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Why do we die of viral infections?

Researchers and opinion leaders cannot seem to make up their minds about what kills us in a variety of serious viral illnesses. Do we die because of too much, or too little, immune activation?

Consider this about Ebola virus from an 2014 NPR feature: “But when you look at the nitty-gritty details of an Ebola infection, a surprising fact surfaces: The virus isn’t what ends up killing you. It’s your own immune system.”

However, a different message shows up in the published literature on Ebola: “it is becoming increasingly evident that an early and robust, but transient, innate immune response and the subsequent activation of adaptive immune response are necessary to protect against fatal infection. If such a host immune response is not generated, the virus evades immune control, and the infection progresses to end-stage disease

Similarly confusing messaging exists for the Sin Nombre hantavirus infection. When I came to New Mexico in the late 1990s, the infection that had captured the attention of our critical care and infectious disease physicians was this Sin Nombre virus, which caused sporadic outbreaks primarily on the Navajo reservation and around the Four Corners region. The Sin Nombre virus is responsible for hantavirus pulmonary syndrome (HPS). I recall taking care of several patients suffering from HPS in the intensive care unit. That was the first time I learned about ECMO – extracorporeal membrane oxygenation. Patients put on ECMO for HPS most often died. I learned that the pathology of the Sin Nombre virus was an over-reactive immune system. Evidence for this came from examining the immune responses of the viruses natural host and reservoir, the deer mouse. The deer mouse does not show evidence of cardiopulmonary damage, or a capillary leak syndrome resulting in pulmonary edema. It was further argued the virus itself did not have a cytopathic effect on infected cells – in other words, the damage from Sin Nombre infection was not the fault of the virus, it was the fault of the immune system. Prescott et al wrote of HPS: “These studies suggest that more robust immune responses are detrimental and that human disease has an immunopathogenic component.”

Too much immune activation for Hantavirus? Easterbrook and Klein cite a “cytokine storm” that is initiated when hantaviruses infect humans and cause severe immunopathology.”

Or is there too little? Hantaviruses interfere with host immune responses and “delay the onset of interferon responses and evading host defense mechanisms that would otherwise inhibit replication

Confusing indeed.

As we have discussed in previous posts, similar cross-messaging exists for COVID-19. So my medical career has been book-ended so far by mysterious and lethal viral illnesses whose pathogenesis is incompletely understood.

Too much: Cytokine storms: When the body attacks itself was a recent feature on about COVID-19 pathology.

Too little: Children survive COVID-19 better because they have a more robust innate immune response to the virus.Children have strong innate immune response due to trained immunity (secondary to live-vaccines and frequent viral infections), leading to probably early control of infection at the site of entry.” argue Dhochak et al. Older people have insufficient early immune responses and therefore unrestrained viral infection.

How do we resolve this paradox? One way is to test immune antagonists in severe viral illnesses. If overactive immunity is the problem, antagonizing those pathways should result in better outcomes.

Evidence in influenza: Anti-inflammatory corticosteroids and anticytokine treatments in severe influenza don’t seem to work. In a 2018 review, Hui and colleagues conclude: “currently there are no immunomodulatory agents that have been conclusively proven to be of benefit in severe influenza.” Corticosteroids were ineffective or be associated with greater risk of superinfection and or mortality in influenza.

Evidence in Ebola virus: Corticosteroids have been associated with persistent infectious complications in survivors of Ebola (although this is based on case reports, the lowest quality of evidence.)

Evidence in original SARS and MERS: The original SARS coronavirus was responsible for about 8000 infections starting in 2003 and about 700 deaths. More recently MERS has killed about 850 patients. An early case series during the 2003 SARS epidemic advocated: “High-dose steroid should be given early to stop the progression of the disease.” This provoked a caution in a letter to NEJM: ‘The use of systemic corticosteroids in patients with the severe acute respiratory syndrome (SARS) is of serious concern.” Based on reports of harm with the use of glucocorticoids in the original SARS and MERS, the WHO did not recommend corticosteroids for coronavirus pulmonary syndromes.

Evidence in COVID-19: The evidence is mixed, with some studies showing increased death with glucocorticoids in COVID-19 and some small studies showing modest benefit.

Other anti-inflammatory and anticytokine treatments exist besides glucocorticoids. One of these, Kevzara, failed in a recent trial. We covered this in a recent post and podcast. Other trials of similar agents are underway in COVID-19. Many of these agents have failed in previous trials involving patients with sepsis.

If, as the NPR and BBC articles describe, excessive immune activation is the cause of lethal Ebola and COVID-19 – not to mention SARS, MERS, Influenza, Ebola, Sin Nombre pulmonary syndrome, as well as dengue hemorrhagic fever, and RSV infection – we should have sufficient evidence by now. Glucocorticoids have been tried repeatedly, without clear evidence of benefit. Anticytokine and anti-inflammatory medications have not worked to date. This should give us pause. Instead, perhaps, immune responses that are too late, too little, or too easily evaded by the virus, are the problem for COVID-19 and for lethal viral infections generally.

Categories: Uncategorized

Joe Alcock

Emergency Physician, Educator, Researcher, interested in the microbiome, evolution, and medicine

2 replies

  1. Dr. Alcock,

    This is one of the most insightful posts you have made as it encompasses the essence of what you have been teaching for a couple of years. You have suggested in the past, that we should be treating the pathogen and not the host; the treatments mentioned in this post that failed, clearly influence the physiology of the host. The state of immunity of the patient will strongly dictate the outcome of this host versus virus battle and unfortunately the physician has little to do with how the patient has taken care of themselves. Nutrient deficiencies, polymorphisms, microbiome/microbiota, stress, age and general living conditions of the patient will have a profound impact on the functioning and [balance of the immune response] when exposed to the virus. The question may be: how do we aid the host in it’s response to the virus? It seems futile to continue treatments that “try to normalize physiology” when the immune response is attempting to change physiology in such a manner [from normal] to hinder the replication and spread of the virus.


  2. This is a question of great interest to me also (as a comparative pathologist); and I’ve heard the same concerns and arguments. In recent years, tolerance (having the host tolerate a low level of infection to avoid excess self-harm) has been advocated, as opposed to resistance (trying to completely eliminate all pathogens regardless of the cost). Sounds good, especially since some chronic infections (HIV, TB, etc. as well as cancer) are extremely difficult to clear without the patients killing themselves first. But I rarely read about the cost of tolerance of constantly having to expend resources to maintain the infection at a low-level state, with the constant threat of recrudescence. Best not to get in that precarious condition in the first place.
    I think it’s a great idea on the use of corticosteroids. I’d suggest that researchers studying animal models of infection should have a corticosteroid-treated group. And everyone should be asking, “What would the infection look like if there were a limited, or even no, immune response?” A) early on in the infection, and B) in a more severe stage of infection. By analogy, one may ask what would happen if their computer got infected with a virus, a virus who’s success depends on replicating and spreading to other computers (but doing nothing else directly harmful). It might spread slowly within the infected computer, but it would be in competition with faster replicating variants that would also benefit from infecting other computers.
    With this perspective, and knowing that viruses need not directly cause cell death, here’s my take, which I think is similar to yours. The infected host’s immune system should assume (based on evolutionary history) that any viral infection (of the type being considered here) has the potential to eventually be lethal. Similarly, an unchecked computer virus programmed only to survive and spread will almost certainly eventually take up more and more memory until the computer essentially becomes non-functional. The owner of an infected computer must assume that the infected computer is eventually doomed even if that particular virus happens to be so slow that the computer is still functional for many more years. The computer owner can’t take that chance. So, it is important to have good antivirus defenses early before things get out of hand and become harder to contain (real or computer virus). A good defense is critical early.
    At a later stage of the infection where the viruses are widespread, more desperate (costly, destructive, and dangerous) measures are needed. One could argue that an infected host (or owner of an infected computer) recognizes that desperate measures are needed, and that the infection (or cancer) will eventually be lethal if untreated. Given that calculation, extreme measures are reasonable, even if they are themselves lethal (since death was going to happen anyway). It may well be that a particular type of virus in a particular type of host was not going to be lethal (hence it would be accurate to say that the immune response was the problem), but it’s asking a lot for an immune system (or computer owner) to correctly make that call. Hence, your test is very important: use corticosteroids to reduce overall immune responsiveness and see what happens. Clearly not a good idea early on, and likely not to be curative in late stages (though it might help in specific instances), though one should expect a temporary improvement, given that most of a patient’s symptoms are host-induced rather than pathogen-induced. [Corticosteroids gave my dog with inoperable cancer a couple of extra weeks of quality life.]
    In the specific case of COVID-19 where clotting is a clinical problem, it would be useful to know if the clotting is an inflammation-associated defense (evolved to inhibit pathogen spreading), if the viruses are actively damaging the endothelium with subsequent clotting, or if the infected endothelium is actively damaging itself (or being damaged by effector immune cells) to inhibit viral replication. Even if the mechanism were known, it might be difficult to develop a practical treatment.
    Great question that biomedicine is awfully late in resolving!

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