OBJECTIVES: After respiratory syncytial virus (RSV), human metapneumovirus (hMPV) was the second-ranked pathogen attributed to severe pneumonia in the PERCH study. We sought to characterize hMPV-positive cases in high burden settings, which have limited data, by comparing to RSV-positive and other cases. METHODS: Children aged 1-59 months hospitalized with suspected severe pneumonia and age/season-matched community controls in seven African and Asian countries had nasopharyngeal/oropharyngeal swabs tested by multiplex PCR for 32 respiratory pathogens, among other clinical and lab assessments at admission. Odds ratios adjusted for age and site (aOR) were calculated using logistic regression. Etiologic probability was estimated using Bayesian nested partial latent class analysis. Latent class analysis identified syndromic constellations of clinical characteristics. RESULTS: HMPV was detected more frequently among cases (267/3887, 6.9%) than controls (115/4976, 2.3%), among cases with pneumonia chest X-ray findings (8.5%) than without (5.5%), and among controls with respiratory tract illness (3.8%) than without (1.8%; all p≤0.001). HMPV-positive cases were negatively associated with the detection of other viruses (aOR=0.18), especially RSV (aOR=0.11; all p<0.0001), and positively associated with the detection of bacteria (aORs 1.77, p=0.03). No single clinical syndrome distinguished hMPV-positive from other cases. Among hMPV-positive cases, 65.2% were aged <1 year and 27.5% had pneumonia danger signs; positive predictive value was 74.5%; mortality was 3.9%, similar to RSV-positive (2.4%) and lower than other cases (9.6%). CONCLUSIONS: HMPV-associated severe pediatric pneumonia in high burden settings was predominantly in young infants and clinically indistinguishable from RSV. HMPV-positives had low case fatality, similar to that in RSV-positives.

Invasive meningococcal disease (IMD) is a severe illness that can have devastating effects; outbreaks are uncommon in the United States. Vaccination is the preferred control measure for IMD outbreaks when a defined population at risk (e.g., college students or persons experiencing homelessness) can be identified. In August 2022, the Virginia Department of Health (VDH) began investigating an IMD outbreak in Virginia's Eastern Health Planning Region, prompted by the detection of four confirmed cases within 8 weeks. Clinical isolates available from three cases were characterized as Neisseria meningitidis serogroup Y, sequence type 1466. A subsequent statewide investigation identified 36 genetically related cases, including seven deaths (case fatality rate = 19.4%) as of March 1, 2024. A majority of patients (63.9%) were in an age group (30-60 years) not generally considered at increased risk for IMD; 78.0% were non-Hispanic Black or African American. No common exposures, affiliations, or risk factors were identified, and a defined population could not be identified for vaccination. VDH recommended quadrivalent (serogroups A, C, W, and Y) meningococcal conjugate vaccination of a subset of close contacts of patients based on IMD risk factors and age range similar to that of patients with identified cases. IMD outbreaks might affect populations without established IMD risk factors. Lack of a well-defined population at risk might prompt exploration of novel control strategies, such as selective vaccination of close contacts.

Invasive meningococcal disease (IMD), caused by infection with the bacterium Neisseria meningitidis, usually manifests as meningitis or septicemia and can be severe and life-threatening (1). Six serogroups (A, B, C, W, X, and Y) account for most cases (2). N. meningitidis is transmitted person-to-person via respiratory droplets and oropharyngeal secretions. Asymptomatic persons can carry N. meningitidis and transmit the bacteria to others, potentially causing illness among susceptible persons. Outbreaks can occur in conjunction with large gatherings (3,4). Vaccines are available to prevent meningococcal disease. Antibiotic prophylaxis for close contacts of infected persons is critical to preventing secondary cases (2).

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.

Meningococcal disease, caused by the bacterium Neisseria meningitidis, is a rare but life-threatening illness that requires prompt antibiotic treatment for patients and antibiotic prophylaxis for their close contacts. Historically, N. meningitidis isolates in the United States have been largely susceptible to the antibiotics recommended for prophylaxis, including ciprofloxacin. Since 2019, however, the number of meningococcal disease cases caused by ciprofloxacin-resistant strains has increased. Antibiotic prophylaxis with ciprofloxacin in areas with ciprofloxacin resistance might result in prophylaxis failure. Health departments should preferentially consider using antibiotics other than ciprofloxacin as prophylaxis for close contacts when both of the following criteria have been met in a local catchment area during a rolling 12-month period: 1) the reporting of two or more invasive meningococcal disease cases caused by ciprofloxacin-resistant strains, and 2) ≥20% of all reported invasive meningococcal disease cases are caused by ciprofloxacin-resistant strains. Other than ciprofloxacin, alternative recommended antibiotic options include rifampin, ceftriaxone, or azithromycin. Ongoing monitoring for antibiotic resistance of meningococcal isolates through surveillance and health care providers' reporting of prophylaxis failures will guide future updates to prophylaxis considerations and recommendations.

Meningococcal disease, caused by the bacterium Neisseria meningitidis, is a sudden-onset, life-threatening illness that typically occurs as meningitis or meningococcemia. The most common signs and symptoms of meningitis include fever, headache, and stiff neck; the most common signs and symptoms of meningococcemia are fever, chills, fatigue, vomiting, diarrhea, cold hands and feet, and severe aches or pain.* Quadrivalent meningococcal conjugate vaccination (MenACWY) is routinely recommended for adolescents and persons at increased risk for meningococcal disease (1), including those with HIV. In 2016, a 2-dose series of MenACWY was recommended by the Advisory Committee on Immunization Practices (ACIP) for persons with HIV and incorporated into the U.S. immunization schedule. Coverage among persons with HIV, however, remains low: in a study of administrative claims data during January 2016–March 2018, only 16.3% of persons with HIV received ≥1 doses of MenACWY vaccine within 2 years after their diagnosis (2). This report describes an increase in meningococcal disease among persons with HIV in the United States in 2022. Data are typically finalized in the fall of the next year; therefore, this report is based on preliminary data for 2022.

BACKGROUND: Pneumonia is the leading cause of death among children younger than 5 years. In this study, we estimated causes of pneumonia in young African and Asian children, using novel analytical methods applied to clinical and microbiological findings. METHODS: We did a multi-site, international case-control study in nine study sites in seven countries: Bangladesh, The Gambia, Kenya, Mali, South Africa, Thailand, and Zambia. All sites enrolled in the study for 24 months. Cases were children aged 1-59 months admitted to hospital with severe pneumonia. Controls were age-group-matched children randomly selected from communities surrounding study sites. Nasopharyngeal and oropharyngeal (NP-OP), urine, blood, induced sputum, lung aspirate, pleural fluid, and gastric aspirates were tested with cultures, multiplex PCR, or both. Primary analyses were restricted to cases without HIV infection and with abnormal chest x-rays and to controls without HIV infection. We applied a Bayesian, partial latent class analysis to estimate probabilities of aetiological agents at the individual and population level, incorporating case and control data. FINDINGS: Between Aug 15, 2011, and Jan 30, 2014, we enrolled 4232 cases and 5119 community controls. The primary analysis group was comprised of 1769 (41·8% of 4232) cases without HIV infection and with positive chest x-rays and 5102 (99·7% of 5119) community controls without HIV infection. Wheezing was present in 555 (31·7%) of 1752 cases (range by site 10·6-97·3%). 30-day case-fatality ratio was 6·4% (114 of 1769 cases). Blood cultures were positive in 56 (3·2%) of 1749 cases, and Streptococcus pneumoniae was the most common bacteria isolated (19 [33·9%] of 56). Almost all cases (98·9%) and controls (98·0%) had at least one pathogen detected by PCR in the NP-OP specimen. The detection of respiratory syncytial virus (RSV), parainfluenza virus, human metapneumovirus, influenza virus, S pneumoniae, Haemophilus influenzae type b (Hib), H influenzae non-type b, and Pneumocystis jirovecii in NP-OP specimens was associated with case status. The aetiology analysis estimated that viruses accounted for 61·4% (95% credible interval [CrI] 57·3-65·6) of causes, whereas bacteria accounted for 27·3% (23·3-31·6) and Mycobacterium tuberculosis for 5·9% (3·9-8·3). Viruses were less common (54·5%, 95% CrI 47·4-61·5 vs 68·0%, 62·7-72·7) and bacteria more common (33·7%, 27·2-40·8 vs 22·8%, 18·3-27·6) in very severe pneumonia cases than in severe cases. RSV had the greatest aetiological fraction (31·1%, 95% CrI 28·4-34·2) of all pathogens. Human rhinovirus, human metapneumovirus A or B, human parainfluenza virus, S pneumoniae, M tuberculosis, and H influenzae each accounted for 5% or more of the aetiological distribution. We observed differences in aetiological fraction by age for Bordetella pertussis, parainfluenza types 1 and 3, parechovirus-enterovirus, P jirovecii, RSV, rhinovirus, Staphylococcus aureus, and S pneumoniae, and differences by severity for RSV, S aureus, S pneumoniae, and parainfluenza type 3. The leading ten pathogens of each site accounted for 79% or more of the site's aetiological fraction. INTERPRETATION: In our study, a small set of pathogens accounted for most cases of pneumonia requiring hospital admission. Preventing and treating a subset of pathogens could substantially affect childhood pneumonia outcomes. FUNDING: Bill & Melinda Gates Foundation.

BACKGROUND: As part of the Vaccine Impact on Diarrhea in Africa (VIDA) Study, we examined the prevalence, clinical presentation, and seasonality of Cryptosporidium in children to understand its relative burden after the introduction of rotavirus vaccine. METHODS: VIDA was a 3-year, age-stratified, matched case-control study of medically attended acute moderate-to-severe diarrhea (MSD) in children aged 0-59 months residing in censused populations at sites in Kenya, Mali, and The Gambia. Clinical and epidemiologic data were collected at enrollment, and a stool sample was tested for enteropathogens by quantitative PCR. An algorithm was created based on the organism's cycle threshold (Ct) and association with MSD to identify the subset of Cryptosporidium PCR-positive (Ct <35) cases most likely to be attributed to MSD. Clinical outcomes were assessed at 2-3 months after enrollment. RESULTS: One thousand one hundred six (22.9%) cases of MSD and 873 controls (18.1%) were PCR positive for Cryptosporidium; 465 cases (42.0%) were considered attributable to Cryptosporidium, mostly among children 6-23 months. Cryptosporidium infections peaked in The Gambia and Mali during the rainy season, while in Kenya they did not have clear seasonality. Compared with cases with watery MSD who had a negative PCR for Cryptosporidium, cases with watery MSD attributed to Cryptosporidium were less frequently dehydrated but appeared more severely ill using a modified Vesikari scale (38.1% vs 27.0%; P < 0.001), likely due to higher rates of hospitalization and intravenous fluid administration, higher prevalence of being wasted or very thin very thin (23.4% vs 14.7%; P < 0.001), and having severe acute malnutrition (midupper arm circumference <115 mm, 7.7% vs 2.5%; P < 0.001). On follow-up, Cryptosporidium-attributed cases had more prolonged and persistent episodes (43.2% vs 32.7%; P <0 .001) and linear growth faltering (change in height-for-age z score between enrollment and follow-up: -0.29 vs -0.17; P < 0.001). CONCLUSIONS: The burden of Cryptosporidium remains high among young children in sub-Saharan Africa. Its propensity to cause illness and further impact children longer term by compromising nutritional status early in life calls for special attention to enable appropriate management of clinical and nutritional consequences.

This review summarizes the recent Global Meningococcal Initiative (GMI) regional meeting, which explored meningococcal disease in North America. Invasive meningococcal disease (IMD) cases are documented through both passive and active surveillance networks. IMD appears to be decreasing in many areas, such as the Dominican Republic (2016: 18 cases; 2021: 2 cases) and Panama (2008: 1 case/100,000; 2021: <0.1 cases/100,000); however, there is notable regional and temporal variation. Outbreaks persist in at-risk subpopulations, such as people experiencing homelessness in the US and migrants in Mexico. The recent emergence of β-lactamase-positive and ciprofloxacin-resistant meningococci in the US is a major concern. While vaccination practices vary across North America, vaccine uptake remains relatively high. Monovalent and multivalent conjugate vaccines (which many countries in North America primarily use) can provide herd protection. However, there is no evidence that group B vaccines reduce meningococcal carriage. The coronavirus pandemic illustrates that following public health crises, enhanced surveillance of disease epidemiology and catch-up vaccine schedules is key. Whole genome sequencing is a key epidemiological tool for identifying IMD strain emergence and the evaluation of vaccine strain coverage. The Global Roadmap on Defeating Meningitis by 2030 remains a focus of the GMI.

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.

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.

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.

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.

BACKGROUND: Whether digitally recorded lung sounds are associated with radiographic pneumonia or clinical outcomes among children in low-income and middle-income countries is unknown. We sought to address these knowledge gaps. METHODS: We enrolled 1-59 month old children hospitalized with pneumonia at eight African and Asian Pneumonia Etiology Research for Child Health sites in six countries, recorded digital stethoscope lung sounds, obtained chest radiographs, and collected clinical outcomes. Recordings were processed and reclassified into binary categories positive or negative for adventitial lung sounds. Listening and reading panels classified recordings and radiographs. Recording classification associations with chest radiographs with World Health Organization (WHO)-defined primary endpoint pneumonia (radiographic pneumonia) or mortality were evaluated. We also examined case fatality among risk strata. RESULTS: Among children without WHO danger signs, wheezing (without crackles) had a lower adjusted odds ratio (aOR) for radiographic pneumonia (0.35, 95% confidence interval (CI) 0.15, 0.82), compared to children with normal recordings. Neither crackle only (no wheeze) (aOR 2.13, 95%CI 0.91, 4.96) or any wheeze (with or without crackle) (aOR 0.63, 95%CI 0.34, 1.15) were associated with radiographic pneumonia. Among children with WHO danger signs no lung recording classification was independently associated with radiographic pneumonia, although trends towards greater odds of radiographic pneumonia were observed among children classified with crackle only (no wheeze) or any wheeze (with or without crackle). Among children without WHO danger signs, those with recorded wheezing had a lower case fatality than those without wheezing (3.8% vs 9.1%, p=0.03). CONCLUSIONS: Among lower risk children without WHO danger signs digitally recorded wheezing is associated with a lower odds for radiographic pneumonia and with lower mortality. Although further research is needed, these data indicate that with further development digital auscultation may eventually contribute to child pneumonia care. This article is protected by copyright. All rights reserved.

BACKGROUND: In 2015, pneumonia remained the leading cause of mortality in children between 1-59 months old. METHODS: Data from 1802 HIV-negative children between 1-59 months old enrolled in the Pneumonia Etiology Research for Child Health (PERCH) study with severe or very severe pneumonia during 2011-14 were used to build a parsimonious multivariable model predicting mortality using backwards stepwise logistic regression. The PERCH severity score, derived from model coefficients, was validated on a second, temporally discrete dataset of a further 1819 cases and compared to other available scores using the c-statistic. RESULTS: Predictors of mortality, across seven low and middle-income countries, were: age <1 year, female sex, 3 or more days of illness prior to presentation to hospital, low weight-for-height, unresponsiveness, deep breathing, hypoxemia, grunting and the absence of cough. The model discriminated well between those who died and those who survived (c-statistic: 0.84), but the predictive capacity of the PERCH 5-stratum score derived from the coefficients was moderate (c=0.76). The performance of the Respiratory Index of Severity in Children (RISC) score was similar (c=0.76). The number of WHO danger signs demonstrated the highest discrimination (c=0.82; 1.5% died if no danger signs, 10% if 1 danger sign and 33% if 2 or more danger signs). CONCLUSIONS: The PERCH severity score could be used to interpret geographic variations in pneumonia mortality and etiology. The number of WHO danger signs on presentation to hospital could be the most useful, of the currently available tools, to aid clinical management of pneumonia.

BACKGROUND: We have previously estimated that respiratory syncytial virus (RSV) was associated with 22% of all episodes of (severe) acute lower respiratory infection (ALRI) resulting in 55 000 to 199 000 deaths in children younger than 5 years in 2005. In the past 5 years, major research activity on RSV has yielded substantial new data from developing countries. With a considerably expanded dataset from a large international collaboration, we aimed to estimate the global incidence, hospital admission rate, and mortality from RSV-ALRI episodes in young children in 2015. METHODS: We estimated the incidence and hospital admission rate of RSV-associated ALRI (RSV-ALRI) in children younger than 5 years stratified by age and World Bank income regions from a systematic review of studies published between Jan 1, 1995, and Dec 31, 2016, and unpublished data from 76 high quality population-based studies. We estimated the RSV-ALRI incidence for 132 developing countries using a risk factor-based model and 2015 population estimates. We estimated the in-hospital RSV-ALRI mortality by combining in-hospital case fatality ratios with hospital admission estimates from hospital-based (published and unpublished) studies. We also estimated overall RSV-ALRI mortality by identifying studies reporting monthly data for ALRI mortality in the community and RSV activity. FINDINGS: We estimated that globally in 2015, 33.1 million (uncertainty range [UR] 21.6-50.3) episodes of RSV-ALRI, resulted in about 3.2 million (2.7-3.8) hospital admissions, and 59 600 (48 000-74 500) in-hospital deaths in children younger than 5 years. In children younger than 6 months, 1.4 million (UR 1.2-1.7) hospital admissions, and 27 300 (UR 20 700-36 200) in-hospital deaths were due to RSV-ALRI. We also estimated that the overall RSV-ALRI mortality could be as high as 118 200 (UR 94 600-149 400). Incidence and mortality varied substantially from year to year in any given population. INTERPRETATION: Globally, RSV is a common cause of childhood ALRI and a major cause of hospital admissions in young children, resulting in a substantial burden on health-care services. About 45% of hospital admissions and in-hospital deaths due to RSV-ALRI occur in children younger than 6 months. An effective maternal RSV vaccine or monoclonal antibody could have a substantial effect on disease burden in this age group. FUNDING: The Bill & Melinda Gates Foundation.

Over the last 20–30 years, enormous reductions have occurred in the absolute and relative burden of pneumonia mortality in young children around the world. Only 20 years ago, when the population of young children was approximately 625 million, approximately 1.7 million young children died from pneumonia before their 5th birthday (Figure 1) [1–4]. Mortality from pneumonia among children aged <5 years fell to 921 000 in 2015, whereas the population of young children rose to >670 million [1, 2, 5]. This remarkable improvement in child survival and health has resulted from advances in social conditions and economic development [6] but has also been influenced by at least 4 pivotal innovations: (1) the development of a global vaccination program, the World Health Organization’s Expanded Program on Immunizations (begun in 1974), which created the architecture around which country investments, donor funding, program strategies, and outcome measurements could be envisioned and implemented; (2) the global consensus to focus funding, programs, and momentum on 6 development targets articulated by the United Nations General Assembly through the Millennium Development Goals (MDGs, agreed upon in 2000) with MDG4 targeting child survival; (3) the advent of large, health-focused nongovernmental organizations; and (4) the founding of the Global Alliance for Vaccines and Immunization (the Gavi Alliance, formally launched at the World Economic Forum in January 2000), a multilateral funding organization that has allowed for an unprecedented pace of introduction and expanded use of life-saving vaccines in low-income countries. In part, as a result of this multidimensional, multisectoral consensus approach enacted through critical large-scale investments in prevention, protection, and treatment, pneumonia mortality has fallen substantially in many parts of the world because the most fatal of the pathogens and the underlying conditions that put children at risk are being targeted.

Background.: The etiologic inference of identifying a pathogen in the upper respiratory tract (URT) of children with pneumonia is unclear. To determine if viral load could provide evidence of causality of pneumonia, we compared viral load in the URT of children with World Health Organization-defined severe and very severe pneumonia and age-matched community controls. Methods.: In the 9 developing country sites, nasopharyngeal/oropharyngeal swabs from children with and without pneumonia were tested using quantitative real-time polymerase chain reaction for 17 viruses. The association of viral load with case status was evaluated using logistic regression. Receiver operating characteristic (ROC) curves were constructed to determine optimal discriminatory viral load cutoffs. Viral load density distributions were plotted. Results.: The mean viral load was higher in cases than controls for 7 viruses. However, there was substantial overlap in viral load distribution of cases and controls for all viruses. ROC curves to determine the optimal viral load cutoff produced an area under the curve of <0.80 for all viruses, suggesting poor to fair discrimination between cases and controls. Fatal and very severe pneumonia cases did not have higher viral load than less severe cases for most viruses. Conclusions.: Although we found higher viral loads among pneumonia cases than controls for some viruses, the utility in using viral load of URT specimens to define viral pneumonia was equivocal. Our analysis was limited by lack of a gold standard for viral pneumonia.

Background.: Lack of a gold standard for identifying bacterial and viral etiologies of pneumonia has limited evaluation of C-reactive protein (CRP) for identifying bacterial pneumonia. We evaluated the sensitivity and specificity of CRP for identifying bacterial vs respiratory syncytial virus (RSV) pneumonia in the Pneumonia Etiology Research for Child Health (PERCH) multicenter case-control study. Methods.: We measured serum CRP levels in cases with World Health Organization-defined severe or very severe pneumonia and a subset of community controls. We evaluated the sensitivity and specificity of elevated CRP for "confirmed" bacterial pneumonia (positive blood culture or positive lung aspirate or pleural fluid culture or polymerase chain reaction [PCR]) compared to "RSV pneumonia" (nasopharyngeal/oropharyngeal or induced sputum PCR-positive without confirmed/suspected bacterial pneumonia). Receiver operating characteristic (ROC) curves were constructed to assess the performance of elevated CRP in distinguishing these cases. Results.: Among 601 human immunodeficiency virus (HIV)-negative tested controls, 3% had CRP ≥40 mg/L. Among 119 HIV-negative cases with confirmed bacterial pneumonia, 77% had CRP ≥40 mg/L compared with 17% of 556 RSV pneumonia cases. The ROC analysis produced an area under the curve of 0.87, indicating very good discrimination; a cut-point of 37.1 mg/L best discriminated confirmed bacterial pneumonia (sensitivity 77%) from RSV pneumonia (specificity 82%). CRP ≥100 mg/L substantially improved specificity over CRP ≥40 mg/L, though at a loss to sensitivity. Conclusions.: Elevated CRP was positively associated with confirmed bacterial pneumonia and negatively associated with RSV pneumonia in PERCH. CRP may be useful for distinguishing bacterial from RSV-associated pneumonia, although its role in discriminating against other respiratory viral-associated pneumonia needs further study.

In pneumonia, specimens are rarely obtained directly from the infection site, the lung, so the pathogen causing infection is determined indirectly from multiple tests on peripheral clinical specimens, which may have imperfect and uncertain sensitivity and specificity, so inference about the cause is complex. Analytic approaches have included expert review of case-only results, case-control logistic regression, latent class analysis, and attributable fraction, but each has serious limitations and none naturally integrate multiple test results. The Pneumonia Etiology Research for Child Health (PERCH) study required an analytic solution appropriate for a case-control design that could incorporate evidence from multiple specimens from cases and controls and that accounted for measurement error. We describe a Bayesian integrated approach we developed that combined and extended elements of attributable fraction and latent class analyses to meet some of these challenges and illustrate the advantage it confers regarding the challenges identified for other methods.

Background: Chest radiographs (CXRs) are frequently used to assess pneumonia cases. Variations in CXR appearances between epidemiological settings and their correlation with clinical signs are not well documented. Methods: The Pneumonia Etiology Research for Child Health project enrolled 4232 cases of hospitalized World Health Organization (WHO)-defined severe and very severe pneumonia from 9 sites in 7 countries (Bangladesh, the Gambia, Kenya, Mali, South Africa, Thailand, and Zambia). At admission, each case underwent a standardized assessment of clinical signs and pneumonia risk factors by trained health personnel, and a CXR was taken that was interpreted using the standardized WHO methodology. CXRs were categorized as abnormal (consolidation and/or other infiltrate), normal, or uninterpretable. Results: CXRs were interpretable in 3587 (85%) cases, of which 1935 (54%) were abnormal (site range, 35%-64%). Cases with abnormal CXRs were more likely than those with normal CXRs to have hypoxemia (45% vs 26%), crackles (69% vs 62%), tachypnea (85% vs 80%), or fever (20% vs 16%) and less likely to have wheeze (30% vs 38%; all P < .05). CXR consolidation was associated with a higher case fatality ratio at 30-day follow-up (13.5%) compared to other infiltrate (4.7%) or normal (4.9%) CXRs. Conclusions: Clinically diagnosed pneumonia cases with abnormal CXRs were more likely to have signs typically associated with pneumonia. However, CXR-normal cases were common, and clinical signs considered indicative of pneumonia were present in substantial proportions of these cases. CXR-consolidation cases represent a group with an increased likelihood of death at 30 days post-discharge.

Background.: Sputum microscopy and culture are commonly used for diagnosing the cause of pneumonia in adults but are rarely performed in children due to difficulties in obtaining specimens. Induced sputum is occasionally used to investigate lower respiratory infections in children but has not been widely used in pneumonia etiology studies. Methods.: We evaluated the diagnostic utility of induced sputum microscopy and culture in patients enrolled in the Pneumonia Etiology Research for Child Health (PERCH) study, a large study of community-acquired pneumonia in children aged 1-59 months. Comparisons were made between induced sputum samples from hospitalized children with radiographically confirmed pneumonia and children categorized as nonpneumonia (due to the absence of prespecified clinical and laboratory signs and absence of infiltrate on chest radiograph). Results.: One induced sputum sample was available for analysis from 3772 (89.1%) of 4232 suspected pneumonia cases enrolled in PERCH. Of these, sputum from 2608 (69.1%) met the quality criterion of <10 squamous epithelial cells per low-power field, and 1162 (44.6%) had radiographic pneumonia. Induced sputum microscopy and culture results were not associated with radiographic pneumonia, regardless of prior antibiotic use, stratification by specific bacteria, or interpretative criteria used. Conclusions.: The findings of this study do not support the culture of induced sputum specimens as a diagnostic tool for pneumonia in young children as part of routine clinical practice.

Background.: We investigated the performance of polymerase chain reaction (PCR) on blood in the diagnosis of pneumococcal pneumonia among children from 7 low- and middle-income countries. Methods.: We tested blood by PCR for the pneumococcal autolysin gene in children aged 1-59 months in the Pneumonia Etiology Research for Child Health (PERCH) study. Children had World Health Organization-defined severe or very severe pneumonia or were age-frequency-matched community controls. Additionally, we tested blood from general pediatric admissions in Kilifi, Kenya, a PERCH site. The proportion PCR-positive was compared among cases with microbiologically confirmed pneumococcal pneumonia (MCPP), cases without a confirmed bacterial infection (nonconfirmed), cases confirmed for nonpneumococcal bacteria, and controls. Results.: In PERCH, 7.3% (n = 291/3995) of cases and 5.5% (n = 273/4987) of controls were blood pneumococcal PCR-positive (P < .001), compared with 64.3% (n = 36/56) of MCPP cases and 6.3% (n = 243/3832) of nonconfirmed cases (P < .001). Blood pneumococcal PCR positivity was higher in children from the 5 African countries (5.5%-11.5% among cases and 5.3%-10.2% among controls) than from the 2 Asian countries (1.3% and 1.0% among cases and 0.8% and 0.8% among controls). Among Kilifi general pediatric admissions, 3.9% (n = 274/6968) were PCR-positive, including 61.7% (n = 37/60) of those with positive blood cultures for pneumococcus. Discussion.: The utility of pneumococcal PCR on blood for diagnosing childhood pneumococcal pneumonia in the 7 low- and middle-income countries studied is limited by poor specificity and by poor sensitivity among MCPP cases.

Background.: Detection of pneumococcus by lytA polymerase chain reaction (PCR) in blood had poor diagnostic accuracy for diagnosing pneumococcal pneumonia in children in 9 African and Asian sites. We assessed the value of blood lytA quantification in diagnosing pneumococcal pneumonia. Methods.: The Pneumonia Etiology Research for Child Health (PERCH) case-control study tested whole blood by PCR for pneumococcus in children aged 1-59 months hospitalized with signs of pneumonia and in age-frequency matched community controls. The distribution of load among PCR-positive participants was compared between microbiologically confirmed pneumococcal pneumonia (MCPP) cases, cases confirmed for nonpneumococcal pathogens, nonconfirmed cases, and controls. Receiver operating characteristic analyses determined the "optimal threshold" that distinguished MCPP cases from controls. Results.: Load was available for 290 of 291 cases with pneumococcal PCR detected in blood and 273 of 273 controls. Load was higher in MCPP cases than controls (median, 4.0 x 103 vs 0.19 x 103 copies/mL), but overlapped substantially (range, 0.16-989.9 x 103 copies/mL and 0.01-551.9 x 103 copies/mL, respectively). The proportion with high load (≥2.2 log10 copies/mL) was 62.5% among MCPP cases, 4.3% among nonconfirmed cases, 9.3% among cases confirmed for a nonpneumococcal pathogen, and 3.1% among controls. Pneumococcal load in blood was not associated with respiratory tract illness in controls (P = .32). High blood pneumococcal load was associated with alveolar consolidation on chest radiograph in nonconfirmed cases, and with high (>6.9 log10 copies/mL) nasopharyngeal/oropharyngeal load and C-reactive protein ≥40 mg/L (both P < .01) in nonconfirmed cases but not controls. Conclusions.: Quantitative pneumococcal PCR in blood has limited diagnostic utility for identifying pneumococcal pneumonia in individual children, but may be informative in epidemiological studies.

Background.: There is limited information on the association between colonization density of upper respiratory tract colonizers and pathogen-specific pneumonia. We assessed this association for Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and Pneumocystis jirovecii. Methods.: In 7 low- and middle-income countries, nasopharyngeal/oropharyngeal swabs from children with severe pneumonia and age-frequency matched community controls were tested using quantitative polymerase chain reaction (PCR). Differences in median colonization density were evaluated using the Wilcoxon rank-sum test. Density cutoffs were determined using receiver operating characteristic curves. Cases with a pathogen identified from lung aspirate culture or PCR, pleural fluid culture or PCR, blood culture, and immunofluorescence for P. jirovecii defined microbiologically confirmed cases for the given pathogens. Results.: Higher densities of H. influenzae were observed in both microbiologically confirmed cases and chest radiograph (CXR)-positive cases compared to controls. Staphylococcus aureus and P. jirovecii had higher densities in CXR-positive cases vs controls. A 5.9 log10 copies/mL density cutoff for H. influenzae yielded 86% sensitivity and 77% specificity for detecting microbiologically confirmed cases; however, densities overlapped between cases and controls and positive predictive values were poor (<3%). Informative density cutoffs were not found for S. aureus and M. catarrhalis, and a lack of confirmed case data limited the cutoff identification for P. jirovecii. Conclusions.: There is evidence for an association between H. influenzae colonization density and H. influenzae-confirmed pneumonia in children; the association may be particularly informative in epidemiologic studies. Colonization densities of M. catarrhalis, S. aureus, and P. jirovecii are unlikely to be of diagnostic value in clinical settings.

Background.: Sputum examination can be useful in diagnosing the cause of pneumonia in adults but is less well established in children. We sought to assess the diagnostic utility of polymerase chain reaction (PCR) for detection of respiratory viruses and bacteria in induced sputum (IS) specimens from children hospitalized with severe or very severe pneumonia. Methods.: Among children aged 1-59 months, we compared organism detection by multiplex PCR in IS and nasopharyngeal/oropharyngeal (NP/OP) specimens. To assess whether organism presence or density in IS specimens was associated with chest radiographic evidence of pneumonia (radiographic pneumonia), we compared prevalence and density in IS specimens from children with radiographic pneumonia and children with suspected pneumonia but without chest radiographic changes or clinical or laboratory findings suggestive of pneumonia (nonpneumonia group). Results.: Among 4232 cases with World Health Organization-defined severe or very severe pneumonia, we identified 1935 (45.7%) with radiographic pneumonia and 573 (13.5%) with nonpneumonia. The organism detection yield was marginally improved with IS specimens (96.2% vs 92.4% for NP/OP specimens for all viruses combined [P = .41]; 96.9% vs 93.3% for all bacteria combined [P = .01]). After accounting for presence in NP/OP specimens, no organism was detected more frequently in the IS specimens from the radiographic pneumonia compared with the nonpneumonia cases. Among high-quality IS specimens, there were no statistically significant differences in organism density, except with cytomegalovirus, for which there was a higher quantity in the IS specimens from cases with radiographic pneumonia compared with the nonpneumonia cases (median cycle threshold value, 27.9 vs 28.5, respectively; P = .01). Conclusions.: Using advanced molecular methods with IS specimens provided little additional diagnostic information beyond that obtained with NP/OP swab specimens.

Background.: Previous studies suggested an association between upper airway pneumococcal colonization density and pneumococcal pneumonia, but data in children are limited. Using data from the Pneumonia Etiology Research for Child Health (PERCH) study, we assessed this potential association. Methods.: PERCH is a case-control study in 7 countries: Bangladesh, The Gambia, Kenya, Mali, South Africa, Thailand, and Zambia. Cases were children aged 1-59 months hospitalized with World Health Organization-defined severe or very severe pneumonia. Controls were randomly selected from the community. Microbiologically confirmed pneumococcal pneumonia (MCPP) was confirmed by detection of pneumococcus in a relevant normally sterile body fluid. Colonization density was calculated with quantitative polymerase chain reaction analysis of nasopharyngeal/oropharyngeal specimens. Results.: Median colonization density among 56 cases with MCPP (MCPP cases; 17.28 x 106 copies/mL) exceeded that of cases without MCPP (non-MCPP cases; 0.75 x 106) and controls (0.60 x 106) (each P < .001). The optimal density for discriminating MCPP cases from controls using the Youden index was >6.9 log10 copies/mL; overall, the sensitivity was 64% and the specificity 92%, with variable performance by site. The threshold was lower (≥4.4 log10 copies/mL) when MCPP cases were distinguished from controls who received antibiotics before specimen collection. Among the 4035 non-MCPP cases, 500 (12%) had pneumococcal colonization density >6.9 log10 copies/mL; above this cutoff was associated with alveolar consolidation at chest radiography, very severe pneumonia, oxygen saturation <92%, C-reactive protein ≥40 mg/L, and lack of antibiotic pretreatment (all P< .001). Conclusions.: Pneumococcal colonization density >6.9 log10 copies/mL was strongly associated with MCPP and could be used to improve estimates of pneumococcal pneumonia prevalence in childhood pneumonia studies. Our findings do not support its use for individual diagnosis in a clinical setting.

Background.: Induced sputum (IS) may provide diagnostic information about the etiology of pneumonia. The safety of this procedure across a heterogeneous population with severe pneumonia in low- and middle-income countries has not been described. Methods.: IS specimens were obtained as part a 7-country study of the etiology of severe and very severe pneumonia in hospitalized children <5 years of age. Rigorous clinical monitoring was done before, during, and after the procedure to record oxygen requirement, oxygen saturation, respiratory rate, consciousness level, and other evidence of clinical deterioration. Criteria for IS contraindications were predefined and serious adverse events (SAEs) were reported to ethics committees and a central safety monitor. Results.: A total of 4653 IS procedures were done among 3802 children. Thirteen SAEs were reported in relation to collection of IS, or 0.34% of children with at least 1 IS specimen collected (95% confidence interval, 0.15%-0.53%). A drop in oxygen saturation that required supplemental oxygen was the most common SAE. One child died after feeding was reinitiated 2 hours after undergoing sputum induction; this death was categorized as "possibly related" to the procedure. Conclusions.: The overall frequency of SAEs was very low, and the nature of most SAEs was manageable, demonstrating a low-risk safety profile for IS collection even among severely ill children in low-income-country settings. Healthcare providers should monitor oxygen saturation and requirements during and after IS collection, and assess patients prior to reinitiating feeding after the IS procedure, to ensure patient safety.

Many pneumonia etiology case-control studies exclude controls with respiratory illness from enrollment or analyses. Herein we argue that selecting controls regardless of respiratory symptoms provides the least biased estimates of pneumonia etiology. We review 3 reasons investigators may choose to exclude controls with respiratory symptoms in light of epidemiologic principles of control selection and present data from the Pneumonia Etiology Research for Child Health (PERCH) study where relevant to assess their validity. We conclude that exclusion of controls with respiratory symptoms will result in biased estimates of etiology. Randomly selected community controls, with or without respiratory symptoms, as long as they do not meet the criteria for case-defining pneumonia, are most representative of the general population from which cases arose and the least subject to selection bias.

Background.: Variable adherence to standardized case definitions, clinical procedures, specimen collection techniques, and laboratory methods has complicated the interpretation of previous multicenter pneumonia etiology studies. To circumvent these problems, a program of clinical standardization was embedded in the Pneumonia Etiology Research for Child Health (PERCH) study. Methods.: Between March 2011 and August 2013, standardized training on the PERCH case definition, clinical procedures, and collection of laboratory specimens was delivered to 331 clinical staff at 9 study sites in 7 countries (The Gambia, Kenya, Mali, South Africa, Zambia, Thailand, and Bangladesh), through 32 on-site courses and a training website. Staff competency was assessed throughout 24 months of enrollment with multiple-choice question (MCQ) examinations, a video quiz, and checklist evaluations of practical skills. Results.: MCQ evaluation was confined to 158 clinical staff members who enrolled PERCH cases and controls, with scores obtained for >86% of eligible staff at each time-point. Median scores after baseline training were ≥80%, and improved by 10 percentage points with refresher training, with no significant intersite differences. Percentage agreement with the clinical trainer on the presence or absence of clinical signs on video clips was high (≥89%), with interobserver concordance being substantial to high (AC1 statistic, 0.62-0.82) for 5 of 6 signs assessed. Staff attained median scores of >90% in checklist evaluations of practical skills. Conclusions.: Satisfactory clinical standardization was achieved within and across all PERCH sites, providing reassurance that any etiological or clinical differences observed across the study sites are true differences, and not attributable to differences in application of the clinical case definition, interpretation of clinical signs, or in techniques used for clinical measurements or specimen collection.