In this episode, I will touch upon the hypotheses and evidence on pathogenesis of serious COVID.
For the references see
Par 1 Reminder on the “case definitions”.
As can be seen below, the “classical” severe and critical COVID usually occurs in the context of a pneumonia, which aggravates to Acute Respiratory Distress Syndrome (ARDS), but it can be associated with systemic complications. There are signs in the lab parameters of hyperinflammation and inappropriate activation of the coagulation system, which can have implications on several organs (heart, liver, kidney and central nervous system). (See slides 2-5 and Ref Covid 104-1,2,3)).
This “classical” (and unfortunately common) syndrome is typically associated with advanced age and/or so-called co-morbidities, such as obesity, diabetes, hypertension, cancer, immune suppression, pre-existing respiratory syndromes (TB, COPD). In principle RT-PCR for SARS-CoV-2 on respiratory samples will be positive in the period preceding this syndrome .
Besides, there is the rare multisystem inflammatory syndrome(s), which was first described in children (slide 6-9) and later also in young adults (slide 10). The difference with the “commonl” severe COVID is that it occurs in young people and that it presents as a systemic disease first with fever, signs of inflammation and multi-organ abnormalities, including gastro-intestinal symptoms abd cordial complications, even tendency to shock but often less prominent respiratory symptoms.
SARS-CoV-2 RT-PCR is not always positive, but there is a recent history of COVID symptoms and/or positive serology (antibodies). Slide 9 shows some similarities, but also a lot of differences with other hyper-inflammatory syndromes in children. (Ref Covid 104-4,5,6)
Although these are distinct clinical syndromes, there is a clear overlap with regard to inflammation, coagulopathy and systemic (especially cardiac and vascular) involvement. Therefore, one can presume partly similar pathogenic mechanisms in a different immunological environment (young versus old/senescent).
Case definition of severe COVID (Mc Arthur Review of Clinical definitions Am J Trop Med Hyg July 2020)
- Symptoms of significant respiratory distress which in adults are:
- Tachypnea > 30 breaths per minute,
- Oxygen saturation > 93%, PaO2/FiO2 ratio < 300 mmHg,
- Lung infiltrates> 50% within 24–48 hours,
- Or clinical assessment of severe distress.
- Most patients will develop a fever and cough
- Other common symptoms:
- Dyspnea, sore throat
- Myalgia and fatigue
- Possible extrapulmonary complication:
- Cardiovascular and hyper-coagulopathy:
- Cardiomyopathy and arrythmias
- Thromboembolisms with pulmonary embolism, stroke, myocardial infarction, and systemic arterial embolism
- End-organ dysfunction: liver and kidney
- Central nervous system:
- Dizziness (18.8%), headache (13.1%), impaired consciousness (7.5%), acute cerebrovascular disease (2.8%), seizure (0.5%), and ataxia (0.5%).
- Stroke, encephalitis, acute transverse myelitis, perfusion abnormalities on CT, and Guillain–Barre syndrome
Critical COVID: Respiratory failure requiring mechanical ventilation, and septic shock or organ
dysfunction necessitating intensive care.
Laboratory: see slide 3-4
- SARS-CoV-2 RT-PCR positive and/or IgM antibodies
- Lymphopenia and neutrophilia
- Coagulopathy: increased D-mers and protrombine time
- Inflammatory markers: CRP
Case definition by of Multisystem inflammatory syndrome in children MIS-C (CDC on May 14, 2020).
(Previously referred to as PIMS-TS Paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2)
- An individual aged <21 years presenting with fever, laboratory evidence of inflammation, and evidence of clinically severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological); AND
- No alternative plausible diagnoses ;AND
- Positive for current or recent SARS-CoV-2 infection by RT-PCR, Antigen test, serology, or antigen test; or Covid-19 exposure within the 4 weeks before the onset of symptoms.
Fever >38.0°C for ≥24 hours, or report of subjective fever lasting ≥24 hours.
Inflammatory markers: one or more of the following: an elevated Creactive protein (CRP), erythrocyte sedimentation rate (ESR), fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase (LDH), or interleukin 6 (IL-6), elevated neutrophils, reduced lymphocytes and low albumin
MIS-A: Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection (MMWR Oct 2020): = very similar to MIS-children
Clinical: Fever > 38 °C
Cardiac symptoms and ECG abnormalities
Pulmonary ground glass opacities
Dermatological abnormalities (mucositis)
Lab abnormalities: Increased ferritin, CRP
SARS-CoV-2: just like in children: some are PCR(+) at admission, other are PCR(-° but have a history of SARS-CoV-2 infection and/or positive serology.
Par 2 Possible pathogenic mechanisms
- Harrison and Brodin (Ref Covid 104-1 and 7) provide a “state of the art” interpretation of the ARDS and systemic complications of “classical severe COVID”: infection of airway epithelial cells, alveolar macrophages, endothelial cells induces an activation of both the interferon and inflammatory cytokines, with recruitment of neutrophils and macrophages, resulting in further escalation of inflammation via the NLRP3 (NOD-Like Receptor Protein3) “inflammasome” activation. This leads to lung edema and also activation of the coagulation system. Mainly the lung and the cardiovascular system will suffer long term consequences. See slides 12-15 and Ref 104-8,9
- The pathogenic schemes proposed by Felsenstein and Malviya for multisystem Inflammatory System (in childhood and adults) bears a lot of resemblance with the scheme for classical COVID in older subjects. These authors propose an additional mechanism for MIS-C, based on “immune complexes”. These syndromes occur late, at a time that SARS-CoV-2 antibodies are present and could create pro-inflammatory antigen-antibody complexes. I could not find any evidence for this mechanism, however. See slides 17-18 and Ref 104-4 and 10)
- Dysfunction of type 1 IFN:
- As summarized in slide 18, Coronaviruses have developed multiple strategies to inhibit/ delay the antiviral type 1 Interferon response (Ref 104-1)
- According to Rowley (slide 19; Ref 104-11), a delayed IFN response could result in an imbalance with overproduction of pro-inflammatory cytokines in the context of MIS-C.
- This mechanism has been shown in “classical severe COVID” (slide 20; Ref 104-12)).
- The impaired type 1 IFN response could in fact be due to genetic errors in the IFN pathways or the presence of auto-antibodies against IFN (slides 21-22; Ref 104-13).
- Superantigenic T cell activation (Ref 104-14, 15, 16)
- The suspicion that SARS-CoV-2 acts like a “super-antigen”, similar to Staphylococcus Enterotoxin-B (SEB), comes from the strong resemblance between the SARS-CoV-2 MISC and bacterial toxic shock syndrome (slide 23). Superantigens activate various T cell clones, with a particular variable beta chain in an uncontrolled way, hence could induce a “cytokine storm”.
- In the next slides 24-28, the evidence on the “super-antigenic nature” of at least two parts of the SARS-CoV-2 spike is provided from by Cheng et al in PNAS
- There is a unique basic sequence PRRR next to the S1-S2 cleavage site, which is highly homologous to SEB indeed
- There are also two different sites that are neurotoxin-like
- In addition there is binding site for the costimulatory CD28 receptor on T cell and a site that resembles ICAM-1 and therefore could provide additional co-stimulation via LFA-1
Clearly, together these sites could provide a “super-stimulus” to T cell clones with particular beta chains in their T cell receptor.
- Analysis of the TCR repertoire in adult COVID-19 patients demonstrates that those with severe hyperinflammatory disease exhibit TCR skewing consistent with superantigen activation (slide 29).
- Finally, in vitro, an monoclonal antibody against the SEB superantigen inhibits SARS-CoV-2 cell entry (slide 30).
We start to have some clues to understand why some people develop serious hyperinflammatory and systemic complications:
- There may be a viral factor: a higher the viral load and variants that have intrinsically higher capacity to interfere with the antiviral defense (primarily type 1 and type 3 IFN) or to express superantigens.
- There are human genetic factors: until now two types have been identified:
- Inborn errors in the interferon pathway
- Particular TCR V-beta chains (which are genetically encoded)
But, most probably also other primary immune deficiencies can have a similar effect.
- Acquired conditions:
- Development of antibodies against type 1 IFN
- Cancers and other acquired immune deficiencies
- Immune senescence:
- High age: inflam-aging, T cell exhaustion etc..,
- Other pro-inflammatory conditions such as diabetes, obesity etc…
One of the unanswered questions is if/how the superantigenic sites could influence vaccine (side) effects in people with particular TCR Vbeta?
Obviously, we will learn more in the coming months.
I have a rather full agenda for next week. So it could take until next weekend for the next episode….
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