The Many Facets of COVID-19: Experts Address Basic & Clinical Research Concepts in the COVID-19 Era

ACR CONVERGENCE 2021—The COVID-19 pandemic has radically altered the landscape of medicine across the U.S. and the world. A great deal of research has been, and is being, conducted to understand the SARS-CoV-2 virus and its implications for all fields of medicine; the rheumatology specialty is no exception. In fact, new concepts in autoimmunity and immunology are being discovered every day, shifting paradigms of how we understand the balance between disease and health. On Nov. 4, experts came together to discuss the implications for rheumatology.

FDA View

Philip Krause, MD, deputy director of the Office of Vaccines Research and Review at the U.S. Food & Drug Administration (FDA), Center for Biologics Evaluation and Research (CBER), Silver Spring, Md., began the session by providing an overview of hot topics related to COVID-19 vaccines and regulation. He noted that the FDA has played a key role in evaluating the safety and efficacy of vaccines against SARS-CoV-2 and, in the process, has had to balance competing goals.

Specifically, the FDA has sought to adhere to a rigorous, evidence-based approach for its scientific review, which can be slow and tedious, while aiming to quickly make vaccines widely available to a public in dire need of protection from the virus. Dr. Krause noted that emergency use authorization (EUA) helps balance these issues. Under EUA, the FDA can permit the use of unapproved medical products, such as vaccines, in times of emergency so long as certain statutory criteria have been met, including that no adequate, approved and available alternatives exist.

Dr. Krause explained that severe side effects related to vaccines have been quite rare and that certain specific adverse events, such as myocarditis or pericarditis, appear to have the highest incidence after the second dose of the mRNA vaccines. Further, data are still unclear regarding the efficacy of providing booster vaccination doses to the general population. Although a booster dose is clearly indicated for immunocompromised patients and those with the highest risk for SARS-CoV-2 infection, what should be done for young, healthy individuals? Should society wait for variant-specific boosters to become available for administration? How well and for how long will booster doses protect against transmission of SARS-CoV-2?

Many questions remain and may take years of research to answer.

Anti-Vaccine Sentiment

The session’s next speaker was Peter Hotez, MD, PhD, dean of the National School of Tropical Medicine, Baylor College of Medicine, Houston. Dr. Hotez discussed, among other things, the three phases of anti-vaccine sentiment that have swept across the U.S. over the past several decades.

The impetus for the first phase was a now-retracted article in The Lancet from 1998 that purportedly demonstrated a correlation between the measles, mumps and rubella (MMR) vaccine and the development of autism.¹ Despite its ultimate retraction 12 years after publication, this article did irreparable damage to trust in vaccination among many Americans and spurred the rapid growth of a sizable anti-vaccine community.

The second phase of this process was the politicization of vaccine policy and explicit links drawn between personal autonomy and civil liberties, as well as the rights of individuals to choose whether they and their children should be vaccinated. Even before the COVID-19 pandemic, spikes in deaths due to measles in the U.S. and abroad were noted by the World Health Organization and others. The current pandemic has only compounded this problem.²

The third and current phase of anti-vaccine sentiment has been the globalization of misinformation about vaccines, with dissemination made possible by widespread internet access and the proliferation of misinformation on social networking sites, such as Facebook.³

Dr. Hotez urged the audience to be vigilant in recognizing misinformation about vaccination against COVID-19 and—in a respectful and compassionate manner—to provide patients with accurate information that will help protect their health.

Rheumatology Patients

Next, Jinoos Yazdany, MD, MPH, Alice Betts Endowed Professor and chief of rheumatology, Zuckerberg San Francisco General Hospital, University of California, San Francisco, discussed COVID-19’s effects on patients with rheumatic conditions. Overall, Dr. Yazdany explained, people with autoimmune diseases have had a similar or slightly increased incidence of initial infection with SARS-CoV-2 compared with the general population. A commonality between patients with autoimmune disease and the general population is that the risk of severe COVID-19 disease grows with increased age and the presence of significant medical co-morbidities, such as diabetes.

Dr. Yazdany described in detail the creation and work of the COVID-19 Global Rheumatology Alliance, a section of the ACR formed in the early days of the pandemic in an international effort to collect data from around the world to statistically evaluate outcomes for patients with rheumatic disease who have developed COVID-19.

In September 2021, Dr. Yazdany and colleagues published a study evaluating associations between the baseline use of biologic or targeted-synthetic disease-modifying anti-rheumatic drugs (DMARDs) and the severity of COVID-19 in more than 2,800 patients with rheumatoid arthritis (RA). The authors found patients treated with rituximab or Janus kinase (JAK) inhibitors had more severe COVID-19 than those on tumor necrosis factor inhibitors (TNFi’s) at baseline.⁴

Using this and other work, Dr. Yazdany noted that rituximab, JAK inhibitors, sulfasalazine, cyclophosphamide, tacrolimus, mycophenolate mofetil and azathioprine appear to be associated with worse outcomes for patients with COVID-19. She also stated that a similar signal is seen with moderate to high doses of glucocorticoids, including doses of 10 mg of prednisone or more per day.

Vaccination against SARS-CoV-2 has helped make inroads for patients, but many fully vaccinated patients on immunosuppressive drug regimens—especially rituximab—remain at risk for severe COVID-19 disease.

Autoimmunity & COVID-19

Next, Steven Holland, MD, director of the Division of Intramural Research and chief of the Immunopathogenesis Section, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Md., addressed attendees. Dr. Holland discussed the fascinating topic of COVID-19-induced autoimmunity.

Although more and more human inborn errors of immunity have been recognized in the medical literature, in recent years, researchers have identified mimics of these diseases due to the presence of anti-cytokine antibodies. Example: Dr. Holland described an adult-onset immunodeficiency with susceptibility to mycobacterial infections due to the presence of anti-interferon-gamma autoantibodies. Similarly, pulmonary alveolar proteinosis and disseminated Nocardia infection can be seen in many patients with autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF).

Dr. Holland said these types of anti-cytokine antibodies can be identified in some patients with autoimmune diseases, such as RA, systemic lupus erythematosus (SLE) and Sjögren’s syndrome, and such autoantibodies have been found to exacerbate or ameliorate relevant gene signatures in SLE and other conditions with respect to type 1 interferon.

In an interesting twist, researchers examined autoantibodies against type 1 interferons in nearly 1,000 patients with life-threatening COVID-19 and found at least 101 of these patients had the autoantibodies. In contrast, the autoantibodies were absent in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were found in only four of 1,227 healthy controls.⁵ In a study from this year, Abers et al. observed that neutralizing type 1 interferon autoantibodies are associated with delayed viral clearance and intensive care unit admission in patients with COVID-19.⁶

Whether or not COVID-19 serves to unmask anti-cytokine autoantibodies is still an area of active research, but Dr. Holland noted that what is clearly true of these autoantibodies is that they can have a significant effect on the function of the adaptive and innate immune systems. They can also play a large role in influencing the severity of COVID-19 infection and deserve increased attention.

On the subject of autoimmunity and COVID-19 infection, Iñaki Ignacio E. Sanz, MD, chief of the Division of Rheumatology and director of the Lowance Center for Human Immunology, Emory University, Atlanta, described how his team’s work on B cell responses in lupus may relate to important pathophysiologic mechanisms in COVID-19. Dr. Sanz and colleagues have previously described extrafollicular B cell responses that contribute to the generation of pathogenic autoreactive antibody-secreting cell (ASC) responses in SLE.⁷

Recently, Woodruff et al. showed that critically ill patients with COVID-19 also demonstrate extrafollicular B cell responses similar to those reported in autoimmune settings and that extrafollicular activation is strongly correlated with class-switched ASC expansions, high concentrations of SARS-CoV-2-neutralizing antibodies and poor clinical outcomes.⁸  

In a separate paper on relaxed peripheral tolerance in patients with COVID-19, Woodruff et al. identified B cell lineages with specificity both to SARS-CoV-2 and to autoantigens, including pathogenic autoantibodies against glomerular basement membrane. They described clinically relevant autoreactivity in these patients that correlated with severity of COVID-19 disease. The authors specifically identified anti-carbamylated protein responses as a common marker of broken peripheral tolerance in severe COVID-19.⁹

MIS-C

Mary Beth Son, MD, section chief of the Rheumatology Program and director of services and outreach at Boston Children’s Hospital, focused on the topic of multi-system inflammatory syndrome in children (MIS-C).

Dr. Son reviewed the case definition for MIS-C published by the U.S. Centers for Disease Control and Prevention (CDC) and reviewed two important stipulations: 1) Patients may fulfill partial or full criteria for Kawasaki disease, but should still be reported as cases of MIS-C if they meet the case definition for this condition; and 2) MIS-C should be considered in any case of pediatric death with evidence of SARS-CoV-2 infection.¹⁰

In reviewing epidemiologic data from across the U.S. and the world, Dr. Son noted that a consistent three- to four-week delay exists between surges of COVID-19 cases and spikes in MIS-C cases, and many children with MIS-C may have had mild or asymptomatic infection. It’s clear that Black and Hispanic children are overrepresented among patients with MIS-C, which may be due, in part, to the higher incidence of severe COVID-19 in these patients, as well as the higher incidence of medical comorbidities, such as obesity, and social risk factors, such as poor access to healthcare.

To distinguish MIS-C from Kawasaki disease and severe acute COVID-19 infection, Dr. Son said gastrointestinal and cardiovascular involvement are common in MIS-C. Also, coronary artery aneurysms are less common in MIS-C than in Kawasaki disease, and severe acute COVID-19 often involves respiratory disease without cardiovascular complications or mucocutaneous involvement.

Regarding treatment of MIS-C, McArdle et al. conducted an international observational cohort study of clinical and outcome data regarding suspected MIS-C cases uploaded by physicians to a web-based database. In examining data from 614 children from 32 countries, the authors found no difference in recovery from MIS-C after primary treatment with intravenous immunoglobulin (IVIG) alone, IVIG plus glucocorticoids or glucocorticoids alone.¹¹

However, Dr. Son and colleagues published a separate article that found initial treatment with IVIG plus glucocorticoids in children and adolescents with MIS-C was associated with a lower risk of new or persistent cardiovascular dysfunction than IVIG alone.¹²

More work clearly remains to discover the best treatment strategies for these patients.

The Cytokine Storm

In a subsequent talk, Puja Mehta, MD, clinical research fellow in respiratory medicine, Rheumatology Specialist Registrar, Centre for Inflammation and Tissue Repair, University College London, U.K., discussed COVID-19 hyperinflammation and cytokine storm syndrome.

The syndrome refers to immune dysregulation with increased circulating cytokine levels, systemic inflammatory symptoms and organ dysfunction disproportionate to the initial trigger. The hyperinflammation seen in cytokine storm syndrome can be caused by primary hemophagocytic lymphohistiocytosis (HLH) or other such entity, genetic abnormalities, secondary HLH as seen in certain rheumatologic diseases, malignancies, infections and immunodeficient states, or cytokine release syndrome due to CAR-T cell therapy and allogeneic stem cell transplantation.

Dr. Mehta’s main question: Is acute severe COVID-19 a cytokine storm syndrome? In an article on this topic in Current Opinion in Rheumatology, Dr. Mehta and David Fajgenbaum, MD, MBA, MSc, FCPP, discuss arguments for and against labeling severe COVID-19 as a cytokine storm syndrome. They note that the beneficial effects of corticosteroids and interleukin (IL) 6 inhibition may suggest that inflammation serves as a modifiable pathogenic component of severe COVID-19. Moreover, they argue that hyperinflammation is a key aspect of severe COVID-19 and that reliable clinical criteria and biomarkers to predict prognosis and response to treatment are needed to help patients.¹³

Building on this topic, Randy Cron, MD, PhD, professor of pediatrics and medicine, University of Alabama at Birmingham, and director, Division of Pediatric Rheumatology and the Pediatric Rheumatology fellowship program, Children’s of Alabama, Birmingham, discussed rheumatologic DMARD and biologic use in the treatment of COVID-19 hyperinflammation. Dr. Cron gave an overview of the myriad clinical studies on this subject and echoed Dr. Mehta in stating that the most severely ill patients with COVID-19 pneumonia suffer a version of cytokine storm with multi-organ failure.

Although not entirely effective in all situations, anti-inflammatory treatments have shown benefits for improving survival of patients with severe COVID-19, including such treatments as glucocorticoids, inhibition of IL-1 and IL-6, inhibition of GM-CSF and JAKi.

Dr. Cron, together with several co-authors, published an article discussing the role of anti-rheumatics in patients with COVID-19. These authors explained that heterogeneity in dosing and absence of uniform inclusion criteria and defined stage of disease in many clinical trials to date have affected conclusions and the ability to compare results between trials. Thus, these issues must be addressed in adequately powered clinical trials to better guide clinicians in the treatment of COVID-19 hyperinflammation.¹⁴

NETs

In the next session, Mariana Kaplan, MD, chief, Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, Md., discussed neutrophil dysregulation and neutrophil extracellular traps (NETs) in COVID-19. NETs, web-like chromatin structures decorated with neutrophil granules’ antimicrobial proteins, have been found to play a role in the protection against certain microbes and the promotion of immune dysregulation, organ damage, vascular injury and thrombosis.

Dr. Kaplan explained that NETs, which have been found to be elevated in patients with COVID-19, contribute to immunothrombosis in the disease and are even present in skin lesions from pediatric patients with the phenomenon known as COVID toe. COVID toe describes chilblains-like lesions seen in the toes of some patients with SARS-CoV-2 infection.

Dr. Kaplan made several key points in her talk: 1) signatures of neutrophil activation are enriched in patients with severe COVID-19 and are associated with poor outcomes; 2) children affected by COVID-19 display aberrant NET formation and degradation; and 3) it remains to be seen if targeting aberrant NET formation or specific neutrophil subsets will modify the natural history of disease or its chronic complications, such as in the form of long COVID-19 or the development of autoimmunity following infection.

The Lungs

Frank van de Veerdonk, MD, PhD, Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Center, The Netherlands, discussed the blockade of the kallikrein-kinin system in COVID-19.

Dr. van de Veerdonk and colleagues made the astute observation in early 2020 that pulmonary edema is a common feature of early COVID-19 disease. They hypothesized that it is due to a localized vascular issue from activation of bradykinin 1 receptor (B1R) and B2R on endothelial cells in the lungs. The SARS-CoV-2 virus enters the lining of the lungs through the ACE2 receptor in a very similar fashion to the related coronavirus that caused the SARS outbreak in the early 2000s. Because ACE2 is needed to inactivate the ligands of B1R, the shortage of available ACE2 receptors created by SARS-CoV-2 infection leads to an abundance of bradykinin and significant, diffuse pulmonary vascular leakage.¹⁵

With this background in mind, Dr. van de Veerdonk discussed clinical trials of lanadelumab, a human monoclonal antibody that targets plasma kallikrein, and icatibant, a selective bradykinin b2 receptor antagonist. Theoretically, both of these medications should disrupt the kallikrein-kinin system and lead to decreased bradykinin products, less pulmonary vascular leakage and, thus, less pulmonary edema. However, in summarizing studies to date, it appears icatibant was much more effective in this regard than lanadelumab.

More work is needed to understand the ways in which the kallikrein-kinin system may be targeted for treatment of COVID-19, particularly early in the course of disease, and how such blockade can be coupled with other immunomodulatory drugs to help patients.

Immune Profiling

For the session’s penultimate talk, Edward Behrens, MD, chief of the Division of Rheumatology at the Children’s Hospital of Philadelphia, spoke on the subject of immune profiling in COVID-19 and SARS-CoV-2 infections. Dr. Behrens highlighted three main articles related to this topic.

In the first article, Kuri-Cervantes et al. comprehensively mapped immune system perturbations in COVID-19 and found the neutrophil to lymphocyte ratio appears to be a prognostic biomarker of disease severity and organ failure.¹⁶

In the second article, Mathews et al. used deep immune profiling in hospitalized COVID-19 patients to identify three immunotypes associated with poor clinical trajectories vs. improving health.¹⁷

In the final article discussed, Wang et al. identified a diverse set of functional autoantibodies associated with varying impacts on immune functionality and different clinical outcomes in patients with COVID-19.¹⁸

Genetic Risks

In the session’s final talk, Helen Su, MD, PhD, chief, Human Immunological Diseases Section, NIAID, NIH, discussed the immunology of COVID-19 genetic risk factors. This talk complemented the presentation by Dr. Holland, particularly with respect to the discussion of genes that participate in type-1 interferon signaling for antiviral immunity. When mutated, these genes can cause monogenic susceptibility to COVID-19 with variable penetrance. Such genes include those that sense viral RNAs to initiate production of type-1 interferon, such as TLR3 and TLR7. Like Dr. Holland, Dr. Su explained that understanding the molecular pathogenesis of COVID-19 helps provide a strong rationale for targeted therapeutic strategies.

From start to finish, the session was remarkable in its breadth and highly impactful in terms of insights into the most important pandemic of this generation.

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Jason Liebowitz, MD, completed his fellowship in rheumatology at Johns Hopkins University, Baltimore, where he also earned his medical degree. He is currently in practice with Skylands Medical Group, N.J.

References

1. Eggertson L. Lancet retracts 12-year-old article linking autism to MMR vaccines. CMAJ. 2010;182(4):E199–E200.
2. Roberts L. Why measles deaths are surging—and coronavirus could make it worse. Nature. 2020 Apr;580(7804):446–447.
3. Yang A, Shin J, Zhou A, et al. The battleground of COVID-19 vaccine misinformation on Facebook: Fact checkers vs. misinformation spreaders. Harvard Kennedy School Misinformation Review. 2021. https://doi.org/10.37016/mr-2020-78.
4. Sparks JA, Wallace ZS, Seet AM, et al. Associations of baseline use of biologic or targeted synthetic DMARDs with COVID-19 severity in rheumatoid arthritis: Results from the COVID-19 Global Rheumatology Alliance physician registry. Ann Rheum Dis. 2021 Sep;80(9):1137–1146. Epub 2021 May 28.
5. Bastard P, Rosen LB, Zhang Q, et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science. 2020 Oct 23;370(6515):eabd4585. Epub 2020 Sep 24.
6. Abers MS, Rosen LB, Delmonte OM, et al. Neutralizing type-I interferon autoantibodies are associated with delayed viral clearance and intensive care unit admission in patients with COVID-19. Immunol Cell Biol. 2021 Oct;99(9):917–921. Epub 2021 Aug 8.
7. Tipton CM, Fucile CF, Darce J, et al. Diversity, cellular origin and autoreactivity of antibody-secreting cell population expansions in acute systemic lupus erythematosus. Nat Immunol. 2015 Jul;16(7):755–765. Epub 2015 May 25.
8. Woodruff MC, Romonell RP, Nguyen DC, et al. Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19. Nat Immunol. 2020 Dec;21(12):1506–1516. Epub 2020 Oct 7.
9. Woodruff MC, Romonell RP, Saini AS, et al. Relaxed peripheral tolerance drives broad de novo autoreactivity in severe COVID-19. medRxiv. 2021 Jul 27;2020.10.21.20216192. Preprint.
10. Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19). U.S. Centers for Disease Control and Prevention. 2020 Mar 27.
11. McArdle AJ, Vito O, Patel H, et al. Treatment of multisystem inflammatory syndrome in children. N Engl J Med. 2021 Jul 1;385(1):11–22. Epub 2021 Jun 16.
12. Son MBF, Murray N, Friedman K, et al. Multisystem inflammatory syndrome in children—initial therapy and outcomes. N Engl J Med. 2021 Jul 1;385(1):23–34. Epub 2021 Jun 16.
13. Mehta P, Fajgenbaum DC. Is severe COVID-19 a cytokine storm syndrome: A hyperinflammatory debate. Curr Opin Rheumatol. 2021 Sep 1;33(5):419–430.
14. Nissen CB, Sciascia S, de Andrade D, et al. The role of antirheumatics in patients with COVID-19. Lancet Rheumatol. 2021 Jun;3(6):e447–e459. Epub 2021 Mar 30.
15. van de Veerdonk FL, Netea MG, van Deuren M, et al. Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome. Elife. 2020 Apr 17;9:e57555.
16. Kuri-Cervantes L, Pampena MB, Meng W, et al. Comprehensive mapping of immune perturbations associated with severe COVID-19. Sci Immunol. 2020 Jul 15;5(49):eabd7114.
17. Mathew D, Giles JR, Baxter AE, et al. Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications. Science. 2020 Sep 4;369(6508):eabc8511. Epub 2020 Jul 15.
18. Wang EY, Mao T, Klein J, et al. Diverse functional autoantibodies in patients with COVID-19. medRxiv. 2021 Feb 1:2020.12.10.20247205. Preprint.