Autopsy series of 68 cases dying before and during the 1918 influenza pandemic peak

Abstract

The 1918 to 1919 "Spanish" influenza pandemic virus killed up to 50 million people. We report here clinical, pathological, bacteriological, and virological findings in 68 fatal American influenza/pneumonia military patients dying between May and October of 1918, a period that includes ~4 mo before the 1918 pandemic was recognized, and 2 mo (September-October 1918) during which it appeared and peaked. The lung tissues of 37 of these cases were positive for influenza viral antigens or viral RNA, including four from the prepandemic period (May-August). The prepandemic and pandemic peak cases were indistinguishable clinically and pathologically. All 68 cases had histological evidence of bacterial pneumonia, and 94% showed abundant bacteria on Gram stain. Sequence analysis of the viral hemagglutinin receptor-binding domain performed on RNA from 13 cases suggested a trend from a more "avian-like" viral receptor specificity with G222 in prepandemic cases to a more "human-like" specificity associated with D222 in pandemic peak cases. Viral antigen distribution in the respiratory tree, however, was not apparently different between prepandemic and pandemic peak cases, or between infections with viruses bearing different receptor-binding polymorphisms. The 1918 pandemic virus was circulating for at least 4 mo in the United States before it was recognized epidemiologically in September 1918. The causes of the unusually high mortality in the 1918 pandemic were not explained by the pathological and virological parameters examined. These findings have important implications for understanding the origins and evolution of pandemic influenza viruses.

Fig. 1.

Troop strength, monthly admissions for, and deaths from, influenza or pneumonia of nonindicated cause at seven United States military training camps, October 1917 to March 1919. The camps include Camp Dodge, Johnston, IA; Camp Funston, Manhattan, KS; Camp Green, Charlotte, NC; Camp Jackson, Columbia, SC; Camp Lee, Petersburg, VA; Camp Travis, San Antonio, TX; and Camp Upton, Yaphank, NY. Data from Walter Reed Hospital, Washington, DC, were not available. Troop-strength data include all officers and enlisted men. Monthly admission and death data by camp were only available for enlisted men. Separate data for “white” and “colored” enlisted men were combined. (A) Number of United States troops by month. (B) Number of admissions for influenza-like illness per 1,000 troops by month. (C) Number of deaths from influenza or pneumonia per 100,000 troops by month. (D) Date of death of the 68 cases in the 1918 autopsy series included in this study.

Fig. 2.

Representative histopathological changes associated with fatal 1918 influenza and pneumonia cases. Photomicrographs of H&E-stained sections are shown. (A) Section of lung with acute pneumonia, showing a bacterial bronchopneumonic pattern consisting of massive infiltration of neutrophils into the lumen of a bronchiole (Br) and into the airspaces of the surrounding alveoli (pandemic peak case 19181008e). (B) Section of lung with acute bacterial pneumonia as in A, showing massive infiltration of neutrophils in the airspaces of the alveoli (pandemic peak case 19181008g). (C) Section of lung showing DAD with hyaline membranes lining alveoli (arrows). The alveolar airspaces contain edema fluid, strands of fibrin, desquamated epithelial cells, and inflammatory cells (pandemic peak case 19181007). (D) Section of lung showing pulmonary hemorrhage. The alveolar airspaces contain erythrocytes, edema fluid, strands of fibrin, desquamated epithelial cells, and inflammatory cells (pandemic peak case 19180922a). (Scale bars, 100 μm.)

Fig. 3.

Tissue Gram stains of fatal 1918 influenza and pneumonia cases. (A) Gram-positive diplococci morphologically compatible with S. pneumoniae (prepandemic peak case 19180603 with lung culture in 1918 positive for pneumococcus and Staphylococcus). (B) Gram-positive cocci in chains morphologically compatible with S. pyogenes (pandemic peak case 19181008c with no available 1918 lung culture information). (C) Gram-positive diplococci morphologically compatible with S. pneumoniae with prominent capsules (see Inset) (pandemic peak case 19180924d with lung culture in 1918 positive for pneumococcus, type II). (D) Gram-positive cocci morphologically compatible with S. aureus (pandemic peak case 19180921 with lung culture in 1918 positive for S. aureus). Magnification 1,000×; Insets show higher power magnification of boxed areas in A–D.

Fig. 4.

Immunohistochemical analyses of fatal 1918 influenza and pneumonia cases. Photomicrographs of anticytokeratin- and anti-influenza–stained sections are shown. Influenza viral antigen (A–C) or cytokeratins (D) are stained reddish-brown on a hematoxylin-stained background. (A) Acute and necrotizing influenza viral bronchitis with infection of the submucosal mucus glands. Influenza viral antigen is readily apparent in the overlying bronchial epithelium (Inset, Lower Left) and in the acinar cells of the submucosal bronchial glands (Inset, Upper Right) (pandemic peak case 19180930b). (B) Acute influenza viral bronchiolitis with infiltration of neutrophils and other inflammatory cells in the lumen of a bronchiole (Br). Influenza viral antigen is readily apparent in the apical cells of the bronchiolar respiratory epithelium (see Inset), (prepandemic peak case 19180602). (C) Influenza viral antigen staining in alveolar epithelial cells and alveolar macrophages (pandemic peak case 19180930b). (Inset) Prominent alveolar antigen staining in the epithelium lining an alveolus and in alveolar macrophages. (D) Acute influenza viral bronchiolitis with infiltration of neutrophils and other inflammatory cells in the lumen of a bronchiole (Br). Cytokeratin staining is readily apparent in the full thickness of the bronchiolar respiratory epithelium, including basal epithelial cells (Inset). Cytokeratin staining of alveolar epithelial cells is also apparent in the top right of the figure (prepandemic peak case 19180602, serial section of same block as B). Scale bars in A–D, 100 μm; bars in Insets, 50 μm.

Fig. 5.

Immunohistochemical analyses of fatal 1918 influenza and pneumonia cases. Photomicrographs of anticytokeratin- and anti-influenza–stained sections are shown. Cytokeratins (A) or influenza viral antigen (B–F) are stained reddish-brown on a hematoxylin-stained background. (A) Alveolar epithelial cells stained for control cytokeratins AE1& AE3 in case 19181001a. (B) Alveolar macrophages in pandemic peak case 19180924d with both cytoplasmic and prominent nuclear staining. (C) Alveolar epithelial cells stained for influenza viral antigen in case 19180924d, with RBD polymorphism G222 (Table S3). (D) Alveolar epithelial cells stained for influenza viral antigen in pandemic peak case 19180930b, with RBD polymorphism D222 (Table S3). (E) Bronchiolar respiratory epithelial cells stained for influenza viral antigen in prepandemic peak case 19180602 with RBD polymorphism G222 (Table S3) (original magnification 1,000×). (F) Bronchiolar respiratory epithelial cells stained for influenza viral antigen in pandemic peak case 19181001e with RBD polymorphism D222 (Table S3) Original magnification 400× (A and D); 1,000× (B, C, E, and F).