Determinants of the Symptoms and Severity of COVID-19: Russian Roulette?

The first assumptions about COVID were that it would be most severe in the elderly because of compromised immune systems and kill those with underlying chronic conditions, or secondary bacterial infections, mirroring the flu. Another was that either it didn’t infect children or at least those under 9 years of age. Then as infected numbers increased some with no underlying conditions and in their 40’s or less began to get severe disease and even die and children, even less than 9, developed Kawasaki-like syndrome, multi organ inflammation. The illusion and bias of the flu comparison began to evaporate. The question is are these outcomes connected by mechanism and logical progression or are they happenstance or a little of both? The alternate immune pathways and their various combined and graded responses (even independently among their components) and interactions with target tissues make for the great variety of symptoms, severity, and level of viral shedding. The data is growing fast and furious outpacing the interpretation and forming of the big picture. However, I will attempt to summarize and at least give a preliminary interpretation with the proviso that it is subject to modification as new data arises. One of the latest indications that the severity is not uniquely tied to immunosuppression but an inappropriate or misdirected immune response is that in some patients IgG arises prior to IgM. It is usually the other way around for the appearance of these two types of antibody. This could result from cross response of antibody memory cells (B cells) against another CoV or T cell independent B cell direct sole response (T cells can help B cells make antibody, CD4 T cells, or be responsible directly for killing virus infected cells specifically, CD8 T cells). Some patients had little or no antibody response, some who were severely ill had strong IgG antibody responses and little T cell response. Some had weak antibody responses and strong T cell responses of various kinds. Some patients made IgE antibody associated with allergic reactions, even anaphylaxis, the most acute and severe reaction. Various levels of cytokines, pro- inflammatory and anti- inflammatory were observed, connected to severity. Gamma Interferon, which blocks viral replication and stimulates non-specific reactive oxygen and nitrogen species production by white blood cells, had a positive effect on patients but others like TNF alpha, interleukins 1 and 6 had a negative effect. Other interferons (alpha and beta) could have either positive or negative effects, depending on their pro- or anti-inflammatory effects. Treatment with IFN-α2b significantly reduced the duration of detectable virus in the upper respiratory tract and in parallel reduced duration of elevated blood levels for the inflammatory markers IL-6 and C reactive protein (CRP) in one study. CRP is a bio marker for heart disease and may be linked to the exacerbation of heart disease in COVID-19. However, the virus can cap its RNA with methyl groups which helps it prevent detection, inhibition of translation into protein, and destruction associated with interferon effects. In children, interleukin 10, an anti- inflammatory, also had a positive effect, as did broad anti-inflammatory drugs like steroids in adults. Children infected but without symptoms have been shown to carry as much or more virus than infected adults. This could indicate that a robust immune response is not always an effective one. In another study 40% of asymptomatic individuals became seronegative and 12.9% of the symptomatic group became negative for IgG in the early convalescent phase following recovery. In addition, asymptomatic individuals exhibited lower levels of 18 pro- and anti-inflammatory cytokines. These data suggest that asymptomatic individuals had a weaker immune response to SARS-CoV-2 infection. They also shed virus longer up to 19 days. Certain subtypes of IgG antibody were associated with more severe responses while others neutralized virus. Studies suggest there are three types of responders: Immunotype 1, comprised of robust CD4 T cell activation, exhausted CD8 T cells and other reduced peripheral blood T cells, linked with more severe disease whereas Immunotype 2, characterized by more effector CD8 T cells, less CD4 T cell activation and proliferating peripheral blood and memory B cells had less severe disease. Immunotype 3, in which minimal lymphocyte activation response was observed, represents ~20% of COVID-19 patientsh and is important to consider as patients who have failed to mount a robust antiviral T and B cell response. Pathology from an immune response too weak resulted in virus-induced pathology, or an immune response that is too strong led to immunopathology. The data suggest that the immune response of hospitalized COVID-19 patients may fall across a spectrum of immune responses, with distinct immunotypes linked to clinical features, disease severity, and temporal changes in response and pathogenesis. Therefore, the immune response has 3 categories: (1) antiviral (some macrophages and dendritic cells, natural killer cells, cytotoxic T cells, helper and suppressor T cells, antibody making B cells and plasma cells, and gamma interferon; other interferons made by tissue cells: alpha and beta); (2) anti-parasitic granulocyte white blood cells (some special B cells that make IgE, eosinophils, basophils (in tissue mast cells), and all kinds of biochemical mediators: histamine, Prostaglandins, leukotrienes, and kinins); and (3) anti- bacterial and fungal (granulocyte: neutrophils, and monocytes and macrophages). COVID-19 can move through all three types. The worst is type 2 which was meant for worms and other multicellular localized parasites and can be locally severe and if generalized, fatal. The first type can yield TNF (tumor necrosis factor) and gamma interferon which can crank up type 2 and antibody linked to infectious agents which can target 3 and cranks up its non-specific killing. Type 2 is also responsible for allergic reactions up to the most severe acute sometimes fatal anaphylaxis. In my graduate (The Cytotoxic Activity of Peroxidases, 1981) and early USAF research (Type B Cytochromes: Sensors and Switches, CRC Press, 1995), I studied the nonspecific (now called innate) immunity in Types 2 and 3 mediated by oxidative burst and nitric oxide (nitrite) production. These when properly directed kill viruses, bacteria and parasites. When improperly directed they cause acute respiratory distress syndrome (ARDS), shock and death as in COVID and intense swelling, hives, edema, nausea, diarrhea, shock and death in allergic reactions. The other immune types are linked to this type and each other. For example, oxidizing CRP makes it enhance clotting like seen in COVID and leukotrienes enhance oxidative burst of granulocytes and gamma interferon enhances oxidative burst and nitric oxide production but favors the later which is more antimicrobial without whole sale damage to tissue like the oxidative burst (superoxide and peroxide). COVID inhibits gamma interferon production but enhances TNF oxidative burst effects. All this nonspecific damage,”burning down the house to get rid of the rats”, leads to chronic lung and other tissue damage which remains in severe COVID patients who have recovered in spite of and to some extent because of Type 3 macrophage cleanup of the damage and subsequent fibrosis. If this all seems too much then I have succeeded in illustrating treating COVID-19 and its outcome is very complex. In the next post, I will distill this down to a progression with various resolution points.