Aug 22, 2008 (CIDRAP News) – It was secondary bacterial pneumonia—not the influenza virus by itself—that killed most of the millions who perished in the 1918 flu pandemic, which suggests that current pandemic preparations should include stockpiling of antibiotics and bacterial vaccines, influenza researchers reported this week.
Experts at the National Institute of Allergy and Infectious Diseases (NIAID) examined pieces of lung tissue preserved from 58 victims of the 1918 pandemic and reviewed reports distilled from thousands of autopsies to reach their conclusions, published online by the Journal of Infectious Diseases.
"Histological and bacteriologic evidence suggests that the vast majority of influenza deaths resulted from secondary bacterial pneumonia," says the report by David M. Morens, MD, Jeffery K. Taubenberger, MD, PhD, and NIAID Director Anthony S. Fauci, MD.
Many accounts of the 1918 pandemic have emphasized how quickly patients succumbed to the infection, creating an impression that a large share of the victims died of the virus's direct effects on the lungs or the immune system's intense response to the infection. But the new report suggests that more than 90% actually died of invading bacterial pneumonia after the virus wiped out cells lining the bronchial tubes and lungs.
"In essence, the virus landed the first blow while bacteria delivered the knockout punch," said Fauci in an NIAID news release.
Lung sections and autopsy reviews
The researchers pursued two strategies. First, they examined sections newly cut from blocks of lung tissue preserved from 58 military members who died during the pandemic, representing all known 1918 flu cases in a tissue collection at the Armed Forces Institute of Pathology.
Second, they reviewed 1918-era literature on influenza pathology and bacteriology, gleaning 109 reports providing useful bacteriologic information from 173 series of autopsies. These covered 8,398 autopsies from 15 countries.
Nearly all of the lung tissue examinations yielded "compelling histologic evidence of severe acute bacterial pneumonia, either as the predominant pathology or in conjunction with underlying pathologic features now believed to be associated with influenza virus infection," including damage to the bronchial epithelium, the report says. Bacteria were often present in "massive numbers."
In perusing the contemporary autopsy studies, the authors found 96 reports of lung tissue culture results from 5,266 patients, in which only 4.2% showed no bacterial growth. In 68 "higher quality" autopsy series, representing 3,074 patients, 92.7% of the lung cultures were positive for at least one bacterial species. Cultures of blood samples from another 1,887 victims were positive for bacteria in 70.3% of cases.
At the time of the pandemic, nearly all experts agreed that deaths were almost never caused by the then-unidentified flu virus itself, "but resulted directly from severe secondary pneumonia caused by well-known bacterial 'pneumopathogens' that colonized the upper respiratory tract," the report states. The most common pathogens were pneumococci, streptococci, and staphylococci.
The authors also reviewed evidence from the relatively mild pandemic of 1957-58 and determined that most deaths were due to secondary bacterial pneumonia. In addition, the "few relevant data from the 1968-1969 pandemic" reflect the same pattern, they write.
"We believe that the weight of 90 years of evidence, including the exceptional but largely forgotten work of an earlier generation of pathologists, indicates that the vast majority of pulmonary deaths from pandemic influenza viruses have resulted from poorly understood interactions between the infecting virus and secondary infections due to bacteria that colonize the upper respiratory tract," the report says.
Severity still unexplained
The researchers say their findings leave the extreme severity of the 1918 pandemic unexplained. Because they found evidence of many different types of invading bacteria, it was probably not due to specific virulent bacterial strains. Instead, they speculate that "any influenza virus with an enhanced capacity to spread to and damage bronchial and/or bronchiolar epithelial cells" could pave the way for bacteria in the upper respiratory tract to invade the lungs and cause a severe infection.
The authors suggest that, as in past pandemics, secondary bacterial pneumonia is likely to be the leading killer in the next pandemic—if it is caused by "a human-adapted virus similar to those recognized since 1918." If that's the case, they assert, pandemic preparations must go beyond the development and stockpiling of influenza vaccines and antiviral drugs; efforts should also include the stockpiling of antibiotics and bacterial vaccines to protect against bacterial pneumonia.
However, the investigators also write that if a derivative of the H5N1 avian flu virus causes a future pandemic, lessons from past pandemics may not be "strictly applicable." That virus's pathogenic mechanisms may be atypical because it is poorly adapted to humans and because it causes unusual pathology in animals. On the other hand, they say that if the H5N1 virus fully adapts to humans, the spectrum of resulting disease could revert to something more similar to what was seen in past pandemics.
Study may change thinking
William Schaffner, MD, an influenza expert and chairman of the Department of Preventive Medicine at the Vanderbilt University School of Medicine in Nashville, said the new study may change the general understanding of the causes of death in the 1918 pandemic.
"The general notion at least heretofore is that there were two kinds of deadly illnesses, the first caused by the virus all by itself," Schaffner told CIDRAP News. "We know that the influenza virus can cause primary pneumonia, and the time course was so brief from onset to death in many patients that it was thought this was likely due to an extremely virulent influenza virus—an influenza virus on steroids."
But it has also been assumed that bacterial pneumonia often complicated flu cases then, as it does today, and was fatal for many patients in that pre-antibiotic era, he added. "So the general notion was that there were two causes of death. The general sense was that the former, the virus, was more important than the latter. This comes largely from repeated stories about the rapidity with which this carried people off."
But the findings of Morens and colleagues indicate that secondary bacterial pneumonia was the more common cause of death. "The impressive thing is, though this is a tiny, tiny sample of what went on, they showed bacterial pneumonia was extraordinarily common," Schaffner said. "I think they make the point that it was in every one of the autopsy sections they examined. I have to tell you that made me sit up."
He suggested one possible source of inadvertent bias in the study: Because the evidence is derived from autopsies, the subjects included in the study could represent a skewed sample. The victims most likely to be autopsied were those who died in hospitals, and they probably were less sick initially and had a longer course of illness than those who died at home, Schaffner said. Those who died at home were much less likely to be autopsied.
Nevertheless, the study is an important contribution for showing that bacterial pneumonia was common in the 1918 pandemic, Schaffner added. "I'm still not convinced that that bimodal concept [of the causes of death in 1918] is not true," he said. "These fellows have nailed the second part; I'm just not sure they represent the entire population of deaths."
Schaffner observed that the idea of including bacterial pneumonia in pandemic planning has already been under discussion for a while. "But the fact that Tony Fauci lends his name to these discussions gives them impetus because of his central role in the pandemic planning process in Washington," he said.
He said the federal stockpile of drugs and medical supplies for public health emergencies includes some antibiotics, but they are mainly intended for bioterrorism-related diseases, such as ciprofloxacin for anthrax. But some of the antibiotics might be useful for both bioterrorism-linked diseases and pneumonia, he said.
No vaccines to prevent bacterial pneumonia have been included in the federal stockpile, Schaffner said. However, he noted that between 40% and 50% of people aged 65 and older have been vaccinated against pneumococcal disease, as recommended by federal guidelines.
Morens DM, Taubenberger JK, Fauci AS. Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness. J Infect Dis 2008 Oct;198 (published online Aug 18) [Full text]
Accompanying commentary by Jonathan A. McCullers on the above report