Emily Breidbart

Faculty peer reviewed

As the threat of the swine flu surfaced in early 2009, doctors and the media referenced the influenza of 1918. Also known as the Spanish flu, this pandemic spread to nearly every part of the world and killed more humans than any other disease in a similar period in known history. According to an epidemiological study done in 2002, this unusually virulent strain of influenza A, subtype H1N1, is said to have killed approximately 50 million people worldwide.[1] At least 700,000 of the dead were Americans.[2]

The crowding and migrations of the First World War may have created the Spanish influenza and certainly helped its rapid spread. It is estimated that for every American soldier who died in battle in World War I, 1.02 died of disease.[2] Soldiers and other healthy young adults were hit hardest by the pandemic. According to the Bureau of Census, in the year 1918, while 1076 males died from the flu between ages 85-89 (3.9 per 1000), 39,958 males aged 25-29 died (146.6 per 1000).[2] What made adults in their twenties and thirties, people in the prime of life, so much more susceptible?

Several theories attempting to explain the virulence of this particular strain of influenza were offered during and after the pandemic. In the 1920s, the symbiosis theory suggested that the Spanish influenza was really a disease of two organisms that worked together to create a uniquely deadly disease.[2]Another long-held theory prominent in the 1920s was proposed by Richard Pfeiffer, one of the century’s giants of bacteriology. He believed that influenza was caused by rod-shaped bacteria, which he named Bacillus influenza, now known as Haemophilus influenzae. Studies of post-mortem victims were inconsistent, but this lack of evidence was blamed on the fact that the bacteria were extremely hard to culture. Moreover, the theory was hard to dismiss when there were no other likely agents found. It took until 1931 for this theory to be disproved. Scientists at the Rockefeller Institute found the cause of influenza in swine to be a virus which was later found to be directly descended from the 1918 killer.[1,3]

Another theory held that the virus was in constant mutation during the pandemic, thereby failing to create herd immunity. Other scientists claimed that the pandemic was really pneumonia, since it was the complications of secondary bacterial infection that often led to death.[2]

Still, these hypotheses failed to answer why the virus seemed to dig its sharpest fangs into young adults. At first, this phenomenon was thought to have a simple explanation: older members of society had been around for the 1889-1890 influenza pandemic and had acquired lasting immunity that younger people did not have. But scientists have since discovered that immunity to influenza probably lasts months to a few years, certainly not decades. Moreover, the mortality rate should have been low for everyone over the age of 30, which it was not.[2]

The appearance of victims’ lungs at autopsy gave the first clues to this question. Pathologists saw devastation of the lungs caused by the usual lobar and bronchopneumonias, but they saw something different in the lungs of 20-40 year old victims who died quickly during the pandemic. A pathologist was quoted as saying “[there was] essentially toxic damage to alveolar walls and exudation of blood and fluid. Very little evidence of bacterial action could be found in some of the cases.”[1] Whereas in bacterial pneumonia the infection rages inside the alveoli, in these lungs, the spaces between the alveoli were also filled, brimming with debris of destroyed cells, white blood cells, immune modulators, and blood.[1]

Frank Macfarlane Burnet, who isolated a strain of influenza A in 1935, posited that the 1918 virus was a virulent strain with which few humans had ever had contact. He explained that a child’s immune system is still learning, but is usually able to match the infection with an immune response, eventually fighting off the infection. After about 40 years of age, the ability to produce extreme inflammation declines, making the body more susceptible to infection. In young adulthood, individuals have acquired immunity to common generalized infections and have the vigor to launch an intense localized inflammatory response.

Influenza infection typically spreads by attaching to epithelial cells. Within fifteen minutes of entering through the airways, the hemagglutinin spikes of the influenza virus bind with sialic acid receptors on epithelial cells. About ten hours after influenza invades a cell, the cell bursts open, releasing thousands of viruses. These viruses attack the immune system directly by inhibiting the release of interferon, usually the body’s first weapon in fighting a viral infection. The inflammatory response releases cytokines, which in large amounts can cause shock.[1]

Most influenza viruses are warded off by the immune system before they gain a solid foothold in the lungs, halting the virus in the upper respiratory tract. Scientists believe that what made the influenza of 1918 unique was the virus’s ability to make its way down the respiratory tract to the epithelial cells of the alveoli. Killer T-cells then became active. The capillaries surrounding the alveoli dilated and poured out fluid composed of white blood cells, antibodies, and cytokines. Cytokines and enzymes effaced the capillaries. More fluid poured into the lung. The cells lining the alveoli were damaged, and hyaline membranes formed. Surfactant production ceased. The body produced fibrous connective tissue, entangling the lung in debris, fibrin, and collagen. Burnet himself noted that “continued exudation of fluid in areas where blocking of smaller bronchi had occurred would produce eventually airless regions.” There was no space for oxygen exchange to occur. The body effectively drowned itself, and death quickly ensued.[1]

Burnet’s theory has historical evidence to back it up. The Black Death killed young adults more readily than children, the middle-aged, or the elderly.[2] The rapid, pathologically unique process of death in people in their 20s and 30s may have been what is known today as acute respiratory distress syndrome (ARDS). While ARDS cannot be blamed for all of the deaths of the Spanish flu, it can help explain the rapid deaths of young healthy people. An Army commission conducted autopsies and reviewed pathology reports of young soldiers who died in 1918 and 1919, and found signs of what would today be called ARDS in half of the cases.[1]

Still, most of the deaths from the influenza of 1918 were due to bacterial pneumonia, for which we now have antibiotics. Currently, it is resistance that is the dilemma. In some parts of the United States, 35% or more of pneumococcal infections are resistant to the antibiotic of choice.[1] ARDS has a poor prognosis: despite advances in understanding its physiopathology, mortality rates remain as high as 40-46%.4 Though it is difficult to imagine a disaster on the scale of the 1918 infuenza almost a century later, a pandemic is not improbable. Now, in the face of a possible threat, efforts should be directed at prevention, which may be our best tool.

Emily Breidbart is a 4th year medical student at NYU School of Medicine.

Faculty peer reviewed by Harold Horowitz MD, Professor, NYU Division of Infectious Diseases and Immunology

1. Barry JM. The Great Influenza. New York, NY: Penguin Group; 2004:154-397.

2. Crosby AM. America’s Forgotten Pandemic. New York, NY: Cambridge University Press;1989:203-223, 269-302.

3. Kolata G. Flu: The Story of the Great Influenza Pandemic of 1918 and the Search for the Virus that Caused It. New York, NY: Farrar, Straus, and Giroux; 1999:69-75.

4. de Hemptinne Z, Remmelink M, Brimioulle S, Salmon I, Vincent, JL. ARDS: a clinicopathological confrontation. Chest. 2009;135(4):944-949.