Clinical research networks are key to accurate and timely assessment of pandemic clinical severity
Authors: Lone Simonsen, Elizabeth Higgs, Robert J Taylor
Journal: The Lancet Global Health (2018)

Influenza pandemics range in severity—from catastrophic (eg, 1918) to relatively mild (eg, 2009). For this reason, WHO is working to include clinical severity measures in its pandemic risk index, which is intended to help guide the public health response.1WHOPandemic influenza severity assessment (PISA). World Health Organisation, Geneva2017http://www.who.int/influenza/surveillance_monitoring/pisa/en/Date accessed: April 28, 2018Google Scholar To be most useful, information about clinical severity should be available soon after a new pandemic threat emerges, whether the threat is from influenza or another emerging virus. One measure of severity is the risk of death among cases, variably defined as people presenting for care, people with symptoms, or people infected (with or without symptoms).2Wong JY Kelly H Ip DKM Wu JT Leung GM Cowling BJ Case fatality risk of influenza A (H1N1pdm09): a systematic review.Epidemiology. 2013; 24: 830-841Crossref PubMed Scopus (86) Google Scholar Another measure is the expected demand for health care—hospital space, and availability of respirators and adequate beds in intensive care units. Government officials need timely, accurate estimates of severity to allocate resources effectively and communicate the risk to the public appropriately. As the 2009 experience revealed, rapid assessment of pandemic clinical severity presents a challenge. The first studies in Mexico predicted the H1N1p virus would kill as many as 2% of laboratory-confirmed cases, on par with the 1918 pandemic, whereas another early study suggested that 0·4% of people with influenza-like illness would die, similar to the moderately severe 1957 Asian H2N2 pandemic.3Fraser C Donnelly CA Cauchemez S et al.Pandemic potential of a strain of influenza A (H1N1): early findings.Science. 2009; 324: 1557-1561Crossref PubMed Scopus (1519) Google Scholar The estimated mortality burden fell more heavily on younger people, which was also reminiscent of the 1918 pandemic. Only several months later did studies from the USA and New Zealand establish that the pandemic was likely to be relatively mild, even though young people were still more affected.4Chowell G Bertozzi SM Colchero MA et al.Severe respiratory disease concurrent with the circulation of H1N1 influenza.N Engl J Med. 2009; 361: 674-679Crossref PubMed Scopus (587) Google Scholar, 5Baker M Wilson N Huang Q et al.Pandemic influenza A(H1N1)v in New Zealand: the experience from April to August 2009.Euro Surveill. 2009; 14: 1-6Crossref Scopus (169) Google Scholar The early overestimates were probably the result of selection bias that skewed study enrolment toward sicker patients, and without baseline data from normal influenza seasons the measurement of clinical severity of the novel pandemic virus compared with seasonal influenza was not possible. The result was that early warnings of a pandemic severity on par with that which occurred in 1918 frightened the world unnecessarily. Global clinical research networks in operation before a pandemic virus emerges could be decisive in obtaining accurate early assessments of pandemic severity and clinical care needs. Ongoing multinational cohort studies, operating in both the northern and southern hemispheres, could provide a baseline clinical severity estimate against which to compare the novel emerging disease. Multinational networks with a wide global presence have a good chance of operating in an area affected by the outbreak. Such expert networks could also provide information on natural history, pathophysiology, biomarkers, pathogen tropism, host and viral genetics, optimal clinical care management, and forecasts of hospital and intensive care unit needs. Additionally, ongoing clinical research networks—with preapproved emergency protocols ready to go—could readily test the efficacy of available antivirals and other treatment options in randomised trials set in the areas of earliest outbreak. During the 2009 pandemic, the US National Institutes of Health adapted the HIV clinical research network INSIGHT to study influenza.6Lynfield R Davey R Dwyer DE et al.Outcomes of influenza A(H1N1)pdm09 virus infection: results from two international cohort studies.PLoS One. 2014; 9: e101785Crossref PubMed Scopus (29) Google Scholar After enrolling a patient with known or suspected influenza, network sites collected demographic, medical history, risk factor and other data, archived biological specimens, and followed up to establish case outcome (on day 14 for outpatients, and on days 28 and 60 for inpatients). Influenza testing was done locally and at a central laboratory. Inclusion of all subjects with acute respiratory illness allowed comparison of clinical severity between seasonal and pandemic influenza, as well as other respiratory illnesses. The combination of the conditional risks of disease progression in the inpatient and outpatient settings enabled estimates of case fatality, and hospital resource needs, with fewer patients, allowing an accurate assessment, even when the virus is not highly lethal.7Simonsen L Higgs E Taylor RJ et al.Using clinical research networks to assess severity of an emerging influenza pandemic.Clin Infect Dis. 2018; 67: 341-349Crossref PubMed Scopus (7) Google Scholar Pre-established global clinical research networks can not only provide faster, more accurate clinical severity assessment, but can also allow physicians to learn how to best treat infected patients, and can serve as platforms for clinical testing of new drugs and vaccines. To fulfil this role, they should first be fully integrated into global pandemic preparedness, with standardised First Few 100 protocols,8Health Protection Agency, Health Protection Scotland, Communicable Disease Surveillance Centre Northern Ireland, and National Public Health Service for Wales. The First Few Hundred (FF100) project: epidemiological protocols for comprehensive assessment of early swine influenza cases in the United Kingdom. 2009.Google Scholar, 9UK Department of HealthUK influenza pandemic preparedness strategy 2011.http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/documents/digitalasset/dh_125346.pdfDate: 2011Date accessed: April 28, 2018Google Scholar regular simulation exercises, and clear plans for how to accelerate crucial clinical research when an emergency arises; data from countries with timely national electronic health data could also be folded into such a framework. In May, WHO and the World Bank jointly established the Global Preparedness Monitoring Board to track pandemic preparedness at the country level. The board will examine key indicators of preparedness, such as a country's capacity to conduct clinical research.10World BankWHO and World Bank group join forces to strengthen global health security.http://www.worldbank.org/en/news/press-release/2018/05/24/who-and-world-bank-group-join-forces-to-strengthen-global-health-securityDate accessed: April 28, 2018Google Scholar The goal is to get all hands on deck quickly—a task made easier if the ship has already launched when the crisis begins, and one that will improve the probability of providing an accurate and timely picture of the true clinical severity of an emerging pandemic, and the ability to respond effectively. LS and RJT have ownership in Sage Analytica. EH declares no competing interests. Clinical research networks and assessing pandemic severityWe agree with the challenges identified and solutions suggested by Lone Simonsen and colleagues (September, 2018)1 regarding the importance of established clinical research networks in the rapid collection and dissemination of high-quality data for assessing outbreak severity. This is a timely Comment, considering the 2009 influenza pandemic, regional experiences with Middle East respiratory syndrome coronavirus and plague, and ongoing Ebola outbreaks. We strongly endorse the observations made regarding the nature and magnitude of the problems identified and the proposed solution of using existing networks with established research infrastructure and proven capabilities. Full-Text PDF Open Access