Clinical Course and Outcomes of COVID-19 Infection in Patients Treated with Rituximab: A Tertiary Care Center Experience

Introduction

Coronavirus is an enveloped, single-stranded RNA virus. Infection with this virus was first reported in Wuhan, China, in December 2019, and it was declared a pandemic in March 2020. Coronavirus disease 2019 (COVID-19) may present as mild to moderate, self-limiting respiratory symptoms such as fever, loss of taste and smell, cough, and shortness of breath, but in some patients, it may be severe enough to require hospitalization and intubation with mechanical ventilation.¹

Rituximab (RTX) is a monoclonal antibody that is used for the treatment of numerous diseases, including rheumatologic, hematologic, nephrologic, neurologic, and oncologic conditions.² RTX targets the B-cell transmembrane protein CD20, leading to B-cell destruction. As a result, RTX suppresses the humoral immunity via B-cell depletion. Although generally well-tolerated with only mild adverse effects such as infusion reactions, headache, and chills, RTX can induce severe immunosuppression, resulting in hypogammaglobulinemia, neutropenia, and reactivation of viral infections.³

There is no consensus on whether immunosuppressive and immunomodulatory agents negatively affect the clinical course and outcome of COVID-19 infection.⁴ To emphasize, some studies found that patients who were already taking immunosuppressive agents are more susceptible to COVID-19 infection and worse outcomes.^1,5 More specifically, multiple studies suggested that patients treated with RTX are at increased risk for severe COVID-19 infection and worse outcomes compared to the general population. Also, several reports revealed higher rates of COVID-19-related hospitalization, respiratory failure requiring intubation and mechanical ventilation, and mortality in patients treated with RTX.^3,6,7

A descriptive study by Martos et al of SARS-CoV-2 infections in patients with rheumatic diseases treated with RTX showed a high rate of severe illness requiring hospitalization (61.5%) and a high mortality rate (23.1%). Similarly, a cohort study by Singh et al showed that the use of RTX in patients with rheumatoid arthritis was associated with worse COVID-19 outcomes such as hospitalization (26%) and ICU admission (6.6%) than in patients receiving conventional synthetic disease-modifying anti-rheumatic drugs.³

Because of the variable results of different studies on the effect of RTX on the course and outcome of COVID-19 infection and because of the limited literature in Saudi Arabia, we aimed to investigate the outcome of COVID-19 infection in patients who received RTX during the period of the COVID-19 pandemic in Saudi Arabia.

Materials and Methods

Aim

To evaluate the clinical course and outcomes of COVID-19 infection among patients treated with RTX for a variety of clinical indications.

Study Design/Setting

This was a retrospective cohort study conducted at King Abdulaziz Medical City (KAMC), Ministry of National Guard-Health Affairs (MNG-HA), Riyadh, Kingdom of Saudi Arabia. KAMC is an academic, government-funded tertiary hospital that combines clinical care, training, and academics with research and state of the art medical technologies.

Inclusion and Exclusion Criteria

Patients aged ≥ 14 years who were treated with RTX for autoimmune connective tissue diseases, hematologic malignancies, benign hematologic diseases, neurologic diseases, or glomerular diseases and had PCR-proven COVID-19 infection were included. Patients who had a poor outcome due to severe underlying disease before infection with COVID-19 or patients with suspected infection with COVID-19 were excluded. After applying the aforementioned criteria, only 35 patients were eligible for inclusion.

Data Collection

Electronic medical records (via the KAMC electronic system - BestCare; Seoul, South Korea: ezCaretech Co) were used to obtain data of all patients who met our inclusion criteria, from 2019 to 2021. The data collected included the following: demographic data such as age, gender, and body mass index, comorbidities including diabetes mellitus (DM), hypertension (HTN), and chronic kidney disease (CKD), the primary diagnosis for which RTX was used, RTX dose, number of RTX doses, other immunosuppressants used, immunoglobulin (IgG, IgM, and IgA) levels, CD19 levels, presenting signs and symptoms of COVID −19, chest x-ray findings on admission, ferritin levels, site of treatment (outpatient, inpatient, or intensive care unit (ICU)), and outcomes (survival or death).

Statistical Analysis

Statistical analysis was performed with SPSS version 28 (IBM Co., Armonk, NY, USA).

Quantitative nonparametric data were presented as median and interquartile range (IQR) and analyzed with the Mann Whitney test. Categorical variables were presented as frequency and percentage (%) and analyzed with the Chi-square test or Fisher’s exact test, as appropriate. A two tailed P value < 0.05 was considered statistically significant.

Ethical Considerations

This study was approved by the Institutional Review Board of the King Abdullah International Medical Research Center, Ministry of National Guard-Health Affairs, Riyadh, Kingdom of Saudi Arabia (RC20/693/R). Because this was a retrospective study, informed consent was waived. Access to the data was restricted to the investigators. Patient confidentiality and privacy were maintained, and no names or medical record numbers were used, and all data were stored in a secure location at National Guard-Health Affairs. This study complies with the Declaration of Helsinki.

Results

Baseline Characteristics

A total of 35 patients (15 men and 20 women) were included. The patients’ mean age was 42.8 ± 16.3 years, and over two-thirds (65.9%, n= 23) of them were ≤ 50 years old. About half of the patients (48.6%, n= 17) were obese with an average BMI of 29.9 ± 11.4 kg/m². The most prominent comorbid condition was HTN, followed by DM and CKD, accounting for 28.6%, 25.7%, and 25.7%, respectively. The most common primary diagnoses for using RTX were neurologic diseases (22.9%), autoimmune connective tissue diseases (20%), and hematological malignancies (20%) Figure 1. Over half (51.4%, n= 18) of the patients received RTX at a dose of 375 mg/m², around a third (37.1%, n= 13) at a dose of 1000 mg/m², and only a few (11.4%, n= 4) at a dose of 500 mg/m². The median frequency of RTX administration was 4 times with an IQR of 3 to 6 times. More than half (51.4%) of the patients were on corticosteroids, and a few were on azathioprine (14.3%), mycophenolate (14.3%), and hydroxychloroquine (11.4%). Hypogammaglobulinemia, defined as low IgG, IgM, and/or IgA, was diagnosed in 37.1% of the patients and 25.7% had low CD19. The mortality rate was 25.7% as shown in Table 1

Table 1 Baseline Characteristics of the Studied Patients (n=35)

Figure 1 The Primary Diagnosis for Using Rituximab.

COVID-19 Data

As summarized in Table 2, 22.9% of the patients had symptomatic COVID-19 infection. The most common presenting symptoms were lower respiratory symptoms, which were reported by more than half (60%, n= 21) of the patients, followed by gastrointestinal and neurological symptoms, each reported by 17.1%. Chest radiography revealed pneumonia in 22.9% and bilateral airspace opacities in 17.1%. More than half (57.1%, n= 20) of the patients were treated as outpatients, and 25.7% were admitted to ICU.

Table 2 COVID-19 Data Among the Studied Patients (n=35)

Mortality

Comparison between survivors and nonsurvivors revealed a statistically significant difference in age, as nonsurvivors were older than those who recovered (P=0.016). Compared with the recovered patients, the nonsurvivors had higher rates of DM (55.6% vs 15.4%, P=0.03), steroid administration (88.9% vs 38.5%, P=0.018), inpatient care (77.8% vs 30.8%, P=0.022), and ICU admission (66.7% vs 11.5%, P=0.003). Nonsurvivor patients had significantly lower immunoglobulins (hypogammaglobulinemia) than the survivors (77.8% vs 23.1%, P=0.006), manifested by an abnormal decrease in either IgG (44.4% vs 7.7%), IgM (66.7% vs 23.1%), or IgA (11.1% vs 7.7%, which was similar between the two groups). Moreover, nonsurvivors had lower CD19 levels than survivors (55.6% vs 15.4% respectively had low CD19, P=0.03) as summarized in Table 3, Figures 2–4.

Table 3 Association Between Mortality and Patients’ Characteristics, Outcome

Figure 2 Association between mortality and age of the studied patients.

Figure 3 Association between mortality and steroids administration of the studied patients.

Figure 4 Association between mortality and hypogammaglobulinemia rate of the studied patients.

Intensive Care Unit Admission

As shown in Table 4, there was a statistically significant association between ICU admission and age, as patients who were admitted to the ICU were older than those who were not admitted (P=0.045). Compared with patients who were not admitted to the ICU, patients admitted to the ICU had higher rates of steroid use (88.9% vs 38.5%, P=0.018) and lower CD19 levels (55.6% vs 15.4%, P=0.03). Patients admitted to the ICU had a higher mortality rate (66.7% vs 11.5%, P=0.003) (Figure 5).

Table 4 Association Between ICU Admission and Patients’ Characteristics, Outcome

Figure 5 Association between ICU admission and steroids administration of the studied patients.

Discussion

In this study, we sought to evaluate the outcome of COVID-19 infection in patients who received RTX for various underlying diseases in Saudi Arabia. We found that RTX at a dose of 375 mg/m2 was the most commonly used protocol. Corticosteroids were used in more than half of the patients. This study showed that a large number of RTX receivers were found to have hypogammaglobulinemia and low CD19. Our study showed a relatively high mortality rate among patients treated with RTX. In addition, patients treated with RTX who did not survive tended to be older, diabetic, taking steroids, and hospitalized or admitted to ICU. Also, hypogammaglobulinemia and lower CD19 levels were found to be associated with a high mortality rate. Moreover, this study showed that there was a statistically significant association between ICU admission and age, steroid use, and low CD19 levels.

Most of our patients were young females, and the most common cause of RTX use was autoimmune diseases such as multiple sclerosis and myasthenia gravis. This can be explained by the fact that autoimmune diseases tend to affect young individuals and have a female tendency.^1,8

Some previous reports found that the use of RTX does not worsen the outcomes of patients with COVID-19 and is not associated with disease progression.⁹ Our study shows a mortality rate of 25.7% in patients treated with RTX.¹ In addition, a large proportion of our cohort were hospitalized (42.9%) and required treatment in the ICU (25.7%). MacKenna et al reported that patients receiving RTX had an increased risk of COVID-19-related hospitalization, ICU admissions, and deaths compared with patients receiving standard systemic therapy.⁸ Similarly, a cohort study by Singh et al showed that RTX use in patients with rheumatoid arthritis is associated with worse COVID-19 outcomes such as hospitalization (26%) and ICU admission (6.6%) compared to those on conventional synthetic disease modifying anti-rheumatic drugs. Likewise, a descriptive study by Martos et al of SARS-CoV-2 infections in patients with rheumatic diseases treated with RTX showed a high rate of severe illness requiring hospitalization (61.5%) and a high mortality rate (23.1%).³ In agreement with ours, Tepasse et al, Stradner et al, and Alpizar-Rodriguez et al also reported that RTX use was associated with a higher risk of severe disease and/or mortality in patients with COVID-19 infection.^9,10

Some immunosuppressants selectively target T lymphocytes and suppress their function, such as calcineurin inhibitors, while largely preserving B cell activity. However, other immunosuppressants, such as RTX, an anti-CD20 monoclonal antibody, result in complete depletion of B cells and suppress B cell functions such as immunoglobulin production. Therefore, the rapid depletion of B cells associated with RTX use can cause secondary hypogammaglobulinemia, which may be persistent or take up to 12 months to recover. Patients with hypogammaglobulinemia develop impaired opsonization and do not form antibodies to exposed antigens. Therefore, these patients develop susceptibility to infection and to the complications that can occur as a result of infection, which may necessitate hospitalization and/or ICU admission.^9,11 There are case reports of persistent COVID-19 infection or delayed serological response to COVID-19 vaccination in patients receiving RTX therapy. These data raise concerns that RTX may directly influence adaptive immune response, which is important for the control and clearance of viral infections.¹²

It is unclear whether the underlying primary diagnosis for which RTX is used alone or in combination with the effect of RTX use and/or additional risk factors, influences mortality. Suppressed immunity and comorbidities are considered the main reasons for the increased infection and mortality rates of COVID-19 in these patients.^13,14 Mortality was reported in a quarter (25.7%) of our patients who were treated with RTX. Also, Ekin et al showed that the mortality rate was 27% in patients with rheumatologic diseases who received RTX.¹¹ In a study of the outcomes of COVID-19 in patients with inflammatory rheumatic diseases, the mortality rate was 11.5% in patients on RTX, which is consistent with some other studies.¹ For clarification, Montero et al mentioned a mortality rate of 16%, and Sharmeen et al reported a mortality rate of 5.9%.^15,16 However, A cohort study by Singh et al and the French national study did not find an association with an increased risk of death in the RTX-exposed vs not-exposed group.^12,17 The differences between these studies could be due to different underlying diseases for which RTX was used. This could also explain the high mortality rate in our study because we included different disease groups such as cancer patients and not only inflammatory rheumatic diseases. Moreover, from these studies, it appears that patients receiving RTX have a higher mortality rate than patients receiving other immunosuppressants. As in our study and in previous studies, patients receiving RTX may have other concomitant diseases, such as DM, HTN, and CKD, which also increase the risk of poor outcomes.^1,11 This study showed that the mortality rate was higher in RTX receivers if they were older, had diabetes, were taking steroids, were hospitalized, needed ICU, or had lower immunoglobulins or CD19. This is consistent with Ekin et al and the French RMD COVID-19 cohort, which also found a higher mortality rate in older patients. However, unlike our study, Ekin et al showed a significant association between COVID-19-related mortality and CKD.¹¹ Some studies have shown that steroids have no association with mortality. In a meta-analysis of seven trials involving a total of 1703 critically ill COVID-19 patients, steroids reduced 28-day mortality compared with standard treatment or placebo.¹⁸ Gianfrancesco et al and the French RMD cohort study, however, found that long-term use of corticosteroids in the treatment of COVID-19 patients increased the risk of severe COVID-19 infection and/or COVID-19 mortality.^19,20 To be more specific in patients treated with RTX, unlike our study, Ekin et al showed no significant association between steroid use and COVID-19-related mortality in RTX patients. Therefore, they concluded that the advantages of steroid use in the treatment of rheumatologic diseases and COVID-19 infections seem to outweigh the disadvantages when used in a timely manner.¹¹

Regarding sex and COVID-19 outcomes, there are some conflicting results in the literature. Several studies conducted in the general COVID-19 population reported higher rates of severe COVID-19 infections and COVID-19-related deaths in men compared with women.^21,22 In our study, no significant association was found between COVID-19-related mortality and gender, and the same was reported by Ekin et al. However, in the French RMD cohort study which investigated the impact of SARS-CoV-2 on patients with inflammatory rheumatic and musculoskeletal diseases, a significant association was found between female sex and death/serious illness.¹⁹ Another cohort study on the outcomes of COVID −19 patients with inflammatory rheumatic diseases showed that women had a more better survival rate compared to men.¹ We believe that gender may not be directly related to severe COVID-19 infections. Rather, the underlying primary diagnosis for which RTX is used could play a role. To clarify this point, most of the available literature addressing RTX and the risk of severe COVID-19 infections and COVID-19-related deaths is related to a specific disease such as rheumatoid arthritis, or a group of diseases such as autoimmune diseases which could predominantly affect a specific gender. However, in our study, the fact that our patients had heterogeneous diagnoses could explain the even gender distribution in our study.

Some patients in RTX may develop hypogammaglobulinemia, which can be persistent and clinically significant and may require antibiotic prophylaxis or immunoglobulin replacement therapy to prevent severe infections and infection-related complications.^23,24 Several risk factors for hypogammaglobulinemia in patients treated with RTX have been reported in the literature including repeated RTX treatments, advanced age, and concurrent glucocorticoid therapy.²⁵ In our study, 37.1% of patients had hypogammaglobulinemia, and Casulo et al reported almost the same percentage (38.54%).²⁶ However, the incidence was higher in Roberts and Ekin et al, 56% and 68.5%, respectively. Unfortunately, not all patients in our study were tested for immunoglobulin levels, which may explain the difference in percentage between our study and the latter two studies. Both our study and Ekin et al showed that there was a significant association between hypogammaglobulinemia and COVID-19-related mortality.¹¹

In our study, the hospitalization rate was 42.9%, which is higher than the general hospitalization rate in the general population.¹ In our study population, 25.71% of patients needed ICU. There was a statistically significant association between ICU admission and older age, steroid use, and lower CD19 . In the study by Ekin et al 28.8% of patients with a history of infection required hospitalization. In the French RMD COVID-19 cohort study of 694 adults, 63% developed mild (not hospitalized), 24% developed moderate (hospitalized out of the ICU), and 13% developed severe (treated/died in the ICU) disease.¹⁹ Previously published studies agree with the high rate of admission rate in people with immunotherapy.^15,20 COVID-19 patients in the general population, comorbidities such as chronic respiratory disease and DM could be the reason for admission.^27,28 In addition, disease-specific factors of the patients could be another explanation for admission as patients with cancer or autoimmune diseases may require more medical attention. To clarify, Sahraian et al showed that in multiple sclerosis patients infected with COVID-19, the hospitalization rate was 25%, Which is higher than the admission rate in the age group of patients with multiple sclerosis in the general population.²⁹ MacKenna et al showed adults with immune-mediated inflammatory diseases are also at increased risk for COVID-19-related ICU admission and death.⁸ Based on the literature, people with immune-mediated inflammatory diseases have a higher risk of COVID-19-related death, critical care admission or death, and hospital admissions than people without immune-mediated inflammatory diseases. The poor outcomes in these patients could be due to underlying diseases, immunotherapy, and/or other comorbidities.^1,8

Study Limitations and Future Directions

This study had some limitations. First, it was a retrospective study, and some defects in the study design cannot be ignored (eg, small sample size, single-center design). Second, some of the patients were not tested for immunoglobulins. Third, data on vaccination were not available, so the effects of vaccination on patient outcomes were ignored in the cohort. We plan to conduct two follow-up studies to assess the effects of vaccination on the outcomes of patients on RTX and the incidence of hypogammaglobulinemia in RTX receivers.

Conclusion

We found that neurological disorders were the most common reason for RTX use. Approximately half of the patients received RTX at a dose of 375 mg/m2. Almost half of the patients received steroids. Hypogammaglobulinemia was seen in 37.1% of patients. ICU admission occurred in 25.7% of cases, and there was a statistically significant association between ICU admission and age, steroid use, and low CD19 levels. The mortality rate was 25.7%, and the mortality rate was higher in patients receiving RTX if they were older, had diabetes, were on steroids, were hospitalized or admitted to the ICU, or had low immunoglobulin or CD19 levels.

Recommendation

Although RTX is an effective and safe medication for the treatment of various autoimmune diseases and hematologic malignancies, still RTX may cause an increased risk of infection and worse outcomes because of its immunosuppressive effects. Based on our findings, we recommend that patients who will start on RTX should be counseled regarding the risk of COVID-19 infection outcomes based on their individual risk factors. RTX should be used with caution or avoided unless the benefits clearly outweigh the risks. Finally, immunoglobulin testing should be performed in all patients started on RTX to know the baseline level of the patients. Multicenter studies with larger samples are needed to validate the results of this study.