Virus World

Researchers reviewed data on the incidence of autoimmune diseases in the post-acute coronavirus disease 2019 period.

Background

COVID-19 has caused unprecedented morbidity and mortality across the globe. The immune protection conferred by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and prior COVID-19 history, coupled with developing effective therapeutic agents, has reduced COVID-19-associated mortality. However, post-COVID-19 conditions continue to increase, particularly new-onset autoimmune diseases in COVID-19 convalescents. Autoimmune diseases have been reported following COVID-19 among adults; however, the prevalence and magnitude of the diseases, and the incidence risks among individuals infected with SARS-CoV-2, compared to uninfected individuals, are not well-characterized. Improving understanding of the impact of COVID-19 on the risk of developing post-acute COVID-19 complications, such as autoimmune disease, could aid in implementing preventive measures and initiating prompt treatment to prevent COVID-19-associated morbidities. The findings would also be highly relevant for future pandemics and to analyze the long-term protective effects of COVID-19 vaccines.

About the review

In the review, researchers presented findings of two large-scale cohort studies, evaluating the incidence of autoimmune diseases following acute SARS-CoV-2 infections using participants' electronic medical records.

Evidence on post-COVID autoimmune disease obtained before the studies

Studies comprising pediatric COVID-19 patients suffering from multisystem inflammatory syndrome among children (MIS-C) have indicated that COVID-19 results in dysregulated immunological responses. The clinical manifestations of MIS-C overlap with hyperinflammatory syndromes, including macrophage activation syndrome, Kawasaki disease, and toxic shock syndrome. The pathophysiology of COVID-19-associated immunological dysfunction includes molecular mimicry by SARS-CoV-2 proteins, multiorgan involvement due to the presence of angiotensin-converting enzyme 2 (ACE2) receptors, essential for SARS-CoV-2 entry into host cells, bystander immune cell activation, autoantigen release following SARS-CoV-2-induced tissue damage, superantigen-regulated lymphocyte activation, and epitope spread. Additionally, factors such as genetic susceptibility, age, and comorbidities may contribute to COVID-19 pathogenesis. A previous study comparing the immune responses in SARS-CoV-2 infection and autoimmune disease reported that tissue damage in both conditions is mainly immune-regulated, demonstrated by the presence of anti-nuclear antibodies, anti-Ro/SSA antibodies, and lupus anticoagulant cold agglutinins in both conditions. A retrospective analysis was performed from January 31, 2020, to June 30, 2021, using the Clinical Practice Research Datalink Aurum database, comprising data from 458,147 and 1,818,929 SARS-CoV-2-infected and uninfected adults, respectively, residing in England. A study preprint reported that the incidence of inflammatory bowel disease, psoriasis, and type 1 diabetes was significantly related to COVID-19.

Findings of the two cohort studies assessed post-COVID autoimmune disease

Chang et al. utilized the TriNetX health research network, comprising six million adults across 48 health organizations globally. The propensity score-matched SARS-CoV-2-infected and uninfected groups comprised 887,455 COVID-19 vaccinees each. Post-COVID-19 autoimmune disease incidence was evaluated between January 1, 2020, and December 31, 2021. At six months of follow-up, autoimmune disease incidence was significantly greater in SARS-CoV-2-infected individuals, including systemic lupus erythematosus, rheumatoid arthritis, vasculitis, type 1 diabetes, and inflammatory bowel disease, with adjusted hazards ratios (aHR) of 2.99,2.98, 1.96, 2.68, and 1.78, respectively. Post-COVID autoimmune disease risk was consistent across ages. Tesch et al. conducted a study, yet to be peer-reviewed, to evaluate autoimmune disease risks among 640,701 unvaccinated individuals having polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infections in 2020. The findings showed that COVID-19 patients were 43.0% more likely to acquire autoimmune conditions, within three to 15.0 months of infection, compared to over one million age- and sex-matched uninfected individuals. Among autoimmune diseases, the incidence rate ratio (IRR) values were the highest for vasculitis. Further, among those with prior history of autoimmune diseases, COVID-19 resulted in a 23.0% higher risk of another autoimmune disease. Generally, most autoimmune diseases were not COVID-19-specific; however, an essential aspect of SARS-CoV-2 infection was a considerable rise in the incidence and spectrum of autoimmune diseases following acute COVID-19.

Conclusions

Based on the review findings, COVID-19 elevates autoimmune disease risks. Due to the retrospective study designs, the two cohort studies could not provide a causal association between COVID-19 and autoimmune disease development. However, the temporal relationship with COVID-19 history provides reliable and compelling evidence that COVID-19 is associated with elevated autoimmune disease development risks. Health governments and authorities must conduct future studies on the topic to obtain national data and increase the generalizability of the findings. The definitive mechanisms, including genetic and epigenetic predilection, underlying the association and related pathophysiology are not completely understood. However, further research must be performed using particular gene-deficient experimental animals, bioinformatic analysis, and biological approaches, e.g., analyzing transcriptomic pandemic data to obtain genomic signatures, and host responses to viral triggers must be evaluated.

Research cited published (April 12, 2023) In Nature Reviews Rheumatology:

https://www.nature.com/articles/s41584-023-00964-y 

Background: Several cases of unusual thrombotic events and thrombocytopenia have developed after vaccination with the recombinant adenoviral vector encoding the spike protein antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (ChAdOx1 nCov-19, AstraZeneca). More data were needed on the pathogenesis of this unusual clotting disorder.

Methods: We assessed the clinical and laboratory features of 11 patients in Germany and Austria in whom thrombosis or thrombocytopenia had developed after vaccination with ChAdOx1 nCov-19. We used a standard enzyme-linked immunosorbent assay to detect platelet factor 4 (PF4)–heparin antibodies and a modified (PF4-enhanced) platelet-activation test to detect platelet-activating antibodies under various reaction conditions. Included in this testing were samples from patients who had blood samples referred for investigation of vaccine-associated thrombotic events, with 28 testing positive on a screening PF4–heparin immunoassay.

Results: Of the 11 original patients, 9 were women, with a median age of 36 years (range, 22 to 49). Beginning 5 to 16 days after vaccination, the patients presented with one or more thrombotic events, with the exception of 1 patient, who presented with fatal intracranial hemorrhage. Of the patients with one or more thrombotic events, 9 had cerebral venous thrombosis, 3 had splanchnic-vein thrombosis, 3 had pulmonary embolism, and 4 had other thromboses; of these patients, 6 died. Five patients had disseminated intravascular coagulation. None of the patients had received heparin before symptom onset. All 28 patients who tested positive for antibodies against PF4–heparin tested positive on the platelet-activation assay in the presence of PF4 independent of heparin. Platelet activation was inhibited by high levels of heparin, Fc receptor–blocking monoclonal antibody, and immune globulin (10 mg per milliliter). Additional studies with PF4 or PF4–heparin affinity purified antibodies in 2 patients confirmed PF4-dependent platelet activation.

Conclusions: Vaccination with ChAdOx1 nCov-19 can result in the rare development of immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4, which clinically mimics autoimmune heparin-induced thrombocytopenia. (Funded by the German Research Foundation.)

Published in NEJM (April 9, 2021):

https://doi.org/10.1056/NEJMoa2104840

See also in NEJM:

https://doi.org/10.1056/NEJMoa2104882 

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients > 80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals <70 years, 2.3% between 70 and 80 years, and 6.3% >80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over-80s, and total fatal COVID-19 cases.

Published in Science Immunology (Aug.19, 2021):

https://doi.org/10.1126/sciimmunol.abl4340

Evidence is growing that self-attacking ‘autoantibodies’ could be the key to understanding some of the worst cases of SARS-CoV-2 infection.   More than a year after COVID-19 emerged, many mysteries persist about the disease: why do some people get so much sicker than others? Why does lung damage sometimes continue to worsen well after the body seems to have cleared the SARS-CoV-2 virus? And what is behind the extended, multi-organ illness that lasts for months in people with ‘long COVID’? A growing number of studies suggest that some of these questions might be explained by the immune system mistakenly turning against the body — a phenomenon known as autoimmunity. “This is a rapidly evolving area, but all the evidence is converging,” says Aaron Ring, an immunologist at the Yale School of Medicine in New Haven, Connecticut.

Early in the pandemic, researchers suggested that some people have an overactive immune response to COVID infection. Immune-system signalling proteins called cytokines can ramp up to dangerous levels, leading to ‘cytokine storms’ and damage to the body’s own cells. Clinical trials have now shown that some drugs that broadly dampen immune activity seem to reduce death rates in critically ill people, if administered at the right time. But scientists studying COVID are increasingly also highlighting the role of autoantibodies: rogue antibodies that attack either elements of the body’s immune defences or specific proteins in organs such as the heart. In contrast to cytokine storms, which tend to cause systemic, short-duration problems, autoantibodies are thought to result in targeted, longer-term damage, says immunologist Akiko Iwasaki, a colleague of Ring’s at Yale.  Even healthy people make autoantibodies, but not generally in large amounts, and the molecules don’t usually seem to cause damage or attack the immune system. Yet researchers also have evidence that nefarious autoantibodies do have a role in many infectious diseases. There are several theories to explain how autoimmunity might emerge from COVID and other infections. Some people might be predisposed to producing autoantibodies that can then wreak havoc during an infection. Alternatively, infections could even trigger the production of autoantibodies. If researchers can establish the link, they might be able to come up with avenues for treatment, both for the repercussions of COVID and for other diseases caused by viruses.

Finding autoantibodies

In late September, a group led by Jean-Laurent Casanova at the Rockefeller University in New York City reported that more than 10% of 987 individuals with severe COVID-19 had antibodies that attacked and blocked the action of type 1 interferon molecules, which normally help to bolster the immune response against foreign pathogens1. That was a striking proportion, the researchers say, because people’s antibody repertoires are normally very dissimilar, and no one in a control group for the study had these antibodies. The researchers also saw the antibodies in people before their COVID-19 infection, so Casanova thinks that some people could be genetically predisposed to produce them. And the autoantibodies were more common in men than women — a possible factor in why COVID seems to hit men harder. The first evidence suggesting that autoantibodies against interferon might put people at higher risk of infectious disease was published in 1984, and evidence has accumulated since then, Casanova says. But now COVID is drawing more attention to the connection. “Now people understand the problem,” he says, “and all of a sudden they realize that what my lab has been doing for 25 years is actually pretty meaningful.” Casanova is now screening 40,000 people to see how many have pre-existing autoantibodies and determine whether their distribution by age, ancestry and gender matches that of severe COVID. Other research groups have supported Casanova’s autoantibody connection. Iwasaki, Ring and others screened 194 patients and hospital workers with varying severities of COVID for a wide range of autoantibodies. Their study, which was posted online in December and has not yet been peer reviewed, found a higher prevalence of autoantibodies against the immune system in infected individuals than in uninfected people. They found autoantibodies that attacked B cells, as well as some that attacked interferon.....

Published in Nature (Jan. 19, 2021):

https://doi.org/10.1038/d41586-021-00149-1