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.”
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 BBC.com 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.
Emergency Physician, Educator, Researcher, interested in the microbiome, evolution, and medicine