Role of community-based cohorts for uncovering the iceberg of disease
Authors: Harish Nair
Journal: The Lancet Global Health (2021)

Sometimes in literature, less is more. Sadly, unlike fiction, for strengthening our understanding of the epidemiology of infectious diseases we need to uncover as much of the seven-eighths of the iceberg that is under water as possible. Traditionally, we have tended to focus on studying more severe disease cases resulting in deaths and hospitalisations because these pose substantial burden on health-care services and the economy.1GBD 2017 Influenza CollaboratorsMortality, morbidity, and hospitalisations due to influenza lower respiratory tract infections, 2017: an analysis for the Global Burden of Disease Study 2017.Lancet Respir Med. 2019; 7: 69-89Summary Full Text Full Text PDF PubMed Scopus (185) Google Scholar However, as has been shown in the past year with SARS-CoV-2, it is important to also look at asymptomatic and mildly symptomatic cases of infectious diseases to understand disease transmission, immunity, and the natural history of disease, including sequelae.2Wu P Liu F Chang Z et al.Assessing asymptomatic, pre-symptomatic and symptomatic transmission risk of SARS-CoV-2.Clin Infect Dis. 2021; (published online March 21.)https://doi.org/10.1093/cid/ciab271Crossref Scopus (15) Google Scholar The non-severe presentations of respiratory viruses like influenza and respiratory syncytial virus still lead to a substantial burden on clinical services, inappropriate use of antibiotics, and work and school absenteeism, which has a substantial economic effect that is not visible and thus goes unrecognised by both the public and policy makers.3Heikkinen T Ojala E Waris M Clinical and socioeconomic burden of respiratory syncytial virus infection in children.J Infect Dis. 2017; 215: 17-23Crossref PubMed Scopus (36) Google Scholar The PHIRST study by Cheryl Cohen and colleagues5Cohen C Kleynhans J Moyes J et al.Asymptomatic transmission and high community burden of seasonal influenza in an urban and a rural community in South Africa, 2017–18 (PHIRST): a population cohort study.Lancet Glob Health. 2021; 9: e863-e874Summary Full Text Full Text PDF Scopus (16) Google Scholar published in The Lancet Global Health makes a valuable contribution to our hitherto poor understanding of respiratory viruses, like respiratory syncytial virus and influenza, that cause substantial disease burden in populations, particularly those at the extremes of age.4GBD 2016 Lower Respiratory Infections CollaboratorsEstimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016.Lancet Infect Dis. 2018; 18: 1191-1210Summary Full Text Full Text PDF PubMed Scopus (582) Google Scholar That the study was done in a high HIV burden setting, South Africa, helps to understand disease transmission and the differential effect of respiratory infections in individuals with and without HIV. Cohen and colleagues5Cohen C Kleynhans J Moyes J et al.Asymptomatic transmission and high community burden of seasonal influenza in an urban and a rural community in South Africa, 2017–18 (PHIRST): a population cohort study.Lancet Glob Health. 2021; 9: e863-e874Summary Full Text Full Text PDF Scopus (16) Google Scholar show a high influenza burden, with a community incidence of PCR confirmed influenza infection of 43·6 (95% CI 39·8–47·7) per 100 person-seasons and an incidence of illness of 24·4 per 100 person-seasons.5Cohen C Kleynhans J Moyes J et al.Asymptomatic transmission and high community burden of seasonal influenza in an urban and a rural community in South Africa, 2017–18 (PHIRST): a population cohort study.Lancet Glob Health. 2021; 9: e863-e874Summary Full Text Full Text PDF Scopus (16) Google Scholar But the rates of infection (67·4 per 100 person-seasons) and illness (49·9 illness episodes per 100 person-seasons) are disproportionately higher in children younger than 5 years. The inclusion of fever and cough—which constitute the WHO case definition for influenza like illness—probably underestimates the true burden of influenza infection by at least five-times (8·5 per 100-person years in those with PCR confirmed influenza and having influenza like illness symptoms vs 43·6 per 100-person years in those with PCR confrimed influenza, irrespective of symptoms).6Fitzner J Qasmieh S Mounts AW et al.Revision of clinical case definitions: influenza-like illness and severe acute respiratory infection.Bull World Health Organ. 2018; 96: 122-128Crossref PubMed Scopus (113) Google Scholar Additionally, influenza illness with at least one symptom was 2·5-times more likely to be medically attended compared with influenza-like illness symptoms (5·8 per 100 person-seasons for influenza illness with at least one symptom vs 2·4 per 100-person years for influenza-like illness). 27 (29%) of 94 individuals with influenza-like illness symptoms sought care and 38 (63%) of 60 individuals with those with influenza-like illness symptoms reported absenteeism from school or work. As many as half of the influenza infections were asymptomatic and reinfections from the same or different influenza subtype within the same season was seen in 70 (15%) 478 of episodes. But the more interesting results are those related to influenza transmission within households. In this cohort, 178 (79%) of 225 households had one or more influenza-positive individuals, with an average of 1·7 (SD 1·3) new introductions and 2·3 (1·3) infected individuals per infected household annually. 10% (95% CI 9–13%) of household contacts of an index case had influenza. The important drivers of influenza infection within a household were children aged younger than 5 years, individuals with two or more symptoms, and those with a shedding duration of 4 days or more. Index cases in children younger than 5 years were more likely to transmit to older children and adults within their household rather than to siblings in their own age group. Asymptomatic individuals transmitted influenza infection to 29 (6%) of 509 household contacts. HIV infection was not associated with increased incidence or transmission of infection. The findings have major programmatic implications for disease surveillance and immunisation programmes. There is a need to revisit the influenza-like illness case definition because this substantially underestimates the true burden of influenza infection.7Andrew MK McElhaney JE McGeer AA et al.Influenza surveillance case definitions miss a substantial proportion of older adults hospitalized with laboratory-confirmed influenza: a report from the Canadian Immunization Research Network (CIRN) Serious Outcomes Surveillance (SOS) Network.Infect Control Hosp Epidemiol. 2020; 41: 499-504Crossref PubMed Scopus (8) Google Scholar The COVID-19 pandemic and surveillance for SARS CoV-2 in the post pandemic world offers an excellent opportunity to modify and expand this case definition to include other respiratory viruses, like respiratory syncytial virus and SARS CoV-2, within the existing influenza surveillance programme.8Broor S Campbell H Hirve S et al.Leveraging the global influenza surveillance and response system for global respiratory syncytial virus surveillance-opportunities and challenges.Influenza Other Respir Viruses. 2020; 14: 622-629Crossref PubMed Scopus (14) Google Scholar Childhood influenza immunisation programmes, such as those in Japan, UK, Canada, and the US can substantially reduce influenza burden not just in young children but also in adults, including those older than 65 years.9Eichner M Schwehm M Eichner L Gerlier L Direct and indirect effects of influenza vaccination.BMC Infect Dis. 2017; 17: 308Crossref PubMed Scopus (36) Google Scholar Immunisation programmes are an excellent way to focus restricted resources in resource-poor settings on a high burden population that is also a key driver of influenza transmission.9Eichner M Schwehm M Eichner L Gerlier L Direct and indirect effects of influenza vaccination.BMC Infect Dis. 2017; 17: 308Crossref PubMed Scopus (36) Google Scholar The rural site for the study is embedded in a health and sociodemographic surveillance system (HDSS) that provides opportunities to track previous exposures and health status, and follow-up participants to understand long-term outcomes with minimal additional investment. Although resource intensive, cohorts similar to those used by Cohen and colleagues5Cohen C Kleynhans J Moyes J et al.Asymptomatic transmission and high community burden of seasonal influenza in an urban and a rural community in South Africa, 2017–18 (PHIRST): a population cohort study.Lancet Glob Health. 2021; 9: e863-e874Summary Full Text Full Text PDF Scopus (16) Google Scholar are important for expanding our understanding of disease epidemiology, immunity to infections, longer term outcomes, contact patterns, and preparing for the next pandemic. When repeated sampling of all individuals irrespective of symptoms twice a week is combined with multiple laboratory confirmed infection endpoints (for multiple viral pathogens), including PCR and serology, the resulting data offer valuable insights into the community burden of infection, drivers of transmission, and provide an opportunity to evaluate the correlation between pathogen detection, immune response, role of co-infections, and interaction between viral pathogens. Coupled with genomic sequencing and extensive mapping of contact patterns inside and outside household, such a cohort offers a unique opportunity to unravel some of the mysteries and improve our understanding of respiratory viruses. I report grants from Innovative Medicines Initiative and National Institute of Health Research; personal fees and grants from WHO and Sanofi; and personal fees from the Bill & Melinda Gates Foundation, Janssen, Abbvie, and Reviral. Asymptomatic transmission and high community burden of seasonal influenza in an urban and a rural community in South Africa, 2017–18 (PHIRST): a population cohort studyApproximately half of influenza infections were symptomatic, with asymptomatic individuals transmitting influenza to 6% of household contacts. This suggests that strategies, such as quarantine and isolation, might be ineffective to control influenza. Vaccination of children, with the aim of reducing influenza transmission might be effective in African settings given the young population and high influenza burden. Full-Text PDF Open Access