In the opening session of the Interdisciplinary Autoimmune Summit 2021, Leonard Calabrese, DO, shared some of the most recent updates in our understanding of COVID-19, particularly within the lens of autoimmunity and immune-mediated inflammatory diseases (IMIDs).
Immunologic lesson number one shared by Dr Calabrese was “learn the choreography” of how viral infections take place. He explained how SARS-CoV and SARS-CoV-2 infect the body at the cellular level, following infection and replication, and oligomerizing the pathogen recognition receptors and activating downstream transcription factors such as interferon (IFN) regulator factors and NF-κB cells. These actions, in turn, activate chemokine and cytokine responses.
It seems, he explained, that an enrichment of rare variants at 13 loci known to govern TLR3- and IRF7-dependent type 1 IFN immunity is critically responsible for producing severe COVID-19 presentation. Further, another observation in the literature found nearly 14% of patients with severe COVID-19 had autoantibodies, vs only 0.3% of patients with mild disease. Notably, IFN autoantibodies are commonly seen in autoimmune diseases such as lupus, dermatomyositis, Sjögren syndrome, and scleroderma, but more prospective study is needed to outline whether there are associations between IFN levels in autoimmunity and severe COVID-19.
COVID-19 can further be looked at in three stages: asymptomatic, nonsevere symptomatic, and severe respiratory inflammatory. In the earlier stages, antivirals (remdesivir), type 1 and type 3 IFNs, immune plasma, and monoclonal antibodies are used for treatment to help bolster the body’s viral defenses. Severe disease, however, requires an immunomodulatory course of action (eg, targeting IL-1, TNF, IL-6, JAKs, Xrt-PD4) to calm the inflammation associated with cytokine release syndrome seen in hospitalized patients.
Dr Calabrese’s second immunologic lesson was “timing is everything,” particularly when it comes to biologic therapy. The greatest example of this, he said, was the discovery of the relationship between glucocorticoids and severe COVID-19. Based on data from two large databases on inflammatory bowel disease (IBD) and rheumatic diseases, use of glucocorticoids appears to be consistently associated with an increased risk of severe COVID-19 and hospitalization. Thus, it was interesting that dexamethasone has been found to reduce deaths by one-third in patients on mechanical ventilation, though Dr Calabrese pointed out that dexamethasone was associated with increased mortality in patients who were not hypoxic or had significant pneumonitis. This particular instance shows that using dexamethasone too early could be dangerous.
IL-6 is perhaps the most attractive targeted therapy based on the data, but it is confusing to see where the therapy sits within use of COVID-19. Recent randomized trial data noted that IL-6 inhibition does not show clear efficacy vs observational studies. A preprint study of the RECOVERY randomized, controlled, open-label platform trial using tocilizumab showed reduced mortality and hospital stays, but conversely, the REMDACTA trial studying the combination therapy of tocilizumab plus remdesivir failed to meet endpoints.
Dr Calabrese to his final immunologic lesson: the relationship between COVID-19 and autoimmune disease.
In patients who do not have IMIDs, COVID-19 can induce autoimmunity and autoimmune responses. However, it’s undefined how SARS-CoV-2 activates these autoimmune pathways.
A number of preprints have shown significant new-onset IgG autoantibodies in hospitalized patients with COVID-19. These autoantibodies are persistent and appear to track with antiviral antibodies. In addition, these autoantibodies do induce immunothrombosis as seen in a murine model. Post-COVID sequaele, or “long COVID,” is another major issue with SARS-CoV-2 infection, with exacerbation of underlying comorbidities (including autoimmune and autoinflammatory diseases) as a possible etiopathogenic mechanism.
A somewhat silver lining, explained Dr Calabrese, is that high-dimensional immune response analysis of COVID-19 has revealed three different immunotypes. It is possible, then, that we are on a pathway to knowing which patients may be the best candidates for certain therapies.
In the post-presentation Q&A, Joseph Merola, MD, MMSc, asked Dr Calabrese if there was anything hot off the presses regarding COVID-19. Dr Calabrese outlined that adenovirus vaccines (ie, those manufactured by Janssen/Johnson & Johnson and AstraZeneca) are under great scrutiny, particularly because of immunothrombosis, especially in patients younger than 55 years.
Similarly, patients with IMIDs do not appear to be more susceptible to immunothrombosis. It seems that those who have experienced this rare adverse effect have not had an IMID background, said Dr Calabrese, and the only linking information so far is that the persons were young and female.
He closed with saying that in his female patients with IMIDs, Dr Calabrese is recommending that they stick to mRNA vaccines out of caution.
Calabrese LH. Advances in understanding of the immunobiology of COVID-19 - implications for autoimmune and autoinflammatory diseases. Presented at: Interdisciplinary Autoimmune Summit; April 15-18, 2021; virtual.