New York Times, October 12, 2009

In 1918 Pandemic, Another Possible Killer: Aspirin

The 1918 flu epidemic was probably the deadliest plague in human history, killing more than 50 million people worldwide. Now it appears that a small number of the deaths may have been caused not by the virus, but by a drug used to treat it: aspirin.
Dr. Karen M. Starko, author of one of the earliest papers connecting aspirin use with Reye’s syndrome, has published an article suggesting that overdoses of the relatively new “wonder drug” could have been deadly.
What raised Dr. Starko’s suspicions is that high doses of aspirin, amounts considered unsafe today, were commonly used to treat the illness, and the symptoms of aspirin overdose may have been difficult to distinguish from those of the flu, especially among those who died soon after they became ill.
Some doubts were raised even at the time. At least one contemporary pathologist working for the Public Health Service thought that the amount of lung damage seen during autopsies in early deaths was too little to attribute to viral pneumonia, and that the large amounts of bloody, watery liquid in the lungs must have had some other cause.
Dr. Starko acknowledged that she did not have autopsy reports or other documents that could prove that aspirin was the problem. “There was a lot of chaos in these places,” she said, “and I’m not sure if there are good records anywhere.”
But of the many factors that might have influenced the outcome in any particular case, Dr. Starko wrote, aspirin overdose stands out for several reasons, including a confluence of historical events.
In February 1917, Bayer lost its American patent on aspirin, opening a lucrative drug market to many manufacturers. Bayer fought back with copious advertising, celebrating the brand’s purity just as the epidemic was reaching its peak.
Aspirin packages were produced containing no warnings about toxicity and few instructions about use. In the fall of 1918, facing a widespread deadly disease with no known cure, the surgeon general and the United States Navy recommended aspirin as a symptomatic treatment, and the military bought large quantities of the drug.
The Journal of the American Medical Association suggested a dose of 1,000 milligrams every three hours, the equivalent of almost 25 standard 325-milligram aspirin tablets in 24 hours. This is about twice the daily dosage generally considered safe today.
Dr. Starko’s paper, published in the Nov. 1 issue of Clinical Infectious Diseases, has stirred some interest, if not enthusiastic endorsement, among other experts.
“I think the paper is creative and asking good questions,” said John M. Barry, author of a book on the 1918 flu titled “The Great Influenza.” “But we don’t know how many people actually took the doses of aspirin discussed in the article.”
The pharmacology of aspirin is complex and was not fully understood until the 1960s, but dosage is crucial. Doubling the dose given at six-hour intervals can cause a 400 percent increase in the amount of the medicine that remains in the body. Even quite low daily doses — six to nine standard aspirin pills a day for several days — can lead to dangerously high blood levels of the drug in some people.
Peter A. Chyka, a professor of pharmacy at the University of Tennessee, said he found Dr. Starko’s theory “intriguing.” Little was known about safe dosages at the time, he said, and doctors often simply raised the amount until they saw signs of toxicity.
“In the context of what we know today about aspirin and aspirinlike products, Starko has made an interesting effort to put this together,” Dr. Chyka said. “There are things other than flu that can complicate a disease like this.”
Although he doubted that more than a small number of deaths could be attributed to aspirin overdose, Dr. David M. Morens, an epidemiologist with the National Institutes of Health, said the paper was valuable in that “it makes an attempt to look at environmental or host factors that may be involved.” He said, “We haven’t been able to explain all the deaths in young adults with the virus itself.”
Dr. Starko was hesitant to estimate how many deaths aspirin overdose could have caused, but suggested that military archives might be one place to look. “I’m hoping others will follow up,” she said, “by examining available treatment records.” By NICHOLAS BAKALAR