075 - Epidemiological Studies in Influenza

People still hadn't worked out exactly what influenza was or wasn't. Was it a disease caused by a single virus, or a collection of symptoms that could be caused by multiple viruses? Part of that was an arbitrary definition. If just one virus, were there different strains? They also strongly suspected that bacterial secondary infections could play an important role sometimes.

So Thomas Francis attempted to define influenza as well as possible at the time, and give some other information about it.¹ He defined what flu is not (common colds, pneumonia, sore throat, diarrhea) and described a typical case. 

He discussed Shope's studies (049) distinguishing the swine flu virus from Haemophilus influenzae suis bacterial infection, and other animal studies in ferrets and mice (such as 074). Also important research growing flu virus on tissue culture or in eggs.

More importantly, he discussed the issue that some had suggested that people don't form immunity against the flu. It's understandable how people could get that impression, considering how the flu virus mutates enough pretty much yearly to be able to reinfect even people who had it the previous year, so we need a new flu vaccine every year. But the presence of at least some immunity is important; otherwise every flu infection could be as scary as avian flu is supposed to be.

Part of the problem was that the techniques for identifying and distinguishing strains of virus weren't very developed at the time. They could try to infect animal models with samples to isolate virus from them, but if the virus were a type that didn't infect such animals very well, it would give a false negative. This happened to Francis: he observed an epidemic of influenza in California in 1936 with all the usual clinical symptoms, but hardly any patient samples gave infectious virus. As others noted:

"Although it has been suggested by Stuart-Harris et al. that in the presence of an epidemic of respiratory disease a certain symptom complex may serve to differentiate influenza from similar but etiologically different diseases, the California epidemic studied by Francis makes this possibility seem unlikely."²

Later, people realized that this was the first identifiable observation of an outbreak of Influenza B.³ Previous studies apparently had focused mainly on Influenza A.

Lastly, Francis discussed attempts to immunize people against the flu. Mostly it was similar to the results in 074: they saw a rise in antibodies against flu for at least a few months, but didn't actually test if it were protective against infection. Interestingly, some tried inoculation with live virus, subcutaneously, and didn't see any evidence of respiratory infection or serious side effects. Looking at antibodies in people who had just recovered from flu (the way they did this was to inject mice with human serum and see if it protected them against viral infection; another technique with questionable assumptions), they found good antibodies in about 30-60%, and also found strong antibodies in about 30% of people who gave negative histories of flu. So, more work to be done.

References:

1.  Francis, T. Epidemiological Studies in Influenza. Am J Public Health Nations Health 27, 211–225 (1937).

2.  Horsfall, Jr., F. L., Hahn, R. G. & Rickard, E. R. Four Recent Influenza Epidemics: An Experimental Study. J Clin Invest 19, 379–392 (1940).

3.  Burnet, F. M., Stone, J. D. & Anderson, S. G. An Epidemic of Influenza B in Australia. The Lancet 247, 807–811 (1946).