Severe COVID-19 Outbreaks in Breakthrough Infections in Patients Treated with B-Cell Degradation Therapy
Severe COVID-19 Outbreaks in Breakthrough Infections in Patients Treated with B-Cell Degradation Therapy

Severe COVID-19 Outbreaks in Breakthrough Infections in Patients Treated with B-Cell Degradation Therapy

In a recent study posted to medRxiv* Preprint server, scientists evaluated the incidence and severity of pioneering severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections among individuals with immune-mediated inflammatory diseases (IMIDs) undergoing B-cell depleting therapy (BCDT).

Examination: Pioneering SARS-CoV-2 infections in immune-mediated disease patients undergoing B-cell depleting therapy. Image credit: Kateryna Kon / Shutterstock


The distribution of SARS-CoV-2 vaccines has been shown to be effective in reducing the incidence of coronavirus disease 2019 (COVID-19) and virus-associated death to a large extent in the general public. Nevertheless, information about those with immunocompromised conditions, including IMIDs, suggests that these cohorts were more likely to break through SARS-CoV-2 infections and severe outcomes, such as intensive care unit (ICU) hospitalization and mortality, despite of that they were fully vaccinated.

The immunosuppressive agents show a diversified ability to limit immune responses to the natural SARS-CoV-2 infections and vaccines. Individuals with IMIDs on BCDTs were associated with severe COVID-19 before receiving SARS-CoV-2 vaccines.

In addition, BCDTs such as ocrelizumab also showed a profound weakening of antibody-mediated immunity given by several vaccines, including those of SARS-CoV-2. Recent studies have shown that although IMID patients on BCDT who received COVID-19 vaccines showed suppression of humoral immunity, a robust cell-mediated immune response to SARS-CoV-2 was maintained in them. However, the frequency and severity of breakthrough SARS-CoV-2 infection in this population are still unclear.

About the study

In this study, the researchers evaluated 1,696 SARS-CoV-2 vaccinated IMID patients on BCDTs for the incidence of breakthrough infections among them and determined their clinical outcomes. The team identified the study cohort by electronically searching pharmacy records at the Cleveland Clinic using IMID-specific International Classification of Disease (ICD) codes and the COVID-19 registry.

Data on demographics, COVID-19 vaccination history, comorbidities, details of BCDT and outcomes, and other therapies were extracted by hand review of each electronic medical record (EMR). Furthermore, the researchers determined risk factors for severe SARS-CoV-2 outcomes among these cohorts using multivariate and univariate logistic regression models.

Survey results

The results indicate that the 1,696 patients with IMID received one, two or three doses of monoclonal antibodies (mAbs) directed against B cells during 2020. In addition, they also received one or more doses of SARS-CoV-2 vaccines. Among the 1,696 COVID-19 vaccinated participants with IMIDs undergoing BCDT, 74 had SARS-CoV-2 breakthrough infections after their first COVID-19 vaccination by December 15, 2021. Of the 74 IMID patients with breakthrough COVID-19, 24, 11, and 6 were hospitalized, required critical care, and died, respectively.

The breakthrough infections were almost equal among neuroinflammatory and arthritis patients. More than 90% of IMID patients were fully vaccinated or boosted against SARS-CoV-2, and only 8.1% had an incomplete vaccination status.

Of the 74 breakthrough SARS-CoV-2 infections, 62 were reported during the Delta Rise in the United States (US) from June 20 to December 15, 2021. The time-adjusted incidence rate of breakthrough SARS-CoV-2 infection in general, before Delta and after Delta were 5.19 per. 1,000 personal months, 2.48 per. 1,000 personal months and 6.59 per. 1,000 personal months.

Nearly 27% and 46% of IMID patients were on BCDT for one to three years and over three years, respectively. About 77% of IMID patients had their last mAb treatment, such as ocrelizumab and rituximab, less than six months before their first SARS-CoV-2 vaccination. Nevertheless, these cohorts developed groundbreaking SARS-CoV-2 infection and severe COVID-19 outcomes.

Of the 21 IMID breakthrough patients COVID-19 treated with anti-SARS-CoV-2 mAb casarivimab / indevimab outpatient, only one person needed SARS-CoV-2 related oxygen-free hospitalization (O2) support and no mortality was reported.


The study results show that individuals with IMIDs on BCDTs were associated with a high risk of breakthrough SARS-CoV-2 infection and severe disease outcomes such as O2 requirements, admission to the intensive care unit and death despite the high COVID-19 vaccination rates. Outpatient use of mAbs such as casarivimab / indevimab in these cohorts reduced the risk of severe COVID-19 failure.

However, the beneficial effect of anti-SARS-CoV-2 mAbs seen during the study period was associated with infections caused by the SARS-CoV-2 pre-Delta and Delta variants and does not necessarily extrapolate to the Omicron variant due to its variations in immunological susceptibility or the future variants.

For now, the available SARS-CoV-2 reduction strategy for high-risk populations such as IMID patients on BCDT is to follow strict non-pharmaceutical interventions such as masking, social distancing, and disinfection.

Nevertheless, future studies are needed to develop effective prophylactic mAbs against the SARS-CoV-2 variants, such as the highly mutated Omicron and the future strains. In addition, it is also recommended to train both general practitioners and patients in outpatient use of current and future anti-SARS-CoV-2 mAb therapies, as only a small number of patients were treated with mAbs in the current study.

*Important message

medRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered as crucial, guide clinical practice / health-related behavior or be treated as established information.

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