Epidemiology, Pathophysiology and Clinical Presentation of Pandemics Over the Last Three Decades: A Critical Narrative Review of the Evidence Base for Prevention, Control and Management

Abstract

Pandemics and pandemic-scale emergencies of the past three decades have produced an unusually large and heterogeneous body of evidence, yet the epidemiological, mechanistic and clinical literatures have largely developed in parallel and have rarely been appraised together. This review examines that literature critically, taking as its material the human immunodeficiency virus pandemic, the 2003 severe acute respiratory syndrome epidemic, the 2009 influenza A(H1N1) pandemic, Middle East respiratory syndrome, the West African and Congolese Ebola virus disease epidemics, the Zika virus epidemic, the ongoing seventh cholera pandemic, coronavirus disease 2019, the multi-country mpox emergencies, and the panzootic spread of highly pathogenic avian influenza A(H5N1). Literature was identified through searches of three openly accessible bibliographic resources and selected institutional sources, with all bibliographic records verified against registry metadata. The synthesis identifies four persistent problems. First, the operational category of a pandemic remains unstable, which affects the timing of declarations, the comparability of burden estimates and the allocation of resources. Second, the principal epidemiological quantities used to guide policy, including reproduction numbers, case fatality ratios and excess mortality, are estimated by methods whose assumptions are frequently unstated and whose disagreements are substantial enough to alter conclusions. Third, mechanistic accounts of severe disease have converged on a small number of shared processes, in particular innate immune dysregulation, endothelial injury and immunothrombosis, but the inferential basis for these accounts rests heavily on cross-sectional and post-mortem material from severely ill patients in high-income settings. Fourth, evidence on countermeasures is markedly stratified, with randomised evidence for vaccines and several therapeutics but predominantly observational and model-based evidence for non-pharmaceutical interventions. Confidence is strongest for the age gradient of severity, for the efficacy of several vaccine platforms and for the existence of a substantial post-acute symptom burden, and weakest for the comparative effectiveness of individual non-pharmaceutical interventions and for the mechanistic basis of post-acute syndromes. Research priorities that follow from these findings concern standardised burden estimation, prospective mechanistic cohorts recruited across the severity spectrum, and pre-agreed trial infrastructure capable of producing interpretable results during the acute phase of an emergency.