Unveiling the viral aetiologies of lower respiratory infections

Lower respiratory infections (LRIs) are the leading infectious cause of morbidity and mortality globally.1Vos T Lim SS Abbafati C et al.Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019.Lancet. 2020; 396: 1204-1222Summary Full Text Full Text PDF PubMed Scopus (7488) Google Scholar The 2019 iteration of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) highlighted the major progress in reducing the incidence and mortality of LRI over the past three decades, from 1990 to 2019. Since the beginning of the COVID-19 pandemic, changes in the epidemiology of multiple causes of LRI, particularly viral LRIs such as influenza and respiratory syncytial virus (RSV), have been reported,2Chow EJ Uyeki TM Chu HY The effects of the COVID-19 pandemic on community respiratory virus activity.Nat Rev Microbiol. 2023; 21: 195-210PubMed Google Scholar most likely a result of implementation of non-pharmaceutical interventions, an evolving ecosystem of respiratory pathogens, and modified contact patterns. Therefore, it becomes necessary to improve the understanding of the global burden of LRIs during the COVID-19 pandemic. In The Lancet Infectious Diseases, the GBD 2021 Lower Respiratory Infections and Antimicrobial Resistance Collaborators report an updated estimation of the global burden of non-COVID-19 LRI up to 2021.3GBD 2021 Lower Respiratory Infections and Antimicrobial Resistance CollaboratorsGlobal, regional, and national incidence and mortality burden of non-COVID-19 lower respiratory infections and aetiologies, 1990–2021: a systematic analysis from the Global Burden of Disease Study 2021.Lancet Infect Dis. 2024; (published online April 15.)https://doi.org/10.1016/S1473-3099(24)00176-2Google Scholar A noteworthy improvement of this study is the estimation of incidence and mortality for 18 different aetiologies of LRI, expanding the scope from the previous GBD studies by incorporating 13 additional aetiologies. Such cause-specific insights are crucial for the development and implementation of targeted interventions. This study serves as an important reference for policy makers, health-care providers, pharmaceutical industries, and researchers. However, while acknowledging the commendable efforts of the authors, it is important to approach the interpretation of the virus-specific estimates in this study with a degree of caution, considering the inherent complexities in the diagnosis of respiratory viruses, which in turn influenced data selection decisions, and the variations in microbial testing over the COVID-19 pandemic. To ascertain viral causes of LRIs, the authors included microbial data from virus-specific ICD codes and lower respiratory tract samples, excluding upper respiratory tract samples, which are commonly used in clinical settings and epidemiological studies.3GBD 2021 Lower Respiratory Infections and Antimicrobial Resistance CollaboratorsGlobal, regional, and national incidence and mortality burden of non-COVID-19 lower respiratory infections and aetiologies, 1990–2021: a systematic analysis from the Global Burden of Disease Study 2021.Lancet Infect Dis. 2024; (published online April 15.)https://doi.org/10.1016/S1473-3099(24)00176-2Google Scholar Existing systematic reviews and multicountry studies in young children4Shi T McLean K Campbell H Nair H Aetiological role of common respiratory viruses in acute lower respiratory infections in children under five years: a systematic review and meta-analysis.J Glob Health. 2015; 5010408Google Scholar, 5O'Brien KL Baggett HC Brooks WA et al.Causes of severe pneumonia requiring hospital admission in children without HIV infection from Africa and Asia: the PERCH multi-country case-control study.Lancet. 2019; 394: 757-779Summary Full Text Full Text PDF PubMed Scopus (484) Google Scholar, 6Bénet T Sánchez Picot V Messaoudi M et al.Microorganisms associated with pneumonia in children <5 years of age in developing and emerging countries: the GABRIEL pneumonia multicenter, prospective, case-control study.Clin Infect Dis. 2017; 65: 604-612PubMed Google Scholar and older adults7Shi T Arnott A Semogas I et al.The etiological role of common respiratory viruses in acute respiratory infections in older adults: a systematic review and meta-analysis.J Infect Dis. 2020; 222: S563-S569Crossref PubMed Google Scholar showed strong evidence for causal attribution of common respiratory viruses, such as RSV and influenza, detected in the upper respiratory tract in LRIs. Excluding such data results in a marked reduction in the amount of data available for estimating viral LRI disease burden, thereby raising concerns about potential selection bias. Furthermore, by reanalysing data from the Child Health and Mortality Prevention Surveillance network, which applied advanced post-mortem methodologies and included nasopharyngeal or oropharyngeal samples and lung samples, we found that including microbial data from nasopharyngeal or oropharyngeal samples (as an addition to lung samples) could identify an additional four (29%) of 14 influenza-attributable deaths and six (17%) of 35 RSV-attributable deaths in children. Evaluation of changes in the global burden of virus-specific LRIs is particularly challenging due to shifts in health-care-seeking behaviours and microbial testing over the COVID-19 pandemic. For influenza, the authors used case counts of influenza reported to WHO's FluNet to model influenza disease burden during the pandemic.3GBD 2021 Lower Respiratory Infections and Antimicrobial Resistance CollaboratorsGlobal, regional, and national incidence and mortality burden of non-COVID-19 lower respiratory infections and aetiologies, 1990–2021: a systematic analysis from the Global Burden of Disease Study 2021.Lancet Infect Dis. 2024; (published online April 15.)https://doi.org/10.1016/S1473-3099(24)00176-2Google Scholar It is worth noting that, due to the changes in the number of tests conducted over time, as driven by testing availability and eligibility, reliance on influenza case counts might produce biased estimates, especially in 2021 and afterwards. FluNet data showed a roughly 20% increase in the total number of influenza tests in 2020, and an 80–180% rise during 2021–23, compared with the 2017–19 average.8WHOInfluenza laboratory surveillance information: influenza detections reported to FluNet.https://app.powerbi.com/view?r=eyJrIjoiNjViM2Y4NjktMjJmMC00Y2NjLWFmOWQtODQ0NjZkNWM1YzNmIiwidCI6ImY2MTBjMGI3LWJkMjQtNGIzOS04MTBiLTNkYzI4MGFmYjU5MCIsImMiOjh9Date accessed: March 6, 2024Google Scholar For RSV, the authors assumed the same degree of changes as seen for influenza during the pandemic, and reported similar reductions in global influenza incidence (60·3% [95% uncertainty interval 47·1–72·9]) reduction) and RSV incidence (63·2% [53·1–72·7] reduction) from 2019 to 2021. However, recent evidence,2Chow EJ Uyeki TM Chu HY The effects of the COVID-19 pandemic on community respiratory virus activity.Nat Rev Microbiol. 2023; 21: 195-210PubMed Google Scholar including a systematic review,9Tang Y Dang X Lv M et al.Changes in the prevalence of respiratory pathogens in children due to the COVID-19 pandemic: a systematic review and meta-analysis.J Infect. 2023; 86: 154-225Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar shows that the changes differed by virus during the COVID-19 pandemic. A study from South Africa10Izu A Nunes MC Solomon F et al.All-cause and pathogen-specific lower respiratory tract infection hospital admissions in children younger than 5 years during the COVID-19 pandemic (2020–22) compared with the pre-pandemic period (2015–19) in South Africa: an observational study.Lancet Infect Dis. 2023; 23: 1031-1041Summary Full Text Full Text PDF PubMed Scopus (12) Google Scholar showed a 48% decline in RSV-associated LRI hospitalisation rates and a 95% decline for influenza in 2020 compared with the 2015–19 average; in 2021 the RSV-associated hospitalisation rate was similar to the pre-pandemic level, yet the influenza-associated hospitalisation rate remained 23% lower. The authors reported an aggregate category of other viruses (other than influenza and RSV), and showed that this category had the second highest incidence among all LRI aetiologies, responsible for 46·4 million (43·6–49·3) episodes of LRI.3GBD 2021 Lower Respiratory Infections and Antimicrobial Resistance CollaboratorsGlobal, regional, and national incidence and mortality burden of non-COVID-19 lower respiratory infections and aetiologies, 1990–2021: a systematic analysis from the Global Burden of Disease Study 2021.Lancet Infect Dis. 2024; (published online April 15.)https://doi.org/10.1016/S1473-3099(24)00176-2Google Scholar This is a most astonishing and worrying number, which underscores the urgent need for identifying other key viral contributors to LRI. Historically, surveillance has predominantly focused on influenza, and only more recently on RSV. With advancements in multipathogen testing techniques, there is a crucial need to expand surveillance efforts to an integrated multipathogen framework. Such multipathogen surveillance is not only essential for a comprehensive understanding of LRI aetiologies, but also important in strengthening pandemic preparedness capacities. XW has received grants from GlaxoSmithKline and consultancy fees from Pfizer, outside of the submitted work. YL has received grants from WHO, the Wellcome Trust, and GlaxoSmithKline, and consultancy fees from Pfizer, outside of the submitted work. Global, regional, and national incidence and mortality burden of non-COVID-19 lower respiratory infections and aetiologies, 1990–2021: a systematic analysis from the Global Burden of Disease Study 2021Substantial progress has been made in reducing LRI mortality, but the burden remains high, especially in low-income and middle-income countries. During the COVID-19 pandemic, with its associated non-pharmaceutical interventions, global incident LRI cases and mortality attributable to influenza and RSV declined substantially. Expanding access to health-care services and vaccines, including S pneumoniae, H influenzae type B, and novel RSV vaccines, along with new low-cost interventions against S aureus, could mitigate the LRI burden and prevent transmission of LRI-causing pathogens.