What the PERCH study means for future pneumonia strategies
Authors: Trevor Duke
Journal: The Lancet (2019)

Identifying the causes of acute lower respiratory infections is challenging in most clinical settings, especially so in hospitals in low-income and middle-income countries where bacteriology and other diagnostic services are scarce. The diseases encompassed within WHO's clinical definition of pneumonia include bacterial and viral pneumonia, acute viral bronchiolitis, and bacterial and viral bronchitis. These conditions can coexist and duel pathogens are common, especially in severely unwell children in low-resource settings. The origin of many cases of bacterial pneumonia in children is an acute viral infection followed by mucosal invasion or drip aspiration of nasopharyngeal (NP) bacteria. In some settings, bacteria colonise the nasopharynx of more than 95% of infants in the first 2 months of life, whereas in other populations, this number is about 30% by age 1–5 years; therefore, the risk of bacterial pneumonia accompanying a viral upper respiratory tract infection varies greatly.1O'Brien KL Nohynek H Group WPVTCW Report from a WHO Working Group: standard method for detecting upper respiratory carriage of Streptococcus pneumoniae.Pediatr Infect Dis J. 2003; 22: e1-e11Crossref PubMed Scopus (299) Google Scholar, 2Gratten M Montgomery J Gerega G et al.Multiple colonization of the upper respiratory tract of Papua New Guinea children with Haemophilus influenzae and Streptococcus pneumoniae.Southeast Asian J Trop Med Public Health. 1989; 20: 501-509PubMed Google Scholar, 3Hill PC Cheung YB Akisanya A et al.Nasopharyngeal carriage of Streptococcus pneumoniae in Gambian infants: a longitudinal study.Clin Infect Dis. 2008; 46: 807-814Crossref PubMed Scopus (131) Google Scholar In The Lancet, the Pneumonia Etiology Research for Child Health (PERCH) Study Group report the findings of the PERCH study,4The Pneumonia Etiology Research for Child Health (PERCH) Study GroupCauses of severe pneumonia requiring hospital admission in children without HIV infection from Africa and Asia: the PERCH multi-country case-control study.Lancet. 2019; (published online June 27)http://dx.doi.org/10.1016/S0140–6736(19)30721–4Google Scholar an impressive attempt at understanding the diverse causes of acute lower respiratory infections in the pneumococcal conjugate vaccine (PCV) era. The group enrolled 4232 children aged 1–59 months admitted to hospital with what WHO previously classified as severe or very severe pneumonia, with the primary analysis population comprised of 1769 children without HIV infection and with a positive chest x-ray in seven countries over 2 years. PERCH found that ten pathogens accounted for almost 80% of WHO-defined pneumonia in the cases studied. The top ten list of pathogens varied between sites, but the universal causes included respiratory syncytial virus (RSV), Streptococcus pneumoniae, parainfluenza virus, Haemophilus influenzae, human metapneumovirus, and Mycobacterium tuberculosis. PERCH enlarges our understanding of the causes of acute lower respiratory infections but might be criticised for not identifying enough pneumococcal infections. The prevalence of S pneumoniae was estimated to be 4·6% (95% CI 3·2–6·2) for severe and 9·7% (6·9–13·1) for very severe pneumonia in the seven countries of the study, and the prevalence (for both severe and very severe pneumonia) varied widely between countries: 15·1% in The Gambia and 17·4% in Mali, and as low as 0·3% in Thailand. Although some countries had moderate to high PCV coverage (70–90% of the populations studied in The Gambia, Mali, and South Africa received one or more doses of PCV), the paradox is that the countries with the lowest attributable fraction of pneumococci also had the lowest PCV coverage (<10% of the study populations in Zambia, Thailand, and Bangladesh had received a dose of PCV, and the attributable fraction of pneumococci in these countries was <10%). These findings might seem to contrast with studies5Greenberg D Givon-Lavi N Ben-Shimol S Ziv JB Dagan R Impact of PCV7/PCV13 introduction on community-acquired alveolar pneumonia in children <5 years.Vaccine. 2015; 33: 4623-4629Crossref PubMed Scopus (59) Google Scholar, 6Pírez MC Algorta G Chamorro F et al.Changes in hospitalizations for pneumonia after universal vaccination with pneumococcal conjugate vaccines 7/13 valent and Haemophilus influenzae type b conjugate vaccine in a pediatric referral hospital in Uruguay.Pediatr Infect Dis J. 2014; 33: 753-759Crossref PubMed Scopus (33) Google Scholar that found reductions of 40% or higher in community-acquired, radiologically confirmed pneumonia requiring hospital admission after the 13-valent PCV (PCV13) was introduced. However, the results of other post-PCV studies show more modest reductions of 10–13% in clinical pneumonia,7Schuck-Paim C Taylor RJ Alonso WJ Weinberger DM Simonsen L Effect of pneumococcal conjugate vaccine introduction on childhood pneumonia mortality in Brazil: a retrospective observational study.Lancet Glob Health. 2019; 7: e249-e256Summary Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 8Sgambatti S Minamisava R Bierrenbach AL et al.Early impact of 10-valent pneumococcal conjugate vaccine in childhood pneumonia hospitalizations using primary data from an active population-based surveillance.Vaccine. 2016; 34: 663-670Crossref PubMed Scopus (29) Google Scholar which is a closer definition to that used in the PERCH study. 31·7% of cases in the PERCH study had wheeze on auscultation, 52·5% had no consolidation or opacification on chest x-ray, and 31·1% had RSV, suggesting that many cases had viral bronchiolitis (with or without pneumonia). Vaccine probe studies have reported cases fulfilling the International Classification of Diseases (ICD) or the WHO-radiographic criteria for pneumonia,9Cherian T Mulholland EK Carlin JB et al.Standardized interpretation of paediatric chest radiographs for the diagnosis of pneumonia in epidemiological studies.Bull World Health Organ. 2005; 83: 353-359PubMed Google Scholar which are different from WHO clinical criteria.10WHOHospital care for children: guidelines for the management of common illnesses with limited resources. World Health Organization, Geneva2013Google Scholar ICD criteria for pneumonia exclude clinical bronchiolitis and, thus, the prevalence is not diluted by all cases with severe acute lower respiratory infections, unlike in the PERCH cohorts. The threshold for these infections with positive chest x-ray in the PERCH study was defined as "consolidation, other infiltrate, or both", and viruses (including in viral bronchiolitis) can be associated with infiltrates on chest x-rays.11Florin TA Plint AC Zorc JJ Viral bronchiolitis.Lancet. 2017; 389: 211-224Summary Full Text Full Text PDF PubMed Scopus (108) Google Scholar, 12Breakell R Thorndyke B Clennett J Harkensee C Reducing unnecessary chest x-rays, antibiotics and bronchodilators through implementation of the NICE bronchiolitis guideline.Eur J Pediatr. 2018; 177: 47-51Crossref PubMed Scopus (19) Google Scholar Although recruitment included 29·3% of cases with very severe pneumonia, enrolling and obtaining consent of those who were most critically ill on presentation might have been challenging; therefore, bacterial causes might be somewhat underestimated. Another reason for the apparent under-representation of bacterial pneumonia could be the origin of pneumonia, which involves an upper respiratory viral infection (which would be found on NP aspirate by the PERCH study method) followed by drip aspiration of dense NP colonisation of S pneumoniae, H influenzae, or both. The typical causal pathway in very severe acute lower respiratory infections in low-income countries often includes household overcrowding and possible genetic factors (which lead to dense bacterial colonisation of the upper airway), smoke exposure, viral respiratory infections, and insufficient breastfeeding and early solid feeding (leading to breaches in barrier and mucosal immunity and drip aspiration of S pneumoniae and H influenzae). Depending on the setting and host factors, where NP colonisation with bacteria is light, RSV or other viral infections will manifest as bronchiolitis (with or without infiltrates on chest x-ray). In other situations, the infant might have signs of bronchiolitis (crackles, wheeze, and hyperinflation, and infiltration or atelectasis on x-ray) but improve or defervesce after treatment with antibiotics, representing mixed viral bronchiolitis and bacterial pneumonia or bronchitis. Conjugate vaccines diminish NP carriage of vaccine-type pneumococci, therefore reducing the risk of one part of the causal pathway for pneumonia, in addition to providing strong humoral protection against bacteraemia. When conjugate vaccines are introduced, severe bacterial pneumonia cases fall, case fatality rates for acute lower respiratory infections might fall, more typical viral bronchiolitis cases rise as a proportion of all acute lower respiratory infections (and with fewer mixed infections), and the overall incidence of these infections drops modestly. The PERCH study establishes other evidence that is important for clinical practice. First, M tuberculosis was found to contribute to 1·9–10·2% of acute pneumonia, varying across the sites, in cases with a positive chest x-ray. This finding is important for clinical guidelines and public health because tuberculosis does not present only with chronic symptoms (although some cases might have been tuberculosis colonisation with ubiquitous acute viral infection). Second, the study showed that finding bacteria in an NP swab or aspirate is not useful in clinical decision making, whereas some viruses (RSV, parainfluenza 1, and human metapneumovirus), when found in NP secretions were likely to be a cause. PERCH found that 14% of all cases of acute lower respiratory infections requiring hospital admission in the populations studied were vaccine preventable. This means that more than 15 million cases of pneumonia requiring hospital admission could be prevented annually with improved coverage of existing vaccines. The PERCH study emphasises that, after conjugate vaccines, the job of addressing acute lower respiratory infections is far from over. This job will require concerted global efforts to produce an effective vaccine against RSV (the cause of more than 30% of acute lower respiratory infections in all countries), a greater focus on public health strategies to prevent and mitigate the severity of acute lower respiratory infections, and improved case-management strategies. The finding that the majority of cases were viral in aetiology also suggests that strategies need to be implemented to restrict antibiotic prescription in acute lower respiratory infections and, particularly, to identify children with the clinical syndrome of acute bronchiolitis, for whom antibiotics can be withheld. This implementation is not easy in low-income and middle-income countries where bacterial and viral acute lower respiratory infections often coexist, and when wheezing is not specific for viral infection. WHO has guidelines on avoiding antibiotics in mild to moderate clinical bronchiolitis and further operational research is needed on how to implement them in different contexts.13Duke T Pneumonia and bronchiolitis in developing countries.Arch Dis Child. 2014; 99: 892-893Crossref PubMed Scopus (6) Google Scholar In the past 20 years, many prevention and case-management strategies have been given less public health emphasis than those for conjugate vaccines. These non-vaccine strategies are often harder to do and require social and economic changes, a focus on equity, and improvements in health systems and quality of care. The advantage of these strategies is that they are not cause specific. Exclusive breastfeeding, better nutrition in the first 2 years of life, protection from indoor air pollution and smoke exposure, healthy housing, care seeking, and improving the quality of primary care and referral case management—including oxygen therapy, identifying and treating comorbidities, monitoring, and supportive care—need more emphasis as part of a strategy for the multiple different causes of acute lower respiratory infections in the conjugate vaccine era. I declare no competing interests. Causes of severe pneumonia requiring hospital admission in children without HIV infection from Africa and Asia: the PERCH multi-country case-control studyIn 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. Full-Text PDF Open Access