In severe cases of COVID-19, Emory researchers have been observing an exuberant activation of immune cells, resembling acute flares of systemic lupus erythematosus (SLE), an autoimmune disease.
Their findings point towards tests that could separate some COVID-19 patients who need immune-calming therapies from others who may not.
They also may begin to explain why some people infected with SARS-CoV-2 produce abundant antibodies against the virus, yet experience poor outcomes.
The results were published online on Oct. 7 in Nature Immunology.
The Emory team’s results converge with recent findings by other investigators, who found that high inflammation in COVID-19 may disrupt the formation of germinal centers, structures in lymph nodes where antibody-producing cells are trained.
The Emory group observed that B cell activation is moving ahead along an “extrafollicular” pathway outside germinal centers—looking similar to they had observed in SLE.
B cells represent a library of blueprints for antibodies, which the immune system can tap to fight infection.
In severe COVID-19, the immune system is, in effect, pulling library books off the shelves and throwing them into a disorganized heap.
Before the COVID-19 pandemic, co-senior author Ignacio (Iñaki) Sanz, MD and his lab were focused on studying SLE and how the disease perturbs the development of B cells.
Sanz is head of the division of rheumatology in the Department of Medicine, director of the Lowance Center for Human Immunology, and a Georgia Research Alliance Eminent Scholar. Co-senior author Frances Eun-Hyung Lee, MD is associate professor of medicine and director of Emory’s Asthma/Allergy Immunology program.
“We came in pretty unbiased,” Sanz says. “It wasn’t until the third or fourth ICU patient whose cells we analyzed, that we realized that we were seeing patterns highly reminiscent of acute flares in SLE.”
In people with SLE, B cells are abnormally activated and avoid the checks and balances that usually constrain them. That often leads to production of “autoantibodies” that react against cells in the body, causing symptoms such as fatigue, joint pain, skin rashes and kidney problems. Flares are times when the symptoms are worse.
Whether severe COVID-19 leads to autoantibody production with clinical consequences is currently under investigation by the Emory team.
Sanz notes that other investigators have observed autoantibodies in the acute phase of the disease, and it will be important to understand whether long-term autoimmune responses may be related to the fatigue, joint pain and other symptoms experienced by some survivors.
“It’s an important question that we need to address through careful long-term follow-up,” he says. “Not all severe infections do this. Sepsis doesn’t look like this.”
In lupus, extrafollicular B cell responses are characteristic of African-American patients with severe disease, he adds. In the new study, the majority of patients with severe infection were African-American.
It will be important to understand how underlying conditions and health-related disparities drive the intensity and quality of B cell responses in both autoimmune diseases and COVID-19, Sanz says.
The study compared 10 critically ill COVID-19 patients (4 of whom died) admitted to intensive care units at Emory hospitals to 7 people with COVID-19 who were treated as outpatients and 37 healthy controls.
People in the critically ill group tended to have higher levels of antibody-secreting cells early on their infection. In addition, the B cells and the antibodies they made displayed characteristics suggesting that the cells were being activated in an extrafollicular pathway.
In particular, the cells underwent fewer mutations in their antibody genes than seen in a focused immune response, which is typically honed within germinal centers.
The Nature Immunology paper was the result of a collaboration across Emory. The co-first authors are Matthew Woodruff, Ph.D., an instructor in Sanz’s lab, and Richard Ramonell, MD, a fellow in pulmonary and critical care medicine at Emory University Hospital.
Ramonell notes that the patients studied were treated early during the COVID-19 pandemic. It was before the widespread introduction of the anti-inflammatory corticosteroid dexamethasone, which has been shown to reduce mortality.
The team’s findings could inform the debate about which COVID-19 patients should be given immunomodulatory treatments, such as dexamethasone or anti-IL-6 drugs. Patients with a greater expansion of B cells undergoing extrafollicular activation also had higher levels of inflammatory cytokines, such as IL-6.
Some COVID-19 patients have been given drugs that push back against IL-6, but results have been mixed in clinical trials. Patients with markers of unregulated immune responses may be appropriate candidates for treatment with anti-inflammatory drugs that target the corresponding pathways, Sanz suggests.
The COVID-19 pandemic has presented several challenges due to insufficient evidence to guide clinical practice. Many patients with severe, refractory rheumatic disease (including vasculitis, systemic lupus erythematosus (SLE), and rheumatoid arthritis) depend on B-cell depletion with anti-CD20 monoclonal antibodies, such as rituximab.
In the current crisis, some clinicians and patients have elected to delay maintenance rituximab therapy because of perceived safety concerns. Pausing rituximab therapy carries a risk of destabilising disease control and might increase the requirement for corticosteroids, which could ironically worsen outcomes in patients with COVID-19.
Initial results from the European League Against Rheumatism COVID-19 registry suggest poor outcomes in patients receiving 10 mg or more prednisolone (n=64), but not in the small numbers of patients (n=37) treated with rituximab.1
However, clinical decision making is further complicated by other observations, such as a severe COVID-19 phenotype being reported in a single patient treated with rituximab for antineutrophil cytoplasmic antibody-associated vasculitis.2
In this Correspondence, we discuss the position of B-cell-mediated adaptive immunity and rituximab therapy in the current pandemic, with regard to both potential safety concerns and, conversely, the potential for rituximab to treat specific COVID-19 complications.
The safety of rituximab in the context of COVID-19 is unclear.
B-cell depletion could compromise antiviral immunity, including development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies, increase the risk of reinfection, and impair vaccine efficacy (once a vaccine becomes available).
The potential risks of hypogammaglobulinaemia secondary to rituximab also need consideration, and the results of clinical trials evaluating convalescent serum are awaited. If trials of convalescent serum show benefit, this could be a potential therapeutic option for patients with immunodeficiency (hypogammaglobulinaemia) secondary to rituximab who develop severe COVID-19.
COVID-19-associated thromboses, severe lung pathology, and hyperinflammation contribute to poor outcomes. These manifestations bear some similarities to those observed in rheumatic diseases, such as antiphospholipid syndrome,3 rheumatic-associated lung disease,4 and macrophage activation syndrome5 secondary to SLE, for which B-cell depletion with rituximab has been shown to be effective.
Antiphospholipid antibodies have also been reported in COVID-19 patients with thromboses, although it is unclear whether these antibodies are pathogenic in this context,3 and lung CT features in some patients with COVID-19 resemble those of fibrotic organising pneumonia (eg, similar to anti-MDA5 anti-synthetase syndrome).4
It is plausible that anti-SARS-Cov-2 antibodies or immune complexes might potentially evoke monocyte or alveolar macrophage activation, thereby contributing to sustained secretion of proinflammatory cytokines and the development of pulmonary disease.
Therefore, could adaptive immunity contribute to poor outcomes in COVID-19, signalling a role for rituximab?
Immunomodulation might improve outcomes in patients with COVID-19-associated hyperinflammation.5
Although rituximab appears to be effective in treatment of hyperinflammation or haemophagocytic lymphohistiocytosis triggered by Epstein-Barr virus, SARS-CoV-2 (unlike Epstein-Barr virus) is not known to reside in B cells.
Therefore, acute B-cell depletion would not be appropriate for COVID-19-associated hyperinflammation. However, rituximab might be useful in specific scenarios in patients with COVID-19 to target chronic adaptive host immune responses. For example, when thrombotic or inflammatory lung complications persist beyond acute infection, and when viral loads are negative or low and anti-SARS-CoV-2 antibodies are positive.
In the context of COVID-19, we call for dedicated research regarding B-cell depletion to better understand the effect and timing of rituximab on patient outcomes and to explore its potential therapeutic use in the management of specific complications of COVID-19, to determine whether judicious use of rituximab might have a role in the pandemic.
PM is a Medical Research Council (MRC) and GlaxoSmithKline (GSK) Experimental Medicine Initiative to Explore New Therapies clinical training fellow, with project funding outside the submitted work. PM receives co-funding from the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre (UCLH BRC).
RCC reports grants from UK Research and Innovation MRC, grants from GSK, and grants from NIHR ULCH BRC during the conduct of the study. VR reports grants from Roche (Basel, Switzerland) outside the submitted work and funding support from MRC. All other authors declare no competing interests.
References
- 1.Gianfrancesco M – Hyrich KL – Al-Adely S – et al.Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry.Ann Rheum Dis. 2020; 79: 859-866
- 2.Guilpain P – Le Bihan C – Foulongne V – et al.Rituximab for granulomatosis with polyangiitis in the pandemic of covid-19: lessons from a case with severe pneumonia.Ann Rheum Dis. 2020; (https://doi.org.10.1136/annrheumdis-2020-217549 published online April 20.)
- 3.Zhang Y – Xiao M – Zhang S – et al.Coagulopathy and antiphospholipid antibodies in patients with Covid-19.N Engl J Med. 2020; 382: e38
- 4. – iannini M – Ohana M – Nespola B – Zanframundo G – Geny B – Meyer ASimilarities between COVID-19 and anti-MDA5 syndrome: what can we learn for better care?.Eur Respir J. 2020; (https://doi.org.10.1183/13993003.01618-2020 published online July 6.)View in 5.Mehta P – McAuley DF – Brown M – Sanchez E – Tattersall RS – Manson JJCOVID-19: consider cytokine storm syndromes and immunosuppression.Lancet. 2020; 395: 1033-1034
More information: Matthew C. Woodruff et al, Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19, Nature Immunology (2020). DOI: 10.1038/s41590-020-00814-z
