The Mother of All Pandemics Is 100 Years Old (and Going Strong)!

Abstract

This year marks the 100th anniversary of the deadliest event in human history. In 1918-1919, pandemic influenza appeared nearly simultaneously around the globe and caused extraordinary mortality (an estimated 50-100 million deaths) associated with unexpected clinical and epidemiological features. The descendants of the 1918 virus remain today; as endemic influenza viruses, they cause significant mortality each year. Although the ability to predict influenza pandemics remains no better than it was a century ago, numerous scientific advances provide an important head start in limiting severe disease and death from both current and future influenza viruses: identification and substantial characterization of the natural history and pathogenesis of the 1918 causative virus itself, as well as hundreds of its viral descendants; development of moderately effective vaccines; improved diagnosis and treatment of influenza-associated pneumonia; and effective prevention and control measures. Remaining challenges include development of vaccines eliciting significantly broader protection (against antigenically different influenza viruses) that can prevent or significantly downregulate viral replication; more complete characterization of natural history and pathogenesis emphasizing the protective role of mucosal immunity; and biomarkers of impending influenza-associated pneumonia.

FIGURE 1—

One of Countless Gravestones and Monuments Remembering Victims of the 1918–1919 Influenza Pandemic Note. Cemetery near the former Lebanon Evangelical Church, 1133 Old Forbes Road, near West Road, Ligonier Township, PA, (gps coordinates 40.234394, -79.177155). The biblical inscription at the bottom refers to Matthew 10:13–16, which discusses Jesus welcoming and blessing little children. Source. Photographed by David M. Morens, September 6, 2018. Printed with permission.

FIGURE 2—

Orphans of the 1918–1919 Influenza Pandemic, Dillingham, AK Source. Photographed in 1919 by Sue Brown French (1896–1980), whose husband Dr. Linus Hiram French (1876–1946) was caring for the orphans. Used by permission of their grandson, Charles Linus Black.

FIGURE 3—

Severe and Mild Pandemics of Presumed Influenza Between 876 and 2018, as a Function of Global Population and Geographic Extent Note. In the era before clipper ships and rapid intercontinental travel (i.e., before the mid-19th century), widespread pandemics were sometimes hemispheric rather than global. Although human crowding and travel are associated with influenza spread and explosivity, the data do not suggest a clear role of human population size in the emergence of pandemics.

FIGURE 4—

Diagram of an Influenza Virus With Its Eight Gene Segments and 11 or More Proteins Note. Pandemics have resulted from (1) direct or intermediate emergences of wild waterfowl viruses, as occurred in the 1918 pandemic (the current pandemic era’s founder virus); (2) from acquisition of gene segments via reassortment of novel hemagglutinin (HA) subtypes with or without reassortment-associated acquisition of other novel genes (so-called antigenic shift); or (3) from complex evolutionary mechanisms such as occurred in the 2009 pandemic. Major HA changes arising in seasonal endemic viruses from intrasubtypic reassortment may also cause pandemics, as happened in 1946, although they are not usually referred to as such. Since 1918, pandemics caused by 1918-descended viruses have occurred in 1957 (referred to as H2N2 viruses after the subtypes of the HA and the neuraminidase [NA] proteins), 1968 (H3N2), and 2009 (H1N1, like its parent 1918 virus). Between pandemics, annual seasonal influenza A viruses are generated by continuous viral genetic mutations (antigenic drift) and by intrasubtypic reassortments. ^aPutative. Source. This figure is modified from Taubenberger and Kash.

FIGURE 5—

Age-Specific 1918–1919 Pandemic Influenza (a) Incidence, (b) Mortality, and (c) Case Fatality: United States Note. P&I = pneumonia and influenza. The bottom figure also compares typical U-shaped age-specific case fatality in 1928–1929 (bottom figure, amber line) with the unique 1918–1919 W-shaped curve of case fatality. A U-shaped curve of age-specific mortality is not shown but is similar in all respects to age-specific case-fatality curves. ^aPer 1000 persons per age group. ^bPer 100 persons ill with pneumonia and influenza per age group.

FIGURE 6—

American Red Cross Nurses During the 1918–1919 Pandemic Note. Trained and volunteer nurses, an important part of the medical and public health response during the pandemic, are credited with saving many lives. Female scientists also stepped into temporary leadership roles when their (male) supervisors entered the military during World War I. Many such progressive women—for example, Rush Medical College’s Ruth Tunnicliff (1876–1946), who worked at the Camp Pike, Little Rock, AR, military training camp, during the 1918 pandemic, and the Rockefeller Institute’s Martha Wollstein (1868–1939)—made important scientific contributions related to influenza. These important advances occurred at the height of the suffragist movement; American women were given state voting rights beginning in 1910 and national voting rights in 1920. Source. Photograph used by permission of the American Red Cross.