By Betty Tran, MD, MSc
Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago
SYNOPSIS: In this retrospective cohort, patients receiving anti-CD20 treatment had worse clinical outcomes, including mortality, in addition to longer durations of infectivity and higher rates of relapse.
SOURCE: Calderón-Parra J, Múñez-Rubio E, Fernández-Cruz A, et al. Incidence, clinical presentation, relapses and outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients treated with anti-CD20 monoclonal antibodies. Clin Infect Dis 2022;74:1786-1794.
Anti-CD20 monoclonal antibodies (mAbs) aim to deplete peripheral B cells and are used in the treatment of B cell proliferative disorders (e.g., non-Hodgkin’s lymphoma, chronic lymphocytic leukemia) and autoimmune disorders (e.g., rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, pemphigus vulgaris, and pemphigus foliaceus). They include the first-generation drug, rituximab; second-generation humanized versions, such as ocrelizumab, veltuzumab, and obinutuzumab; and the full human anti-CD20 mAb, ofatumumab.1
This was a retrospective observational study of patients treated with any anti-CD20 mAb from a Spanish tertiary teaching hospital from January 2019 through December 2020. All patients with confirmed COVID-19 via rapid antigenic test, reverse transcriptase-polymerase chain reaction (RT-PCR), or outpatient diagnosis based on clinical and radiographic findings (testing was limited during March and April 2020 because of high patient volume) after at least one dose of anti-CD20 treatment were included. Of the 477 patients receiving anti-CD20 treatment, 57 (13.5%) contracted COVID-19 after starting treatment, a rate of infection similar to the general population in the study’s setting. Among the 57 patients, 17 (29.8%) used concomitant corticosteroids and 10 (17.5%) had other immunosuppression (e.g., chemotherapy, tacrolimus, mycophenolate, or azathioprine).
Overall, of the 57 patients with COVID-19 after anti-CD20 treatment, 25 (43.9%) required hospital admission compared to 14.7% of the general population in the study’s setting. In total, five patients died during hospital admission (8.8% of all COVID-19 patients, 20% of admitted patients), which was a higher mortality than that reported worldwide (2.1%) and in Spain (2.6%) for the general population. All of the patients who died had received their last dose of anti-CD20 within six months of their COVID-19 diagnosis. Patients who had received their last dose of anti-CD20 mAb within six months of being diagnosed with COVID-19 also were more likely to have severe disease, although the finding was not statistically significant (48.9% vs. 18.0%, P = 0.090).
Of the 25 admitted patients, 21 (84%) received treatment with corticosteroids, 12 (48%) received tocilizumab, and three were treated with convalescent plasma; no patients were treated with remdesivir. There were no significant differences in mortality by treatment category. Concomitant treatment with corticosteroids or other immunosuppressants as an outpatient was not associated with increased mortality.
Among 19 patients with more than one RT-PCR result, the median duration of positivity was 22 days (interquartile range [IQR], 13-40 days), with a maximum of 65 days. Persistently positive RT-PCR, defined as a cycle threshold (Ct) < 30, for more than 30 days, was associated with increased mortality (33.3% vs. 0%, P = 0.043). A recurrence was defined as a clinical episode of symptoms consistent with COVID-19 with repeat positive or persistently positive RT-PCR > 90 days after the initial episode. Of the 52 initial survivors, nine (17.3%) had recurrences, all of whom had received their last dose of anti-CD20 within six months of their COVID-19 diagnosis. Chronic treatment with corticosteroids or other immunosuppressants was not associated with recurrence. Median time from initial diagnosis to first recurrence was 51 days (IQR, 40-56 days); four patients had more than one episode. The investigators did not suspect reinfection (i.e., recurrence with a known epidemiologic exposure) in any of the recurrence cases. Management plans for the nine recurrences included permutations of corticosteroids, convalescent plasma, remdesivir, tocilizumab, immunoglobulins, and no specific treatment. All nine patients with recurrences survived.
COMMENTARY
Since initial reports of a novel coronavirus identified in the Wuhan province of China were broadcast in December 2019, many COVID-19-directed treatments have emerged, including several vaccines directed against COVID-19. Although hospitalization and death rates have had peaks coincident with multiple variant strains of SARS-CoV-2, currently we have more tools in our armamentarium compared to the beginning of the pandemic. What remains consistent, however, is the threat COVID-19 poses to patients who are chronically immunocompromised. These patients have an increased risk of severe outcomes, hospitalization, and death.2 In addition, they also may have delayed viral clearance, which not only leads to increased morbidity, but is posited to contribute to the emergence of new concerning variants as a result of selective pressures when these patients are treated with monoclonal antibodies.3,4
Anecdotally, our current intensive care unit (ICU) COVID-19 census is composed primarily of such patients, many of whom received anti-CD20 mAbs and subsequently were diagnosed with COVID-19 weeks to months prior to their current hospitalization. Despite receiving empiric corticosteroids for possible organizing pneumonia related to COVID-19 infection, some have not clinically responded; their RT-PCRs remain consistently positive with lower cycle thresholds suggestive of poor viral clearance and ongoing infection.
Humoral immunity likely plays a large role in the host response to SARS-CoV based on the correlation between natural antibody status and reduced risk of reinfection and the therapeutic effect of monoclonal antibodies in facilitating viral clearance in early infection.5 However, many questions remain regarding the role of antibodies in later stage infection. This study is in agreement with others that have reported increased risk of severe COVID-19 infection among those with dysregulated humoral immune responses; whether quantitative or functional deficits of immunoglobulins are involved is not clear.5
For such patients with chronic B cell depletion and persistent infection with SARS-CoV-2, there are no well-studied treatment options. Small case series using convalescent plasma and SARS-CoV-2-specific monoclonal antibodies have been reported with some benefit.6-8 Emergency use authorization (EUA), however, limits use of COVID-19-specific mAbs in addition to oral antivirals, such as nirmatrelvir with ritonavir and molnupiravir, to the outpatient setting; inpatient use of these medications requires an emergency investigational new drug (EIND) application to the manufacturer.
Although the current study showed no association between mortality and SARS-CoV-2 recurrence and corticosteroid use, at our institution, we generally aim to taper off corticosteroids if there is no clinical response after about two to three weeks to allow the patient’s innate immune system more opportunity to “bounce back” over time with the waning effects of their anti-CD20 treatment. Although we have made significant progress in the management of COVID-19 overall, we eagerly await future therapeutic trials potentially involving SARS-CoV-2-specific monoclonal antibodies and antivirals in this subpopulation of immunocompromised patients with protracted COVID-19 infection.
REFERENCES
- Du FH, Mills EA, Mao-Draayer Y. Next-generation anti-CD20 monoclonal antibodies in autoimmune disease treatment. Auto Immun Highlights 2017;81:12.
- Jakharia N, Subramanian AK, Shapiro AE. COVID-19 in the immunocompromised host, including people with human immunodeficiency virus. Infect Dis Clin N Am 2022;36:397-421.
- Morishita M, Suzuki M, Matsunaga A, et al. Prolonged SARS-CoV-2 infection associated with long-term corticosteroid use in a patient with impaired B-cell immunity. J Infect Chemotherapy 2022;28:971-974.
- Scherer EM, Babiker A, Adelman MW, et al. SARS-CoV-2 evolution and immune escape in immunocompromised patients. N Engl J Med 2022;386:2436-2438.
- Jones JM, Farugi AJ, Sullivan JK, et al. COVID-19 outcomes in patients undergoing B cell depletion therapy and those with humoral immunodeficiency states: A scoping review. Pathog Immun 2021;6:76-103.
- Hueso T, Pouderoux C, Pere H, et al. Convalescent plasma therapy for B-cell-depleted patients with protracted COVID-19. Blood 2020;136:2290-2295.
- Betrains A, Godinas L, Woei-A-Jin FJSH, et al. Convalescent plasma treatment of persistent severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2) infection in patients with lymphoma with impaired humoral immunity and lack of neutralizing antibodies. B J Haem 2021;192:1100-1105.
- Bailly B, Pere H, Veyer D, et al. Persistent coronavirus disease 2019 (COVID-19) in an immunocompromised host treated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific monoclonal antibodies. Clin Infect Dis 2022;74:1706-1707.
In this retrospective cohort, patients receiving anti-CD20 treatment had worse clinical outcomes, including mortality, in addition to longer durations of infectivity and higher rates of relapse.
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