneumonia enrolled in the Pneumonia Etiology Research for Child Health study in Lusaka, Zambia between 2011 and 2014. Bacteria identification and virulence genes detection were performed by PCR and DNA sequencing, while antimicrobial susceptibility testing was determined by the Kirby-Bauer method. RESULTS: All the M. catarrhalis isolates were obtained from good-quality sputum samples and were the predominant bacteria. These isolates harbored virulence genes copB (100%), ompE (69.2%), ompCD (71.4%), uspA1 (92.3%), and uspA2 (69.2%) and were all ß-lactamase producers. They showed resistance to ampicillin (100%), amoxicillin (100%), trimethoprim-sulfamethoxazole (92.3%), ciprofloxacin (46.2%), chloramphenicol (45.1%), erythromycin (36.3%), tetracycline (25.3%), cefuroxime (11.0%), and amoxicillin-clavulanate (2.2%), with 71.4% displaying multi-drug resistant phenotype but all susceptible to imipenem (100%). CONCLUSION: This study showed that M. catarrhalis isolates were the predominant or only bacterial isolates from the sputum samples analyzed. The findings provide supportive evidence for the pathogenic potential role of this bacterium in pediatric pneumonia. High multidrug resistance was also observed amongst the isolates, which can result in affected patients not responding to standard treatment, leading to prolonged illness, increased healthcare costs, and risk of death.

Digitally recorded and remotely classified lung auscultation compared with conventional stethoscope classifications among children aged 1-59 months enrolled in the Pneumonia Etiology Research for Child Health (PERCH) case-control study.

BACKGROUND: Diagnosis of pneumonia remains challenging. Digitally recorded and remote human classified lung sounds may offer benefits beyond conventional auscultation, but it is unclear whether classifications differ between the two approaches. We evaluated concordance between digital and conventional auscultation. METHODS: We collected digitally recorded lung sounds, conventional auscultation classifications and clinical measures and samples from children with pneumonia (cases) in low-income and middle-income countries. Physicians remotely classified recordings as crackles, wheeze or uninterpretable. Conventional and digital auscultation concordance was evaluated among 383 pneumonia cases with concurrently (within 2 hours) collected conventional and digital auscultation classifications using prevalence-adjusted bias-adjusted kappa (PABAK). Using an expanded set of 737 cases that also incorporated the non-concurrently collected assessments, we evaluated whether associations between auscultation classifications and clinical or aetiological findings differed between conventional or digital auscultation using χ2 tests and logistic regression adjusted for age, sex and site. RESULTS: Conventional and digital auscultation concordance was moderate for classifying crackles and/or wheeze versus neither crackles nor wheeze (PABAK=0.50), and fair for crackles-only versus not crackles-only (PABAK=0.30) and any wheeze versus no wheeze (PABAK=0.27). Crackles were more common on conventional auscultation, whereas wheeze was more frequent on digital auscultation. Compared with neither crackles nor wheeze, crackles-only on both conventional and digital auscultation was associated with abnormal chest radiographs (adjusted OR (aOR)=1.53, 95% CI 0.99 to 2.36; aOR=2.09, 95% CI 1.19 to 3.68, respectively); any wheeze was inversely associated with C-reactive protein >40 mg/L using conventional auscultation (aOR=0.50, 95% CI 0.27 to 0.92) and with very severe pneumonia using digital auscultation (aOR=0.67, 95% CI 0.46 to 0.97). Crackles-only on digital auscultation was associated with mortality compared with any wheeze (aOR=2.70, 95% CI 1.12 to 6.25). CONCLUSIONS: Conventional auscultation and remotely-classified digital auscultation displayed moderate concordance for presence/absence of wheeze and crackles among cases. Conventional and digital auscultation may provide different classification patterns, but wheeze was associated with decreased clinical severity on both.

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.

Infant deaths from respiratory syncytial virus in Lusaka, Zambia from the ZPRIME study: a 3-year, systematic, post-mortem surveillance project.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections and a key driver of childhood mortality. Previous RSV burden of disease estimates used hospital-based surveillance data and modelled, rather than directly measured, community deaths. Given this uncertainty, we conducted a 3-year post-mortem prevalence study among young infants at a busy morgue in Lusaka, Zambia-the Zambia Pertussis RSV Infant Mortality Estimation (ZPRIME) study. METHODS: Infants were eligible for inclusion if they were aged between 4 days and less than 6 months and were enrolled within 48 h of death. Enrolment occurred mainly at the University Teaching Hospital of the University of Zambia Medical School (Lusaka, Zambia), the largest teaching hospital in Zambia. We extracted demographic and clinical data from medical charts and official death certificates, and we conducted verbal autopsies with the guardian or next of kin. RSV was identified using reverse transcriptase quantitative PCR and stratified by age, time of year, and setting (community vs facility deaths). By combining the PCR prevalence data with syndromic presentation, we estimated the proportion of all infant deaths that were due to RSV. FINDINGS: The ZPRIME study ran from Aug 31, 2017, to Aug 31, 2020, except for from April 1 to May 6, 2020, during which data were not collected due to restrictions on human research at this time (linked to COVID-19). We enrolled 2286 deceased infants, representing 79% of total infant deaths in Lusaka. RSV was detected in 162 (7%) of 2286 deceased infants. RSV was detected in 102 (9%) of 1176 community deaths, compared with 10 (4%) of 236 early facility deaths (<48 h from admission) and 36 (5%) of 737 late facility deaths (≥48 h from admission). RSV deaths were concentrated in infants younger than 3 months (116 [72%] of 162 infants), and were clustered in the first half of each year and in the poorest and most densely populated Lusaka townships. RSV caused at least 2·8% (95% CI 1·0-4·6) of all infant deaths and 4·7% (1·3-8·1) of community deaths. INTERPRETATION: RSV was a major seasonal cause of overall infant mortality, particularly among infants younger than 3 months of age. Because most RSV deaths occurred in the community and would have been missed through hospital-based surveillance, the global burden of fatal RSV has probably been underestimated. FUNDING: Bill & Melinda Gates Foundation.

Adherence to and enforcement of non-pharmaceutical interventions (NPIs) for COVID-19 prevention in Nigeria, Rwanda, and Zambia: A mixed-methods analysis.

INTRODUCTION: In the early parts of the COVID-19 pandemic, non-pharmaceutical interventions (NPIs) were implemented worldwide, including in sub-Saharan Africa, to prevent and control SARS-CoV-2 transmission. This mixed-methods study examines adherence to and enforcement of NPIs implemented to curb COVID-19 in Nigeria, Rwanda, and Zambia, leading up to the 10,000th case of laboratory-confirmed COVID-19 in each country. Additionally, we aim to evaluate the relationship between levels and changes of NPIs over time and changes in COVID-19 cases and deaths. METHODS: This mixed-methods analysis utilized semi-structured interviews and a quantitative dataset constructed using multiple open data sources, including the Oxford COVID-19 Government Response Tracker. To understand potential barriers and facilitators in implementing and enforcing NPIs qualitative data were collected from those involved in the COVID-19 response and analyzed using NVivo. Quantitative results were analyzed using descriptive statistics, plots, ANOVA, and post hoc Tukey. RESULTS: Individual indicator scores varied with the COVID-19 response in all three countries. Nigeria had sustained levels of strict measures for containment and closure NPIs, while in Rwanda there was substantial variation in NPI score as it transitioned through the different case windows for the same measures. Zambia implemented moderate stringency throughout the pandemic using gathering restrictions and business/school closure measures but maintained low levels of strictness for other containment and closure measures. Rwanda had far more consistent and stringent measures compared to Nigeria and Zambia. Rwanda's success in implementing COVID-related measures was partly due to strong enforcement and having a population that generally follow the recommendations of their government. CONCLUSION: Various forces either facilitated or hindered adherence and compliance to COVID-19 control measures. The lessons learned and recommendations gleaned through interviews with experts involved in the COVID-19 pandemic and quantitative analysis of NPI implementation can be applied to future outbreaks, epidemics, and pandemics. Recommendations include engaging communities, using a risk-based approach to implement containment and closure NPIs, and providing social and economic support to citizens during periods of lockdowns and other measures that interrupt the ability to make a living.

What is the prevalence of COVID-19 detection by PCR among deceased individuals in Lusaka, Zambia? A postmortem surveillance study.

OBJECTIVES: To determine the prevalence of COVID-19 postmortem setting in Lusaka, Zambia. DESIGN: A systematic, postmortem prevalence study. SETTING: A busy, inner-city morgue in Lusaka. PARTICIPANTS: We sampled a random subset of all decedents who transited the University Teaching Hospital morgue. We sampled the posterior nasopharynx of decedents using quantitative PCR. Prevalence was weighted to account for age-specific enrolment strategies. INTERVENTIONS: Not applicable-this was an observational study. PRIMARY OUTCOMES: Prevalence of COVID-19 detections by PCR. Results were stratified by setting (facility vs community deaths), age, demographics and geography and time. SECONDARY OUTCOMES: Shifts in viral variants; causal inferences based on cycle threshold values and other features; antemortem testing rates. RESULTS: From 1118 decedents enrolled between January and June 2021, COVID-19 was detected among 32.0% (358/1116). Roughly four COVID-19+ community deaths occurred for every facility death. Antemortem testing occurred for 52.6% (302/574) of facility deaths but only 1.8% (10/544) of community deaths and overall, only ~10% of COVID-19+ deaths were identified in life. During peak transmission periods, COVID-19 was detected in ~90% of all deaths. We observed three waves of transmission that peaked in July 2020, January 2021 and ~June 2021: the AE.1 lineage and the Beta and Delta variants, respectively. PCR signals were strongest among those whose deaths were deemed 'probably due to COVID-19', and weakest among children, with an age-dependent increase in PCR signal intensity. CONCLUSIONS: COVID-19 was common among deceased individuals in Lusaka. Antemortem testing was rarely done, and almost never for community deaths. Suspicion that COVID-19 was the cause of deaths was highest for those with a respiratory syndrome and lowest for individuals <19 years.

Persistent Immune Activation in Human Immunodeficiency Virus-Infected Pregnant Women Starting Combination Antiretroviral Therapy After Conception.

This study evaluated the impact of human immunodeficiency virus (HIV) and combination antiretroviral therapy (cART) on immune activation during pregnancy in a Zambian cohort of HIV-exposed but uninfected children followed up from birth. Activated CD8+ T cells (CD38+ and HLA-DR+) were compared among HIV-uninfected (n = 95), cART experienced HIV-infected (n = 111), and cART-naive HIV-infected (n = 21) pregnant women. Immune activation was highest among HIV-infected/cART-naive women but decreased during pregnancy. Immune activation HIV-infected women who started cART during pregnancy was reduced but not to levels similar to those in HIV-uninfected women. The effects of elevated maternal immune activation in pregnancy on subsequent infant health and immunity remain to be determined.

Histopathological Evaluation of Deceased Persons in Lusaka, Zambia With or Without Coronavirus Disease 2019 (COVID-19) Infection: Results Obtained From Minimally Invasive Tissue Sampling.

BACKGROUND: Although much has been learned about the pathophysiology of coronavirus disease 2019 (COVID-19) infections, pathology data from patients who have died of COVID-19 in low- and middle-income country settings remain sparse. We integrated minimally invasive tissue sampling (MITS) into an ongoing postmortem surveillance study of COVID-19 in deceased individuals of all ages in Lusaka, Zambia. METHODS: We enrolled deceased subjects from the University Teaching Hospital Morgue in Lusaka, Zambia within 48 hours of death. We collected clinical and demographic information, a nasopharyngeal swab, and core tissue biopsies from the lung, liver, and kidneys for pathologic analysis. Individuals were considered eligible for MITS if they had a respiratory syndrome prior to death or a COVID-19+ polymerase chain reaction (PCR) nasopharyngeal swab specimen. Samples were retested using quantitative reverse transcriptase PCR. RESULTS: From June to September 2020 we performed MITS on 29 deceased individuals. PCR results were available for 28/29 (96.5%) cases. Three had a COVID-19+ diagnosis antemortem, and 5 more were identified postmortem using the recommended cycle threshold cut-point <40. When expanding the PCR threshold to 40 ≤ cycle threshold (Ct) ≤ 45, we identified 1 additional case. Most cases were male and occurred in the community The median age at death was 47 years (range 40-64). Human immunodeficiency virus (HIV)/AIDS, tuberculosis, and diabetes were more common among the COVID-19+ cases. Diffuse alveolar damage and interstitial pneumonitis were common among COVID-19+ cases; nonspecific findings of hepatic steatosis and acute kidney injury were also prevalent in the COVID-19+ group. Vascular thrombi were rarely detected. CONCLUSIONS: Lung abnormalities typical of viral pneumonias were common among deceased COVID-19+ individuals, as were nonspecific findings in the liver and kidneys. Pulmonary vascular thrombi were rarely detected, which could be a limitation of the MITS technique. Nonetheless, MITS offers a valuable alternative to open autopsy for understanding pathological changes due to COVID-19.

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.

Epidemiology and Seasonality of Endemic Human Coronaviruses in South African and Zambian Children: A Case-Control Pneumonia Study.

Endemic human coronaviruses (HCoV) are capable of causing a range of diseases from the common cold to pneumonia. We evaluated the epidemiology and seasonality of endemic HCoVs in children hospitalized with clinical pneumonia and among community controls living in countries with a high HIV burden, namely South Africa and Zambia, between August 2011 to October 2013. Nasopharyngeal/oropharyngeal swabs were collected from all cases and controls and tested for endemic HCoV species and 12 other respiratory viruses using a multiplex real-time PCR assay. We found that the likelihood of detecting endemic HCoV species was higher among asymptomatic controls than cases (11% vs. 7.2%; 95% CI: 1.2-2.0). This was however only observed among children > 6 months and was mainly driven by the Betacoronavirus endemic species (HCoV-OC43 and -HKU1). Endemic HCoV species were detected through the year; however, in Zambia, the endemic Betacoronavirus species tended to peak during the winter months (May-August). There was no association between HIV status and endemic HCoV detection.

Introduction to the Site-specific Etiologic Results From the Pneumonia Etiology Research for Child Health (PERCH) Study.

The Pneumonia Etiology Research for Child Health (PERCH) study evaluated the etiology of severe and very severe pneumonia in children hospitalized in 7 African and Asian countries. Here, we summarize the highlights of in-depth site-specific etiology analyses published separately in this issue, including how etiology varies by age, mortality status, malnutrition, severity, HIV status, and more. These site-specific results impart important lessons that can inform disease control policy implications.

The Etiology of Pneumonia in Zambian Children: Findings From the Pneumonia Etiology Research for Child Health (PERCH) Study.

BACKGROUND: Childhood pneumonia in developing countries is the foremost cause of morbidity and death. Fresh information on etiology is needed, considering the changing epidemiology of pneumonia in the setting of greater availability of effective vaccines, changing antibiotic use and improved access to care. We report here the Zambia site results of the Pneumonia Etiology Research for Child Health study on the etiology of pneumonia among HIV-uninfected children in Lusaka, Zambia. METHODS: We conducted a case-control study of HIV-uninfected children age 1-59 months admitted with World Health Organization-defined severe or very severe pneumonia to a large tertiary care hospital in Lusaka. History, physical examination, chest radiographs (CXRs), blood cultures and nasopharyngeal/oropharyngeal swabs were obtained and tested by polymerase chain reaction and routine microbiology for the presence of 30 bacteria and viruses. From age and seasonally matched controls, we tested blood and nasopharyngeal/oropharyngeal samples. We used the Pneumonia Etiology Research for Child Health integrated analysis to determine the individual and population etiologic fraction for individual pathogens as the cause of pneumonia. RESULTS: Among the 514 HIV-uninfected case children, 208 (40.5%) had abnormal CXRs (61 of 514 children were missing CXR), 8 (3.8%) of which had positive blood cultures. The overall mortality was 16.0% (82 deaths). The etiologic fraction was highest for respiratory syncytial virus [26.1%, 95% credible interval (CrI): 17.0-37.7], Mycobacterium tuberculosis (12.8%, 95% CrI: 4.3-25.3) and human metapneumovirus (12.8%, CrI: 6.1-21.8). CONCLUSIONS: Childhood pneumonia in Zambia among HIV-uninfected children is most frequently caused by respiratory syncytial virus, M. tuberculosis and human metapneumovirus, and the mortality remains high.

The Etiology of Pneumonia in HIV-infected Zambian Children: Findings From the Pneumonia Etiology Research for Child Health (PERCH) Study.

BACKGROUND: Despite recent declines in new pediatric HIV infections and childhood HIV-related deaths, pneumonia remains the leading cause of death in HIV-infected children under 5. We describe the patient population, etiology and outcomes of childhood pneumonia in Zambian HIV-infected children. METHODS: As one of the 9 sites for the Pneumonia Etiology Research for Child Health study, we enrolled children 1-59 months of age presenting to University Teaching Hospital in Lusaka, Zambia, with World Health Organization-defined severe and very severe pneumonia. Controls frequency-matched on age group and HIV infection status were enrolled from the Lusaka Pediatric HIV Clinics as well as from the surrounding communities. Clinical assessments, chest radiographs (CXR; cases) and microbiologic samples (nasopharyngeal/oropharyngeal swabs, blood, urine, induced sputum) were obtained under highly standardized procedures. Etiology was estimated using Bayesian methods and accounted for imperfect sensitivity and specificity of measurements. RESULTS: Of the 617 cases and 686 controls enrolled in Zambia over a 24-month period, 103 cases (16.7%) and 85 controls (12.4%) were HIV infected and included in this analysis. Among the HIV-infected cases, 75% were <1 year of age, 35% received prophylactic trimethoprim-sulfamethoxazole, 13.6% received antiretroviral therapy and 36.9% of caregivers reported knowing their children's HIV status at time of enrollment. A total of 35% of cases had very severe pneumonia and 56.3% had infiltrates on CXR. Bacterial pathogens [50.6%, credible interval (CrI): 32.8-67.2], Pneumocystis jirovecii (24.9%, CrI: 15.5-36.2) and Mycobacterium tuberculosis (4.5%, CrI: 1.7-12.1) accounted for over 75% of the etiologic fraction among CXR-positive cases. Streptococcus pneumoniae (19.8%, CrI: 8.6-36.2) was the most common bacterial pathogen, followed by Staphylococcus aureus (12.7%, CrI: 0.0-25.9). Outcomes were poor, with 41 cases (39.8%) dying in hospital. CONCLUSIONS: HIV-infected children in Zambia with severe and very severe pneumonia have poor outcomes, with continued limited access to care, and the predominant etiologies are bacterial pathogens, P. jirovecii and M. tuberculosis.

Epidemiology of the Rhinovirus (RV) in African and Southeast Asian Children: A Case-Control Pneumonia Etiology Study.

Rhinovirus (RV) is commonly detected in asymptomatic children; hence, its pathogenicity during childhood pneumonia remains controversial. We evaluated RV epidemiology in HIV-uninfected children hospitalized with clinical pneumonia and among community controls. PERCH was a case-control study that enrolled children (1-59 months) hospitalized with severe and very severe pneumonia per World Health Organization clinical criteria and age-frequency-matched community controls in seven countries. Nasopharyngeal/oropharyngeal swabs were collected for all participants, combined, and tested for RV and 18 other respiratory viruses using the Fast Track multiplex real-time PCR assay. RV detection was more common among cases (24%) than controls (21%) (aOR = 1.5, 95%CI:1.3-1.6). This association was driven by the children aged 12-59 months, where 28% of cases vs. 18% of controls were RV-positive (aOR = 2.1, 95%CI:1.8-2.5). Wheezing was 1.8-fold (aOR 95%CI:1.4-2.2) more prevalent among pneumonia cases who were RV-positive vs. RV-negative. Of the RV-positive cases, 13% had a higher probability (>75%) that RV was the cause of their pneumonia based on the PERCH integrated etiology analysis; 99% of these cases occurred in children over 12 months in Bangladesh. RV was commonly identified in both cases and controls and was significantly associated with severe pneumonia status among children over 12 months of age, particularly those in Bangladesh. RV-positive pneumonia was associated with wheezing.

Global burden of acute lower respiratory infection associated with human parainfluenza virus in children younger than 5 years for 2018: a systematic review and meta-analysis.

BACKGROUND: Human parainfluenza virus (hPIV) is a common virus in childhood acute lower respiratory infections (ALRI). However, no estimates have been made to quantify the global burden of hPIV in childhood ALRI. We aimed to estimate the global and regional hPIV-associated and hPIV-attributable ALRI incidence, hospital admissions, and mortality for children younger than 5 years and stratified by 0-5 months, 6-11 months, and 12-59 months of age. METHODS: We did a systematic review of hPIV-associated ALRI burden studies published between Jan 1, 1995, and Dec 31, 2020, found in MEDLINE, Embase, Global Health, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Global Health Library, three Chinese databases, and Google search, and also identified a further 41 high-quality unpublished studies through an international research network. We included studies reporting community incidence of ALRI with laboratory-confirmed hPIV; hospital admission rates of ALRI or ALRI with hypoxaemia in children with laboratory-confirmed hPIV; proportions of patients with ALRI admitted to hospital with laboratory-confirmed hPIV; or in-hospital case-fatality ratios (hCFRs) of ALRI with laboratory-confirmed hPIV. We used a modified Newcastle-Ottawa Scale to assess risk of bias. We analysed incidence, hospital admission rates, and hCFRs of hPIV-associated ALRI using a generalised linear mixed model. Adjustment was made to account for the non-detection of hPIV-4. We estimated hPIV-associated ALRI cases, hospital admissions, and in-hospital deaths using adjusted incidence, hospital admission rates, and hCFRs. We estimated the overall hPIV-associated ALRI mortality (both in-hospital and out-hospital mortality) on the basis of the number of in-hospital deaths and care-seeking for child pneumonia. We estimated hPIV-attributable ALRI burden by accounting for attributable fractions for hPIV in laboratory-confirmed hPIV cases and deaths. Sensitivity analyses were done to validate the estimates of overall hPIV-associated ALRI mortality and hPIV-attributable ALRI mortality. The systematic review protocol was registered on PROSPERO (CRD42019148570). FINDINGS: 203 studies were identified, including 162 hPIV-associated ALRI burden studies and a further 41 high-quality unpublished studies. Globally in 2018, an estimated 18·8 million (uncertainty range 12·8-28·9) ALRI cases, 725 000 (433 000-1 260 000) ALRI hospital admissions, and 34 400 (16 400-73 800) ALRI deaths were attributable to hPIVs among children younger than 5 years. The age-stratified and region-stratified analyses suggested that about 61% (35% for infants aged 0-5 months and 26% for 6-11 months) of the hospital admissions and 66% (42% for infants aged 0-5 months and 24% for 6-11 months) of the in-hospital deaths were in infants, and 70% of the in-hospital deaths were in low-income and lower-middle-income countries. Between 73% and 100% (varying by outcome) of the data had a low risk in study design; the proportion was 46-65% for the adjustment for health-care use, 59-77% for patient groups excluded, 54-93% for case definition, 42-93% for sampling strategy, and 67-77% for test methods. Heterogeneity in estimates was found between studies for each outcome. INTERPRETATION: We report the first global burden estimates of hPIV-associated and hPIV-attributable ALRI in young children. Globally, approximately 13% of ALRI cases, 4-14% of ALRI hospital admissions, and 4% of childhood ALRI mortality were attributable to hPIV. These numbers indicate a potentially notable burden of hPIV in ALRI morbidity and mortality in young children. These estimates should encourage and inform investment to accelerate the development of targeted interventions. FUNDING: Bill & Melinda Gates Foundation.

Asymptomatic Bordetella pertussis infections in a longitudinal cohort of young African infants and their mothers.

Recent pertussis resurgence in numerous countries may be driven by asymptomatic infections. Most pertussis surveillance studies are cross-sectional and cannot distinguish asymptomatic from pre-symptomatic infections. Longitudinal surveillance could overcome this barrier, providing more information about the true burden of pertussis at the population level. Here we analyze 17,442 nasopharyngeal samples from a longitudinal cohort of 1320 Zambian mother/infant pairs. Our analysis has two elements. First, we demonstrate that the full range of IS481 qPCR CT values provides insight into pertussis epidemiology, showing concordance of low and high CT results over time, within mother/infant pairs, and in relation to symptomatology. Second, we exploit these full-range qPCR data to demonstrate a high incidence of asymptomatic pertussis, including among infants. Our results demonstrate a wider burden of pertussis infection than we anticipated in this population, and expose key limitations of threshold-based interpretation of qPCR results in infectious disease surveillance.

Upper Respiratory Tract Co-detection of Human Endemic Coronaviruses and High-density Pneumococcus Associated With Increased Severity Among HIV-Uninfected Children Under 5 Years Old in the PERCH Study.

BACKGROUND: Severity of viral respiratory illnesses can be increased with bacterial coinfection and can vary by sex, but influence of coinfection and sex on human endemic coronavirus (CoV) species, which generally cause mild to moderate respiratory illness, is unknown. We evaluated CoV and pneumococcal co-detection by sex in childhood pneumonia. METHODS: In the 2011-2014 Pneumonia Etiology Research for Child Health study, nasopharyngeal and oropharyngeal (NP/OP) swabs and other samples were collected from 3981 children <5 years hospitalized with severe or very severe pneumonia in 7 countries. Severity by NP/OP detection status of CoV (NL63, 229E, OC43 or HKU1) and high-density (≥6.9 log10 copies/mL) pneumococcus (HDSpn) by real-time polymerase chain reaction was assessed by sex using logistic regression adjusted for age and site. RESULTS: There were 43 (1.1%) CoV+/HDSpn+, 247 CoV+/HDSpn-, 449 CoV-/HDSpn+ and 3149 CoV-/HDSpn- cases with no significant difference in co-detection frequency by sex (range 51.2%-64.0% male, P = 0.06). More CoV+/HDSpn+ pneumonia was very severe compared with other groups for both males (13/22, 59.1% versus range 29.1%-34.7%, P = 0.04) and females (10/21, 47.6% versus 32.5%-43.5%, P = 0.009), but only male CoV+/HDSpn+ required supplemental oxygen more frequently (45.0% versus 20.6%-28.6%, P < 0.001) and had higher mortality (35.0% versus 5.3%-7.1%, P = 0.004) than other groups. For females with CoV+/HDSpn+, supplemental oxygen was 25.0% versus 24.8%-33.3% (P = 0.58) and mortality was 10.0% versus 9.2%-12.9% (P = 0.69). CONCLUSIONS: Co-detection of endemic CoV and HDSpn was rare in children hospitalized with pneumonia, but associated with higher severity and mortality in males. Findings may warrant investigation of differences in severity by sex with co-detection of HDSpn and SARS-CoV-2.