Selection and characteristics of sources of evidence
Our iatrogenic B cell depletion search yielded 102 results. Twelve articles were removed after being deemed unrelated through screening of title and abstract. An additional 40 articles were excluded for wrong study type or irrelevant outcomes. The final analysis consisted of 50 studies: 13 cohort studies and 37 small case series or case reports. Our hIEI search yielded 51 results. Opinion articles, ecologic studies, and articles unrelated to COVID-19 hIEI clinical outcomes were excluded. Seven articles were included for final analysis including three case reports [19–21]. three cohort studies [22–24], and one literature review of case reports . Duplicate patient reports across studies were accounted for, and only patients with clearly defined hIEIs from cohort studies were included. Table I lists a summary of the papers included in this scoping review by condition studied.
Section A. Do patients with compromised humoral immunity from iatrogenic B cell depletion therapy have greater risk of COVID-19 infection compared to the general population?
Epidemiologic studies of incidence without comparators
Six studies (4 in patients with Multiple Sclerosis (MS), 1 in patients with rheumatic disease, and 1 in patients with pediatric nephrotic syndrome) identified the incidence of SARS-CoV-2 infection among patients on B cell depleting therapies (Table II). Four of these studies Incidence rates ranged from 0-33%, and all data was collected between April and May of 2020. None of the studies provided direct comparisons to incidence rates within the general population at the time of the study data collection.
Epidemiologic studies of incidence of SARS-CoV-2 infection with comparators
Two studies of patients with multiple sclerosis compared B cell depletion therapy patients’ risk of SARS-CoV-2 infection to patients with the same disease not on B cell depleting therapies (Table II). Both studies found an increased risk of infection among their patients on B cell depleting therapies compared to those not on B cell depleting therapies [26,27]. No studies of patients with rheumatic disease or nephrotic syndrome included a comparator group not on B cell depletion therapy.
Two additional studies in persons with multiple sclerosis (PwMS) reported comparisons between rates of anti-CD20 use among SARS-CoV-2 positive and negative patients. A retrospective study in Italy of 784 PwMS with suspected (n=593) or confirmed (n=191) COVID-19 found that PwMS with a suspected or confirmed SARS-CoV-2 infection were treated with Ocrelizumab at a significantly higher frequency than the general Italian PwMS population (OR=1·84,95%CI=1·31-2·56) , and New York study of SARS-CoV-2 positive/suspect positive PwMS noted a relatively high proportion of SARS-CoV-2 infected patients on anti-CD20 therapies (44.7%) compared with their PwMS population in which 33.1% of patients take anti-CD20 therapies . Based on the data mentioned above, there are no consistent findings that iatrogenic B cell depletion increases the risk of acquiring COVID-19.
Section B: Are patients with compromised humoral immunity at risk for more severe outcomes from COVID-19 than patients with functioning humoral systems?
Iatrogenic B cell depletion – Effects on COVID-19 disease severity
Through case reports, we identified 54 individual cases of COVID-19 among patients on anti-CD20 medications (supplementary table) reporting a variety of severity variables. 74% were hospitalized (29/39), 28% were treated outpatient (11/39), and 23% were in the ICU (9/39). Their reported duration of symptoms averaged 28.8 days.
Among case series assessing severity (Table III), two clinical case series (one in PwMS and one in patients with rheumatic disease) examined the severity of COVID-19 among patients on B cell depleting therapies compared to patients not on B cell depleting therapies. Odds ratio of severe infection ranged from 2.59 (1.43-4.67)  and 4.34(1.77-10.63)  compared to patients with the same disease not on B cell depleting therapies. Among studies examining patients with rheumatic disease a recent series from a French Registry of patients, using multivariate analysis, found that rituximab use was associated with an increased risk of severe infection (defined as requiring ICU admission or death) compared to mild or moderate(defined as requiring hospital admission) (OR=4.34 (1.77–10.63)) . Among the studies of PwMS, only a single study examined the influence of B cell depleting therapy on mortality in comparison to other immune based therapies, where Sormani et al.  found an increased risk of severe disease (defined as developing at least one of death, ICU admission, diagnosis of pneumonia, or hospitalization) among patients on anti-CD20 agents Ocrelizumab or Rituximab compared to PwMS with COVID-19 not on B cell depleting therapies adjusting for likely cofactors that could affect disease outcome (OR= 2.59 (1.43-4.67)) .
In terms of variables reflecting disease severity, death is the most specific. Ten case series were identified that provided mortality rates among patients on CD-20 depleting therapies with COVID-19 or suspected COVID-19 (Tables II and III). Among these, 5 studies focused on PwMS, 4 on patients with rheumatic diseases, and one in patients with cancer (Tables II and III). The number of patients on B cell depleting drugs in these series ranged from 3 to 1858 and the mortality ranged from 0 to 33% (Tables II and III).
Two studies of rheumatic diseases incorporated multivariable logistic regression analysis and a comparator group to assess risk of mortality among those with rheumatic disease on B cell depleting therapy (Table III) [30,31]. In the French Registry, the odds ratio for death among patients on rituximab compared to a matched control group was elevated (4.04, 1.35-12.04) . In the largest study of patients with rheumatic disease and COVID-19, the Global Rheumatology Alliance analyzed 3729 patients (192 of which were on rituximab) and found rituximab carried the highest odds of death compared to patients on methotrexate monotherapy in both unadjusted and adjusted multivariable logistic regression models (adjusted for potential explanatory variables including other medications and comorbidities; OR 4.04, 2.32-7.03) . Unfortunately, no study among PwMS provided a focused statistical analysis of mortality rates among B cell depleted patients. Thus, based upon these data with their inherent limitations it appears that iatrogenic B cell depletion may be associated with both increased risk of severe disease and risk of mortality among patients both with rheumatic disease as well as multiple sclerosis.
Humoral Inborn Errors of Immunity - Effects on COVID-19 disease severity
Our search identified 69 unique patients (37.7% female) with hIEIs and confirmed SARS-CoV-2 infection from across the globe (Table IV). The majority of patients (42) had common variable immunodeficiency (CVID) [19,22–25]. Thirteen patients had agammaglobulinemia (10 X-linked, three autosomal recessive) [21–25]. Five patients had specific immunoglobulin deficiencies (IgG, IgA, or both) [20,22–24]; four patients had otherwise unspecified hypogammaglobulinemia [22,23]; two patients each had hyper-IgM disease[22,24] and antibody deficiency with syndromic features ; and one patient had activated PI3K delta syndrome (APDS) . The age distribution of the cohort ranged from pediatric patients to the elderly (>75), though patients with agammaglobulinemia were younger on average than their CVID counterparts (no patient older than 54). Mean age could not be calculated due to incomplete data.
The risk of SARS-CoV-2 infection among patients with hIEI remains incompletely understood, as most studies examined clinical outcomes in hIEI patients with confirmed SARS-CoV-2 infection rather than incidence of infection. However, one large cohort study of 4718 patients with primary immunodeficiencies (PIDs) in Iran, including 1001 with hIEIs alive during the pandemic, found 19 confirmed cases of SARS-CoV-2 infection, with four cases among hIEI patients. Overall, the incidence of infection in this PID cohort was only 1.23 fold higher than the general population. Importantly, as the authors noted, the external validity of this may be limited due to pediatric skew of the cohort as well as increased precautions taken by patients with PIDs .
Within the CVID cohort (45% female) identified by our search, 10 patients (24%) required intensive care and/or mechanical ventilation. Sixteen patients were hospitalized without intensive care, and the 16 remaining patients were either asymptomatic or received outpatient care only. Treatment regimens varied from supportive care only to aggressive multidrug regimens of antibiotics, steroids, and immunomodulatory agents. Patient comorbidities also varied significantly, from none to chronic lung, liver, endocrine, cardiovascular, and kidney disease. In total, seven (16.7%) CVID patients died, all of them female. Among 12 CVID patients without notable comorbidities, one died, and among seven patients age 65 or older, two died [19,22–25].
Among 13 agammaglobulinemia patients (100% male), one patient required intensive care, nine patients were hospitalized without intensive care, and three patients were either asymptomatic or received outpatient care only. Treatment varied from supportive care only to convalescent plasma infusions, antibiotics, and immunomodulatory agents. Strikingly, although over half (7) of these patients had pre-existing comorbid lung disease (e.g., COPD, bronchiectasis), all of them recovered from COVID-19 [21–25].
Based on these limited data, it appears that patients with dysregulated humoral immune responses, such as CVID, may be more susceptible to severe COVID-19 than patients with ostensibly more severe, but select, humoral immunodeficiency states characterized by agammaglobulinemia.