Severe Coronavirus Disease 2019 (COVID-19) is Associated With Elevated Serum Immunoglobulin (Ig) A and Antiphospholipid IgA Antibodies

Abstract

Background Severe coronavirus disease 2019 (COVID-19) frequently entails complications that bear similarities to autoimmune diseases. To date, there is little data on possible IgA-mediated autoimmune responses. Here, we aim to determine whether COVID-19 is associated with a vigorous total IgA response and if IgA antibodies are associated with complications of severe illness. Since thrombotic events are frequent in severe COVID-19 and resemble hypercoagulation of antiphospholipid syndrome (APS), our approach focused on antiphospholipid antibodies (aPL). Methods In this retrospective cohort study clinical data and aPL from 64 patients with COVID-19 were compared from three independent tertiary hospitals (one in Liechtenstein, two in Switzerland). Samples were collected from April 9 th to May 1 st, 2020. Results Clinical records of 64 patients with COVID-19 were reviewed and divided into a cohort with mild illness (mCOVID) (41%), a discovery cohort with severe illness (sdCOVID) (22%) and a confirmation cohort with severe illness (scCOVID) (38%). Total IgA, IgG and aPL were measured with clinical diagnostic kits. Severe illness was significantly associated with increased total IgA (sdCOVID, P=0.01; scCOVID, p-value<0.001), but not total IgG. Among aPL, both cohorts with severe illness significantly correlated with elevated anti-Cardiolipin IgA (sdCOVID and scCOVID, p-value<0.001), anti-Cardiolipin IgM (sdCOVID, P=0.003; scCOVID, P<0.001), and anti-Beta2 Glycoprotein-1 IgA (sdCOVID and scCOVID, P<0.001). Systemic lupus erythematosus was excluded from all patients as a potential confounder. Conclusions Higher total IgA and IgA-aPL were consistently associated with severe illness. These novel data strongly suggest that a vigorous antiviral IgA-response, possibly triggered in the bronchial mucosa, induces systemic autoimmunity.

Characteristic of IgA and IgG antibody response to SARS-CoV-2 infection in an Italian referral Covid-19 Hospital

“…However, we failed to find any difference when blood samples were stratified for time since the onset of symptoms. The same evidence has been highlighted in the studies conducted by Huang and collegues and Hasan Ali and collegues where a higher IgA response was observed in critical and more sever patients [34,35].…”

Autoimmune and Rheumatic Manifestations Associated With COVID-19 in Adults: An Updated Systematic Review

“…As demonstrated in Table 2, the presence of antiphospholipid antibodies (aPL) has been observed in COVID-19 patients around the world (18)(19)(20)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55). The association between aPL and disease severity was shown in three studies (39,54,56), but not in another study (46). Lupus anticoagulant and non-criteria IgA anti-β2glycoprotein-I/anticardiolipin antibodies (57) were the most prevalent aPL, with the prevalence of 3-92, 0-37, and 0-32% in patients with moderate to severe disease ( Figure 2).…”

Why Is COVID-19 More Severe in Patients With Diabetes? The Role of Angiotensin-Converting Enzyme 2, Endothelial Dysfunction and the Immunoinflammatory System

“…The B-cell response is also likely dysregulated, although reports are inconsistent, confounded by methodological issues surrounding the detection of antigen-specific immunoglobulins ( 166 , 167 ) and whether systemic (circulatory) or local (particularly mucosal) responses were assessed ( 168 ). For example, enhanced secretory mucosal IgA responses, detected in the circulation in severe COVID-19, were hypothesised to confer damaging effects via induction of inflammatory cytokines ( 169 – 171 ); although IgA levels in saliva from COVID-19 patients showed only a moderate correlation with COVID-19 severity ( 172 ) and other studies found no difference with disease severity ( 155 ). Circulating IgG levels were higher in patients with severe COVID-19, which has been hypothesised to promote macrophage hyper-inflammatory responses ( 173 ); although the effect of viral load on the secretion of antibodies has not been ruled out.…”