Results from 7-country project highlights the need for new vaccines

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Respiratory syncytial virus (RSV) and other viruses now appear to be the main causes of severe childhood pneumonia in low- and middle-income countries, highlighting the need for vaccines against these pathogens, according to a study from a consortium of scientists from around the world, led by a team at the Johns Hopkins Bloomberg School of Public Health.

Pneumonia is the leading cause of death worldwide among children under 5 years old, with about 900,000 fatalities and more than 100 million reported cases each year. This makes pneumonia a greater cause of childhood mortality than malaria, tuberculosis, HIV, Zika virus and Ebola virus combined.

The study was the largest and most comprehensive of its kind since the 1980s. It included nearly 10,000 children in seven African and Asian countries. After testing for viruses, bacteria, and other pathogens in children with severe hospitalised pneumonia – and in community children without pneumonia – the study found that 61% of severe pneumonia cases were caused by viruses led by RSV, which alone accounted for 31% of cases.

“Prior to this study, we didn’t know which specific viruses and bacteria are now causing most of the severe childhood pneumonia cases in the world, but public health organisations and vaccine manufacturers really need that information to work toward reducing the substantial childhood mortality that pneumonia still causes,” says study co-principal investigator Dr Maria Deloria Knoll, a senior scientist in the Bloomberg School’s department of international health, and associate director of science at the Johns Hopkins International Vaccine Access Centre (IVAC).

Identifying the germs that cause pneumonia is difficult in individual cases and much more so on a scale of thousands of cases, especially in low- and middle-income countries where most pneumonia deaths occur. Researchers in prior pneumonia studies simply lacked the microbiological and analytical resources to produce estimates of the major pneumonia pathogens, Knoll says. And, in the past two decades, many low- and middle-income countries have introduced effective vaccines against known major bacterial causes of pneumonia – Haemophilus influenzae type b and Streptococcus pneumonia – so the global mix of pathogens causing childhood pneumonia has changed as a result.

The new, IVAC-led study, known as the Pneumonia Aetiology Research for Child Health (PERCH) study, included 4,232 cases of severe hospitalised pneumonia among children under 5 years and 5,119 community children without pneumonia during a two-year period. The study was carried out at sites in Bangladesh, The Gambia, Kenya, Mali, South Africa, Thailand, and Zambia.

For their study, researchers took nasal and throat swabs as well as blood, sputum and other fluid samples from cases and controls and tested them for pathogens using state-of-the-art laboratory techniques. Cases for the primary analysis were limited to those whose pneumonia was confirmed by chest X-ray, and children with HIV were considered in a separate analysis because the causes of their pneumonia would likely differ from those without HIV. With analytic methods unique for an aetiology study, the researchers compared the pathogens found in samples from severe pneumonia cases to those from other children in the community in order to estimate the likeliest cause of each case. In this way they were able to identify the leading causes of childhood pneumonia among children in these settings.

The researchers concluded that, across all study sites combined, viruses accounted for 61.4% of cases, bacteria for 27.3% of cases, Mycobacterium tuberculosis for 5.9% of cases. Fungal and unknown causes accounted for the remainder of cases.

RSV accounted for nearly a third of all cases and was the leading cause of severe pneumonia in each of the seven countries studied. Other top causes were rhinovirus, human metapneumovirus, para-influenza viruses, and S. pneumoniae bacteria.

“We now have a much better idea of which new vaccines would have the most impact in terms of reducing illness and mortality from childhood pneumonia in these countries,” says Dr Katherine O’Brien, who led the PERCH study as a professor at the Johns Hopkins Bloomberg School of Public Health and now serves as director of immunisations, vaccines and biologicals at the World Health Organisation.

RSV has long been known as a common and potentially serious respiratory pathogen among children and the elderly. It remains the leading cause of pneumonia in children younger than 1 year in the US, according to the Centre for Disease Control and Prevention. Several RSV vaccine candidates are being developed and evaluated in clinical trials. A monoclonal antibody therapy, palivizumab, is available for the prevention of RSV disease in children with underlying medical conditions but is not suitable programmatically or financially for widespread use in routine immunisation programmes.

The analytical technique developed for the study to estimate the cause of individual cases of childhood pneumonia is called the Bayesian Analysis Kit for Aetiology Research (BAKER), and is available online as an open-source application for use by other public health researchers.

“Estimating the aetiology of pneumonia was like a complex jigsaw puzzle where the picture could only be seen clearly by assembling multiple, different pieces of information using innovative epidemiologic and statistical methods,” says Dr Scott Zeger, Malone professor of biostatistics in the Bloomberg School’s department of biostatistics.

The principal investigator for the PERCH study was O’Brien. PERCH was a collaboration involving more than a dozen institutions and programs including the Bloomberg School; University of the Witwatersrand; Kenya Medical Research Institute-Wellcome Trust Research Programme; University of Oxford; University of Maryland School of Medicine and Centre pour le Développement des Vaccins-Mali; Thailand Ministry of Public Health-US Centres for Disease Control and Prevention Collaboration; Boston University School of Public Health and University Teaching Hospital-Lusaka; Medical Research Council Unit The Gambia; icddr,b; University of Otago and Canterbury Health Laboratories; and The Emmes Company.

PERCH was supported by grant 48968 from The Bill & Melinda Gates Foundation.

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.

The Pneumonia Aetiology Research for Child Health (PERCH) Study Group

Johns Hopkins Bloomberg School of Public Health material
The Lancet abstract

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