Introduction

A variety of factors have been found to be associated with worse outcomes for patients diagnosed with COVID-19 including age, sex, body-mass index (BMI), and smoking status1,2,3,4. Outcomes for immunocompromised patients who develop COVID-19 remains an area of active study as this population may have special vulnerabilities to the disease. Biologic therapies that target B-cell function are effective for a range of indications from rheumatologic diseases to treatment for malignancy. However, immunosuppressive therapies may impair humoral responses to SARS-CoV-2 infection, leading to suboptimal immunity and continued risk for severe infection5,6,7.

Some authors have reported increased severity of COVID-19 in patients with history of B-cell depletion treatment8,9,10,11,12,13. The primary goal of this study was to compare outcomes of patients hospitalized with COVID-19 who had received B-cell depletion therapy with a matched contemporaneous cohort by severity of illness of admission, in a large registry within one hospital system, to further assess the effect of this treatment on outcomes.

Methods

This study was developed using the JH-CROWN: COVID Precision Medicine Analytics Platform Registry, which includes inpatient and outpatient records for patients who tested positive for SARS-CoV-2 in the Johns Hopkins Health System (JHHS). The JHHS comprises six hospitals and over forty outpatient facilities located in Maryland, Florida and Washington, DC. The research was approved by the Johns Hopkins Institutional Review Board. Patients hospitalized within the JHHS for COVID-19 infection during the period of March 1, 2020 until November 30, 2021 were eligible for inclusion. A query identified patients who were previously treated with B-cell depletion therapy on or after September 1, 2019 and who were subsequently hospitalized in the Johns Hopkins Health System with a laboratory-confirmed SARS-CoV-2 infection. No common platform for SARS-CoV-2 testing was employed during the period of study. B-cell depletion therapy was defined as rituximab, ocrelizumab, obinutuzumab, ibritumomab tiuxetan, and ofatumumab. A full list of medication search terms is included in the Appendix. Individual charts were reviewed to ensure that only patients who previously received B-cell depletion therapy on or after September 1, 2019 and prior to hospitalization with SARS-CoV-2 infection were included in the analysis. September 1, 2019 was chosen as it is six months prior to the start of COVID-19 hospitalizations among JHHS patients and would reflect the biologic effects of prior B-cell therapy. JHHS instituted mandatory screening of hospitalized patients for SARS-CoV-2 during the study period; patients with an incidentally positive SARS-CoV-2 test were eligible for analysis. The need to obtain informed consent was waived by the Johns Hopkins University School of Medicine Institutional Review Board (IRB00247569).

Outcomes

The primary outcome was time to death from hospital admission. The secondary outcome was time to a composite outcome of severe illness or death from hospital admission. An additional secondary outcome was time to clinical improvement from the date of hospital admission, defined as a 2-point decrease in World Health Organization (WHO) severity score or discharge alive from the hospital within 30 days. The WHO Severity score is a 10-point scale ranging from 0 (uninfected) to 10 (deceased)14.

Disease severity at admission was defined by the highest WHO severity score in the first 12 h of the patient’s admission. Severe illness was defined as score ≥ 6. Failure of clinical improvement was censored at the last day of follow-up or 30 days, whichever came first. Patients who were discharged alive were censored at 30 days.

Statistical analysis

A two-step, hybrid approach was used to account for the differences between the groups with and without B-cell therapy. In the first step, patients hospitalized with COVID-19 who received prior B-cell treatment were identified. Then a comparison group from the registry of patients who had not received B-cell therapy but matched on characteristics with the treated patient was selected. Matching criteria included age at time of hospitalization (± 5 years), timing of hospitalization (± 28 days), sex at birth, race, WHO COVID-19 disease severity, COVID-19 specific treatments (remdesivir, dexamethasone), and vaccination status before admission. All the patients who were matched to the b-cell cohort were included in the comparison group.

The second step employed overlap weighting, a propensity score (PS) approach, to further address differences between the B-cell treatment population and controls15. The PS score, indicating the likelihood of receiving B-cell depletion treatment, was derived from age, race, sex, body mass index (BMI), COVID-19 severity on the WHO scale, smoking status, existing comorbidities, specific COVID-19 treatments, and vaccination status at the time of admission. Medical comorbidities included hypertension, chronic obstructive lung disease, congestive heart failure, chronic kidney disease, end stage renal disease, human immunodeficiency virus, cirrhosis and cancer. Comorbidities were determined from relevant ICD codes present in the medical record. Use of overlap weighting based on the propensity score estimated from a logistic model leads to an exact balance for all covariates between different groups16,17.

Finally, inverse probability weighted Cox regression was used to estimate the association between B-cell depletion treatment and outcomes of interests. Age, BMI, COVID-19 specific medications and vaccination information were included as covariates in Cox regression models based on clinical interest and knowledge. The proportional hazards assumption was tested for violation using individual covariates and each outcome. A prespecified subgroup analysis was conducted to examine effects in patients with B-cell depletion treatment less than 90 days prior to COVID-19 hospitalization. For the sensitivity analysis we used the original control group and reperformed overlap weighting for the subgroup. All data analyses were executed using R software version 4.0.2 (R Foundation for Statistical Computing, Vienna, Austria)18.

Results

A total of 9,233 patients were admitted to the Johns Hopkins Health System between March 1, 2020 and November 30, 2021 with COVID-19. Seventy-two of the patients hospitalized with COVID-19 within JHHS had been treated with B-cell depletion therapy after September 1, 2019. Twenty-one patients were excluded from the analysis due to receiving B-cell depletion therapy after testing positive for SARS-CoV-2. One patient treated with B-cell depletion was excluded due to missing BMI records (Fig. 1). A control group of 186 distinct patients was selected from the original cohort of patients based on the method described above. Summary statistics of the cohort and the matched controls are presented in Table 1. After performing overlap weighting, absolute standardized differences were no longer present indicating balanced covariates. The indications and timing of prior B-cell depletion therapy is summarized in Table 2. The proportional hazards assumption was individually evaluated for individual covariates and outcomes. There were no violations of the assumption for mortality, severe illness or death, or clinical improvement.

Fig. 1
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Identification of study cohort of patients treated with prior B-cell depletion and hosptialization for COVID-19 between March 1, 2020 and November 30, 2021.

Table 1 Characteristics of Patients before overlap weighting adjustment.
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Table 2 Disease characteristics of cases with B-cell depletion therapy prior to COVID-19.
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Patients who had received prior B-cell depletion therapy had a 30-day mortality rate of 6.0% (n = 3) compared to 3.8% (n = 7) in the control group. This difference was not statistically significant in overlap weighting-adjusted regression analysis, adjusted hazard ratio (aHR) 1.45 (95% confidence interval (CI) 0.30 to 6.95). The time to severe illness or death from time of hospitalization was 2.4 days (IQR 0.5 to 4.0 days) in the B-cell depletion group and 2.2 days (IQR 1.0 to 4.4 days) among controls. In adjusted analysis there was no difference between the B cell depletion group and the controls, aHR 0.91 (95% CI 0.41 to 2.03). (Fig. 2).

Fig. 2
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Time to death (a) and severe disease or death within 30 days of impatient admission (b).

Patients treated with B-cell depletion experienced longer time to clinical improvement, (aHR 0.65 ([0.45–0.94]). In this analysis, a reduced adjusted hazard (aHR < 1) indicated that time to event (in this case clinical improvement) was prolonged. The median time to improvement or hospital discharge was 6.3 days in the B-cell depleted group (IQR 3.3 to 11.2 days) and 4.2 days in the control group (IQR 2.2 to 7.7 days) (Table 3).

Table 3 Outcome comparisons between patients with and without B-cell depletion therapy.
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Subgroup analysis was performed for patients who had received B-cell depletion treatment within 90 days of COVID-19 hospitalization. There were no significant differences in 30-day mortality or time to severe illness compared to the control group. Among patients treated with B-cell depletion within the past 90 days, the B-cell depletion treatment group similarly experienced a longer median time to clinical improvement 6.3 days (IQR 2.9 to 10.9 days) vs. 4.2 days (IQR 2.2 to 7.7 days), aHR 0.54 (95% CI 0.33 to 0.89). These findings are illustrated in Fig. 3.

Fig. 3
Fig. 3The alternative text for this image may have been generated using AI.
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Cumulative improvement rate for (a) all patients treated with B-cell depletion therapy and (b) patients who received B-cell therapy within 90 days.

Discussion

This study has several important findings. First, patients who received B-cell depletion therapies matched to patients with similar demographic characteristics, comorbidities and severity of COVID-19 at hospital admission did not experience higher mortality rates within 30 days. Second, patients with prior B-cell depletion therapy experienced increased time to clinical improvement compared to matched controls. Finally, remote or more proximal treatment with B-cell depletion therapy did not result in different mortality rates.

The literature is mixed regarding the impact of B-cell depletion on outcomes with COVID-19. Prior work has found no increased risk in patients with lymphoid malignancies treated with B-cell depletion19,20,21,22 while other authors have demonstrated an increased risk of severe disease in patients treated with B-cell depletion9,11,23 and death8,10,13,24 in various populations treated with B-cell depletion. This discrepancy is likely explained due to heterogeneity within comparable studies including different eras, matching technique, particularly use of severity of illness on admission, and immunization in the population. A matched national cohort study in France of 63 patients with rheumatological and musculoskeletal diseases treated with rituximab, demonstrated a higher rate of severe disease but did not find increased risk of death9. A retrospective observational study in Spain including 57 patients treated with B-cell depletion for any indication found a higher rate of severe illness, longer length of stay and higher risk of death in patients with SARS-CoV-2 infection compared to patients without this treatment13. A comparative cohort study of 114 patients with rheumatological illness, using multivariate regression, found a higher mortality rate in recipients of B-cell depletion therapy compared to matched controls8. A large study including information from 42 health systems in the USA found an increased risk of in-hospital death in patients who had received rituximab prior to COVID-19 hospitalization; however, when stratified by sex, rituximab was associated with higher in-hospital death in women with cancer but not for women with rheumatological conditions or at all in men24. To account for these differences, risk may vary based on indications for B-cell treatment, comorbidities, center-specific management, different phases of the pandemic and different viral variants. This study also incorporates COVID-19 vaccination in matching which may affect disease outcomes. More recent work looking at vaccinated patients, has suggested that patients with prior B-cell depletion treatment have a higher rate of hospitalization due to breakthrough infection, although incidence is very low25,26.

This study attempts to match across a variety of factors. Notable strengths including access to granular hospitalization data and severity of illness, manual chart review of individual records, and use of propensity score matching to isolate effect of B-cell depletion. It also has several limitations. This study reflects the treatment of patients at a tertiary care center who were infected with SARS-CoV-2 prior to the rise of the Omicron variant which may have implications for disease severity. Use of overlap propensity score weighting is a statistical attempt to control differences between heterogenous populations whose treatment with B-cell depletion therapy may be further confounded by other unaccounted differences between groups. While we performed extensive matching, we did not account for baseline use of medications such as steroids which may account for some of the differences noted. This study is limited by its size and may be insufficiently powered to detect a mortality difference given the low incidence. Although the Johns Hopkins Health System treats many immunocompromised patients, these are part of a large and heterogeneous patient population with many different underlying diseases, whereas centers specializing in the treatment of cancer, for example, may have larger numbers of patients who had received B-cell depletion, and a more comparable control group. In particular, patients in this study were matched according to presence of any cancer diagnosis, not on the type of cancer and stage, both of which are important prognostic features, which further limits the matching technique. Similarly, additional chemotherapy beyond B-cell depletion was not accounted for in the matching process. The current study also did not consider immunoglobulin levels or treatment with monoclonal antibodies which may also contribute to the likelihood of progressing to severe illness and death. Additionally, a minority of patients with B-cell depletion were vaccinated, which further limits generalizability. The registry does not account for patients who may have been treated with B-cell depletion outside of the Johns Hopkins Health System; however, this likely accounts for a very small number of patients.

Conclusions

This study illustrates that patients treated with B-cell depletion experienced prolonged hospitalization due to SARS-CoV-2 infection but did not show an increased mortality compared to similar patients who had not received B-cell depletion therapy. These findings suggest that, in some settings, prior B-cell depletion therapy may not necessarily portend an adverse outcome in terms of mortality from COVID-19 however the study may be underpowered to determine a difference. Larger studies utilizing data from multiple centers would be helpful to confirm these findings. More research on the effect of vaccination status on outcomes, the impact of prompt treatment or pre-exposure prophylaxis with SARS-CoV-2 monoclonal antibodies, the incidence of PASC and persistent SARS-CoV-2 PCR positivity in this population, as well as the impact of future variants, will be needed to best protect and care for this vulnerable population.