Bacteria and Influenza: The Streptococcus Vaccine Is One Way to Prepare Against the Unknown

There are two excellent papers in the August edition of Emerging Infectious Diseases (open access) about influenza that suggest alternative (or parallel) ways of dealing with an influenza pandemic (note: by "alternative", I don't mean woo). The standard response that is typically discussed is an influenza vaccine--and I've mentioned before how important it is to increase our influenza vaccination surge capacity (not only is it good for dealing with a pandemic, but could serve as a source of vaccine production against the annual epidemic).

There's a problem with this strategy.

We can't be certain what the type of influenza that will lead to an epidemic will be. In other words, we're playing catch-up with a very short clock. After we identify an epidemic strain, it will take at weeks, if not several months, to begin vaccine production. Even if the U.S. were to hoard its vaccine supplies, it would take months to cover a significant fraction of the population.

However, there is something that we do know will happen if there is an epidemic: many, if not most, influenza patients will die, not from the virus itself, but from the secondary bacterial infection--and most of these infections will be caused by Streptococcus pneumoniae for which there is a highly effective vaccine, even against serotypes not included in the vaccine.

So that's the punchline, now to the papers. I'll focus on the Brundage and Shanks paper, which is a historical review of the 1918-1919 pandemic. The authors note:

The findings of sharply different clinical courses and outcomes in subgroups of infected persons of similar ages, sociocultural circumstances, and prior health states belie the importance of host immune intensity and cardiac stroke volume as the definitive determinants of clinical outcomes after infection. Undoubtedly, factors other than the inherent virulence of the virus or the robustness of the host's immune response affected the clinical expressions of influenza infections. In his classic review, E.O. Jordan concluded that "one of the chief reasons for the great variation in case-fatality in different groups is undoubtedly the nature and relative abundance of secondary invaders ... The excessively high mortality in certain army camps, on certain transports and in particular hospitals or barracks seems most readily explicable in this way"

What's interesting (in a kind of horrific way) is the mechanism by which the 1918 strain led to bacterial infection; this is from a review published in 1927 (italics mine):

"(1) The influenza virus weakens the resistant power of the pulmonary tissues so that various bacteria are able to play the role of secondary invaders; (2) the precise nature of the secondary--and tertiary--invaders is largely a matter of accident, dependent on the occurrence of particular bacteria in the respiratory tract of persons at the time of infection, and in the case of group outbreaks, on their occurrence in contacts; (3) the character of the resulting pneumonia, clinical and pathologic, is largely determined by the nature of the secondary invaders, whether Pfeiffer bacillus, streptococcus, pneumococcus, or other organisms; (4) there seems little doubt that the influenza virus, besides depressing the general pulmonary resistance, also acts directly on the pulmonary tissues, causing capillary necrosis, edema, and hemorrhage; (5) it seems to be true, therefore, that the fatal outcome of influenza pneumonia is determined partly by the degree to which the influenza virus depresses local and general pulmonary resistance, and partly by the virulence and nature of the bacteria which invade the tissues in the wake of the specific virus."

In other words, influenza physically damages the lungs (possibly through the "cytokine storm" effect), which makes it much easier for the bacteria that live in and on you to cause disease (think of it as Revenge of the Boogers). The review authors summarize this quite well:

For most patients, infection with the virus was clinically expressed as an "influenza-like illness" that was transiently debilitating but rarely fatal. In addition, however, the virus induced aberrant immune responses, including excessive and prolonged production of interferons, proinflammatory cytokines, and chemokines, particularly among young adults. The pathophysiologic effects included inflammation and destruction of respiratory epithelium; immune cell infiltration of lung tissue with edema and hemorrhage; and ultimately, degradation or destruction of virtually all physical and immune defenses of the lower respiratory tract. Increased susceptibility of the lower respiratory tract enabled invasion by preexisting or newly acquired colonizing strains of bacteria. The synergistic effects of infection with the virus, aberrant immune responses to the virus, and secondary opportunistic bacterial pneumonias were severe and often fatal.

Finally, for brief periods and to varying degrees, affected hosts became "cloud adults" who increased the aerosolization of colonizing strains of bacteria, particularly pneumococci, hemolytic streptococci, H. influenzae, and S. aureus. For several days during local epidemics--particularly in crowded settings such as hospital wards, military camps, troop ships, and mines--some persons were immunologically susceptible to, infected with, or recovering from infections with influenza virus. Persons with active infections were aerosolizing the bacteria that colonized their noses and throats, while others--often, in the same "breathing spaces"--were profoundly susceptible to invasion of and rapid spread through their lungs by their own or others' colonizing bacteria.

I don't mean to downplay the serious of influenza infection by itself--over one percent of the annual non-pandemic influenza cases are fatal, and only one-quarter of those are associated with bacterial infection* (although this is consistent with the virus killing mostly immunologically weakened people, the elderly, and infants). But we can do a lot during a pandemic if a vaccine isn't ready or widely available by vaccinating against S. pneumoniae and other pulmonary pathogens. We also need rapid diagnostics that can identify bacterial infections and which antibiotics will be effective against these infections.

The advantage of these strategies is that we do not have to know what the influenza strain is--stockpiling and preparing these technologies could begin today, if we so choose.

In lieu of an influenza vaccine, these two steps could save many lives. And it wouldn't be a bad idea to have these systems in place all of the time, either....

*These data haven't been published yet, but I've seen compelling evidence that one of the most common bacterial pathogens is routinely missed because clinical labs can't grow it on standard laboratory media. The one-quarter figure should be seen as a lower bound, not a definitive figure.

Cited articles: Brundage JF, Shanks GD. Deaths from bacterial pneumonia during 1918-19 influenza pandemic. Emerg Infect Dis [serial on the Internet]. 2008 Aug [date cited]. Available from http://www.cdc.gov/EID/content/14/8/1193.htm DOI: 10.3201/eid1408.071313

Gupta RK, George R, Nguyen-Van-Tam JS. Bacterial pneumonia and pandemic influenza planning. Emerg Infect Dis [serial on the Internet]. 2008 Aug [date cited]. Available from http://www.cdc.gov/EID/content/14/8/1187.htm DOI: 10.3201/eid1407.070751