Pathogenic Responses among Young Adults during the 1918 Influenza Pandemic

G. Dennis Shanks

and John F. Brundage

Author affiliations: Australian Army Malaria Research Institute, Enoggera, Queensland, Australia (G.D. Shanks); Armed Forces Health Surveillance Center, Silver Spring, Maryland, USA (J.F. Brundage)

Abstract

Of the unexplained characteristics of the 1918–19 influenza pandemic, the extreme mortality rate among young adults (W-shaped mortality curve) is the foremost. Lack of a coherent explanation of this and other epidemiologic and clinical manifestations of the pandemic contributes to uncertainty in preparing for future pandemics. Contemporaneous records suggest that immunopathologic responses were a critical determinant of the high mortality rate among young adults and other high-risk subgroups. Historical records and findings from laboratory animal studies suggest that persons who were exposed to influenza once before 1918 (e.g., A/H3Nx 1890 pandemic strain) were likely to have dysregulated, pathologic cellular immune responses to infections with the A/H1N1 1918 pandemic strain. The immunopathologic effects transiently increased susceptibility to ultimately lethal secondary bacterial pneumonia. The extreme mortality rate associated with the 1918–19 pandemic is unlikely to recur naturally. However, T-cell–mediated immunopathologic effects should be carefully monitored in developing and using universal influenza vaccines.

The influenza pandemic of 1918–19 was the most deadly single event in recorded history. Because of its unique severity and global effects, it is the prototype of a global natural disaster. In recent years, fears of recurrence of an influenza pandemic similar to that in 1918 have motivated planning, preparations, and allocations of resources by public health and other government agencies, nongovernmental organizations, medical care providers, pharmaceutical and medical device manufacturers, medical researchers, private businesses, and persons worldwide (1).
Because of severe consequences and current relevance of the 1918 pandemic, it is essential to review its events and effects, determine their underlying causes, and assess likelihood of a recurrence. These tasks are difficult because the 1918 pandemic occurred at the end of World War I, before influenza viruses were discovered and before influenza vaccines, antiviral and antibacterial drugs, and intensive medical care were available. Fortunately, abundant and detailed written records exist of clinical, laboratory, and epidemiologic events during the pandemic period (2–6). In addition, isolates of the virus that caused the lethal second wave of the pandemic (in the fall of 1918 in most locations) have been reconstructed from preserved remains of patients who died (7). These isolates have been used to determine the genetic relationships between the 1918 pandemic influenza strain and subsequent seasonal and pandemic A/H1N1 strains (8). Genetic relationships between the 1918 pandemic strain and strains that caused the clinically mild first wave of epidemics in 1918 and pandemics before 1918 remain undefined (9–11).
It is commonly believed that the 1918 pandemic resulted from the sudden emergence and worldwide spread of an inherently hypervirulent influenza strain. However, this view is inconsistent with several well-documented characteristics of the pandemic. In this report, we review unique, poorly understood, or unexplained clinical and epidemiologic characteristics of the 1918 pandemic. Also, we present hypotheses that are scientifically credible, consistent with the historical record, and account for epidemiologic and clinical manifestations of the pandemic. Finally, we discuss implications of our hypotheses regarding pandemic influenza preparedness and research and development of universal influenza vaccines (12).