Background:Patients with predominantly antibody deficiency (PAD) have lower anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antibody levels after initial 2-dose SARS-CoV-2 vaccination than healthy controls do; however, the anti-spike antibody responses and neutralization function in patients with PAD following subsequent immunizations remain understudied. Objective:We sought to characterize anti-spike antibody responses in adults with PAD over the course of 5 SARS-CoV-2 vaccine doses and identify diagnostic and immunophenotypic risk factors for low antibody response. Methods:We evaluated anti-spike antibody levels in 117 adult patients with PAD and 192 adult healthy controls following a maximum of 5 SARS-CoV-2 immunizations. We assessed neutralization of the SARS-CoV-2 wild-type strain and the Omicron BA.5 variant and analyzed infection outcomes. Results:The patients with PAD had significantly lower mean anti-spike antibody levels after 3 SARS-CoV-2 vaccine doses than the healthy controls did (1,439.1 vs 21,890.4 U/mL [P < .0001]). Adults with secondary PAD, severe primary PAD, and high-risk immunophenotypes had lower mean anti-spike antibody levels following vaccine doses 2, 3, and/or 4 but not following vaccine dose 5. Compared with patients with mild and moderate PAD, patients with severe PAD had a higher rate of increase in anti-spike antibody levels over 5 immunizations. A strong positive correlation was observed between anti-spike antibody levels and neutralization of both the SARS-CoV-2 wild-type strain and the Omicron BA.5 variant. Most infections were managed on an outpatient basis. Conclusions:In all of the patients with PAD, anti-spike antibody levels increased with successive SARS-CoV-2 immunizations and were correlated with neutralization of both the SARS-CoV-2 wild-type strain and the Omicron BA.5 variant. Secondary PAD, severe primary PAD, and high-risk immunophenotypes were correlated with lower mean anti-spike antibody levels following vaccine doses 2 through 4. Patients with severe PAD had the highest rate of increase in anti-spike antibody levels over 5 immunizations. These data suggest a clinical benefit to sequential SARS-CoV-2 immunizations, particularly among high-risk patients with PAD.

Daratumumab is an anti-CD38 monoclonal antibody approved for the treatment of multiple myeloma (MM) that targets both malignant and normal plasma cells. Potential effects of daratumumab therapy include hypogammaglobulinemia and increased risk for infections. We performed the largest retrospective analysis to date including 737 MM patients receiving daratumumab at our institution. We evaluated demographics, immunoglobulin (Ig) levels, and infection history. Hypogammaglobulinemia (IgG ≤ 600mg/dl) was evaluated pre- and post-daratumumab. Change in mean IgG levels was analyzed by a paired t-test. Infections were evaluated pre- and post-daratumumab infusion (day 0±100) and compared via McNemar's test. Risk factors for hypogammaglobulinemia and infection were calculated using logistic and Poisson regressions. We included 737 patients who had received daratumumab (58% male, mean age 69 years [STD±12]). Following daratumumab therapy, 319/737 (43.3%) developed severe infections; 244 (33.1%) of which required hospitalization. The prevalence of hypogammaglobulinemia increased following treatment with daratumumab (pre: 309/558 patients [55.4%] to post: 277/379 [73.1%]). Pre-existing hypogammaglobulinemia was a risk factor for hypogammaglobulinemia post-daratumumab (OR 8.95; 95% CI 5.19-15.46; p<0.0001). Of those with IgG levels checked both pre- and post-daratumumab, mean nadir IgG level decreased significantly (928.3 to 760.1 mg/dL; p=0.02). There was an increase in patients with infections post-daratumumab (pre: 15.8% to post: 21.1%, p=0.005). A greater decrease in IgG level (>168mg/dL) after daratumumab was associated with significantly higher rates of infection (IRR 1.47; 95% CI 1.26-1.73; p<0.0001). Daratumumab was associated with increasing hypogammaglobulinemia and increased infections. Further analyses are needed to elucidate the effects of daratumumab and identify mitigating factors.

Patients with Predominantly Antibody Deficiency (PAD) demonstrate lower anti-SARS-CoV-2 spike antibody response after initial two-dose SARS-CoV-vaccination; however, their response over subsequent SARS-CoV-2 immunizations remains understudied.

Adults with predominantly antibody deficiency (PAD) are at risk for lower anti-spike antibody responses following the initial two-dose SARS-CoV-2 immunization series compared to healthy controls; however, the immunophenotypic risk factors for low anti-spike antibody responses remain understudied, particularly following subsequent vaccine doses. Anti-spike antibody levels were assessed in 117 adults with PAD and varying immunophenotypes following a maximum of five SARS-CoV-2 vaccine doses using analysis of covariance and Spearman's rank correlation coefficient. Patients with PAD (n=117) had mild (23.1%), moderate (31.7%), or severe (45.2%) clinical disease. Patients with low class-switched memory B cells (< 2% of total CD19+ B cells), low absolute counts of CD19+ B cells (≤ 90 cells/uL), and low absolute counts of CD4+ T cells (≤ 419 cells/uL) initially demonstrated lower anti-spike antibody levels following SARS-CoV-2 vaccine doses two, three and/or four. Total absolute CD19+ B cell count was a predominant immunophenotypic factor positively associated with anti-spike antibody levels following doses two through four. In contrast, after five SARS-CoV-2 vaccine doses, no significant differences in anti-spike antibody levels were identified between these high and low risk immunophenotypic groups (absolute B cell count: 5,080.2 versus normal range 10,888.6 U/mL, p = 0.1; absolute T cell count: 4,617.6 versus 11,198.7 U/mL, p = 0.05; and class-switched memory B cell frequency: 7,621.3 versus 11,665 U/mL, p = 0.3). Adults with PAD and high-risk immunophenotypes, particularly those with low absolute CD19+ B cells, low absolute CD4+ T cells, and low class-switched memory B cells, may particularly benefit from sequential SARS-CoV-2 immunizations.

Efgartigimod, an anti-neonatal Fc receptor (FcRn) monoclonal antibody recently approved for IgG-mediated autoimmune diseases, such as myasthenia gravis, accelerates IgG destruction via FcRn inhibition. Due to recent FDA approval of efgartigimod, data regarding the risk of hypogammaglobulinemia and infections in patients receiving efgartigimod is limited.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with predominant antibody deficiency (PAD) is associated with high morbidity, yet data regarding the response to SARS-CoV-2 immunization in PAD patients, including additional dose vaccine, are limited. OBJECTIVE: To characterize antibody response to SARS-CoV-2 vaccine in PAD patients and define correlates of vaccine response. METHODS: We assessed the levels and function of anti-SARS-CoV-2 antibodies in 62 PAD patients compared with matched healthy controls at baseline, at 4 to 6 weeks after the initial series of immunization (a single dose of Ad26.COV2.S [Janssen] or two doses of BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]), and at 4 to 6 weeks after an additional dose immunization, if received. RESULTS: After the initial series of SARS-CoV-2 vaccination, PAD patients had lower mean anti-spike antibody levels compared with matched healthy controls (140.1 vs 547.3 U/mL; P = .02). Patients with secondary PAD (eg, B-cell depletion therapy was used) and those with severe primary PAD (eg, common variable immunodeficiency with autoinflammatory complications) had the lowest mean anti-spike antibody levels. Immune correlates of a low anti-spike antibody response included low CD4(+) T helper cells, low CD19(+) total B cells, and low class-switched memory (CD27(+)IgD/M-) B cells. In addition, a low (<100 U/mL) anti-spike antibody response was associated with prior exposure to B-cell depletion therapy, both at any time in the past (odds ratio = 5.5; confidence interval, 1.5-20.4; P = .01) and proximal to vaccination (odds ratio = 36.4; confidence interval, 1.7-791.9; P = .02). Additional dose immunization with an mRNA vaccine in a subset of 31 PAD patients increased mean anti-spike antibody levels (76.3 U/mL before to 1065 U/mL after the additional dose; P < .0001). CONCLUSIONS: Patients with secondary and severe primary PAD, characterized by low T helper cells, low B cells, and/or low class-switched memory B cells, were at risk for low antibody response to SARS-CoV-2 immunization, which improved after an additional dose vaccination in most patients. (C) 2022 American Academy of Allergy, Asthma & Immunology

Background Non-invasive biomarkers of immune checkpoint inhibitor-associated acute tubulointerstitial nephritis (ICI-nephritis) are urgently needed. Because ICIs block immune checkpoint pathways that include cytotoxic T lymphocyte antigen 4 (CTLA4), we hypothesized that biomarkers of immune dysregulationpreviously defined in patients with congenital CTLA4 deficiency, including elevated soluble interleukin-2 receptor alpha (sIL-2R) and flow cytometric cell-based markers of B and T cell dysregulation in peripheral blood may aid the diagnosis of ICI-nephritis.Methods A retrospective cohort of patients diagnosed with ICI-nephritis was compared with three prospectively enrolled control cohorts: ICI-treated controls without immune-related adverse events, patients not on ICIs with hemodynamic acute kidney injury (hemodynamic AKI), and patients not on ICIs with biopsy proven acute interstitial nephritis from other causes (non-ICI-nephritis). sIL-2R level and flow cytometric parameters were compared between groups using Wilcoxon rank sum test or Kruskal-Wallis test. Receiver operating characteristic curves were generated to define the accuracy of sIL-2R and flow cytometric biomarkers in diagnosing ICI-nephritis. The downstream impact of T cell activation in the affected kidney was investigated using archived biopsy samples to evaluate the gene expression of IL2RA, IL-2 signaling, and T cell receptor signaling in patients with ICI-nephritis compared with other causes of drug-induced nephritis, acute tubular injury, and histologically normal controls.Results sIL-2R level in peripheral blood was significantly higher in patients with ICI-nephritis (N=24) (median 2.5-fold upper limit of normal (ULN), IQR 1.9–3.3), compared with ICI-treated controls (N=10) (median 0.8-fold ULN, IQR 0.5–0.9, p<0.001) and hemodynamic AKI controls (N=6) (median 0.9-fold-ULN, IQR 0.7–1.1, p=0.008). A sIL-2R cut-off point of 1.75-fold ULN was highly diagnostic of ICI-nephritis (area under the curve >96%) when compared with either ICI-treated or hemodynamic AKI controls. By peripheral blood flow cytometry analysis, lower absolute CD8+T cells, CD45RA+CD8+ T cells, memory CD27+B cells, and expansion of plasmablasts were prominent features of ICI-nephritis compared with ICI-treated controls. Gene expressions for IL2RA, IL-2 signaling, and T cell receptor signaling in the kidney tissue with ICI-nephritis were significantly higher compared with controls.Conclusion Elevated sIL-2R level and flow cytometric markers of both B and T cell dysregulation may aid the diagnosis of ICI-nephritis.

Nodular regenerative hyperplasia (NRH) is associated with high morbidity and mortality in patients with common variable immunodeficiency (CVID). While liver biopsy is the gold standard for NRH diagnosis, a non-invasive technique could facilitate early disease recognition, monitoring, and/or immune intervention. We performed a cross-sectional analysis of ultrasound-based transient elastography (TE) in patients with CVID to evaluate liver stiffness and compared this between patients with (N = 12) and without (N = 6) biopsy-proven NRH. Additionally, these data were compared to a cohort followed at our institution for non-alcoholic fatty liver disease (NAFLD) (N = 527), a disease for which TE has routine diagnostic use. Clinical and pathologic features of NRH were evaluated as correlates of liver stiffness, and receiver operating characteristic curves were used to define a liver stiffness cutoff with diagnostic utility for NRH among CVID patients. CVID patients with NRH had a more severe disease presentation compared to those without. This included increased autoinflammatory disease comorbidities, combined B-cell and T-cell dysfunction, and abnormal liver biochemistries (specifically an increased mean alkaline phosphatase level [proximal to TE, 250 vs. 100 U/L; p = 0.03; peak, 314 vs. 114 U/L; p = 0.02). Results of TE demonstrated a significantly elevated liver stiffness in CVID patients with NRH (mean 13.2 ± 6.2 kPa) as compared to both CVID patients without NRH (mean 4.6 ± 0.9 kPa) and non-CVID patients with NAFLD (mean 6.9 ± 5.5 kPa) (p < 0.01). No single or composite histopathologic feature of NRH correlated with liver stiffness including nodule size, nodule density, sinusoidal dilation, fibrosis, and/or lymphocytosis. In contrast, liver stiffness by TE was significantly correlated with clinical parameters of portal hypertension, including an elevated hepatic venous pressure gradient, an increased splenic longitudinal diameter, presence of varices, and presence of peripheral edema. A liver stiffness of greater than or equal to 6.2 kPa was a clinically significant cutoff for NRH in CVID patients. We propose that TE has diagnostic utility in CVID, particularly in the presence of immunophenotypic features such as combined B-cell and T-cell dysfunction, autoinflammatory comorbidities, and/or abnormal liver tests. Elevated liver stiffness by TE should raise suspicion for NRH in patients with CVID and prompt expedited evaluation by hepatology.

Effective vaccination is imperative for protection against severe SARS-CoV-2 infection, particularly in immunodeficient populations. Unfortunately, those with immunodeficiency often mount inadequate vaccine responses. We aimed to study the immunogenicity of SARS-CoV-2 vaccines in patients with immunodeficiency. Sixty-two patients with immunodeficiency at our center who received the BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna) or Ad26.COV2.S (Janssen) SARS-CoV-2 vaccine series with SARS-CoV-2 spike antibody levels available were evaluated. SARS-CoV-2 spike antibodies were compared to healthy controls matched by age and time from vaccination at a 1:1 ratio. A subset of patients received additional mRNA vaccine dose(s). Participants with positive SARS-CoV-2 PCR or nucleocapsid antibody (if not on replacement immunoglobulin) were excluded. Participants with immunodeficiency (N=62) had lower spike antibody titers than healthy controls (N=62, mean 1699 v. 3307 U/mL, p=0.02). Those with specific antibody deficiency and IgG subclass deficiency (N=8) demonstrated higher spike antibody titer compared to those with more severe immune phenotypes (N=54, 4338 v. 1308 U/mL, p=0.01). Those with switched memory B-cells <2% (N=24) had reduced odds of positive spike antibody titer (>/=100 U/mL, OR 0.09, 95%CI 0.02-0.5). An additional mRNA vaccine dose after initial series resulted in an increase in titer for most patients (59 v. 952 U/mL, p=0.05). SARS-CoV-2 vaccination resulted in lower spike antibody levels in patients with immunodeficiency. Patients with severe immunodeficiency, especially those with low switched memory B-cells, had highest risk of inadequate vaccine response. An additional vaccine dose increased SARS-CoV-2 antibodies in those with incomplete responses after initial series.

Background: Rituximab is a B-cell depleting agent used in B-cell malignancies and autoimmune diseases. A subset of adult patients may develop prolonged and symptomatic hypogammaglobulinemia following rituximab treatment. However, this phenomenon has not been well delineated in the pediatric population. Objectives: This study sought to determine the prevalence, risk factors, and clinical significance of hypogammaglobulinemia following rituximab therapy in children. Methods: This was a multicenter, retrospective cohort study that extracted clinical and immunological data from pediatric patients who received rituximab. Results: The cohort comprised 207 patients (median age, 12.0 years). Compared to baseline values, there was a significant increase in hypogammaglobulinemia post-rituximab therapy, with an increase in prevalence of hypo-IgG (28.7%-42.6%; P = .009), hypo-IgA (11.1%-20.4%; P = .02), and hypo-IgM (20.0%-62.0%; P < .0001). Additionally, low IgG levels at any time post-rituximab therapy were associated with a higher risk of serious infections (34.4% vs 18.9%; odds ratio, 2.3; 95% CI, 1.1-4.8; P = .03). Persistent IgG hypogammaglobulinemia was observed in 27 of 101 evaluable patients (26.7%). Significant risk factors for persistent IgG hypogammaglobulinemia included low IgG and IgA levels pre-rituximab therapy. Nine patients (4.3%) within the study were subsequently diagnosed with a primary immunodeficiency, 7 of which received rituximab for autoimmune cytopenias. Conclusions: Hypogammaglobulinemia post-rituximab treatment is frequently diagnosed within the pediatric population. Low IgG levels are associated with a significant increase in serious infections, and underlying primary immunodeficiencies are relatively common in children receiving rituximab, thus highlighting the importance of immunologic monitoring both before and after rituximab therapy.

BACKGROUND:Massachusetts began newborn screening (NBS) for severe combined immunodeficiency (SCID) using measurement of T-cell receptor excision circles (TRECs) from dried blood spots. OBJECTIVE:We describe developments and outcomes from the first 10 years of this program (February 1, 2009, to January 31, 2019). METHODS:TREC values, diagnostic, and outcome data from all patients screened for SCID were evaluated. RESULTS:NBS of 720,038 infants prompted immunologic evaluation of 237 (0.03%). Of 237, 9 were diagnosed with SCID/leaky SCID (4% of referrals vs 0.001% general population). Another 7 were diagnosed with other combined immunodeficiencies, and 3 with athymia. SCID/leaky SCID incidence was approximately 1 in 80,000, whereas approximately 1 in 51,000 had severe T-cell lymphopenia for which definitive treatment was indicated. All patients with SCID/leaky SCID underwent hematopoietic cell transplant or gene therapy with 100% survival. One patient with athymia underwent successful thymus transplant. No known cases of SCID were missed. Compared with outcomes from the 10 years before SCID NBS, survival trended higher (9 of 9 vs 4 of 7), likely due to a lower rate of infection before treatment. CONCLUSIONS:Our data support a single NBS testing-and-referral algorithm for all gestational ages. Despite lower median TREC values in premature infants, the majority for all ages are well above the TREC cutoff and the algorithm, which selects urgent (undetectable TREC) and repeatedly abnormal TREC values, minimizes referral. We also found that low naïve T-cell percentage is associated with a higher risk of SCID/CID, demonstrating the utility of memory/naïve T-cell phenotyping as part of follow-up flow cytometry.

Chimeric antigen receptor T- (CAR T) cell therapy has revolutionized the treatment of relapsed and refractory hematologic malignancies. The two first FDA-approved CAR T-cell therapies, tisagenlecleucel and axicabtagene ciloleucel, target the CD19+ receptor on B-cells, and have potential adverse effects including B-cell aplasia and hypogammaglobulinemia. There are sparse data on immunologic outcomes in these patients. We performed a retrospective evaluation of patients receiving CAR T-cell therapy in a large healthcare system. We evaluated demographics, indication for CAR T-cell therapy, frequency of immunologic evaluation, and hypogammaglobulinemia pre- and post-CAR T-cell therapy. Hypogammaglobulinemia was stratified as mild (Immunoglobulin G [IgG] <650mg/dL), moderate (IgG <400mg/dL) or severe (IgG <200mg/dL). We identified 101 patients who received tisagenlecleucel or axicabtagene ciloleucel for diffuse large B-cell lymphoma (n=88), follicular lymphoma (n=11), and CNS lymphoma (n=2). Of 59/101 patients with immunoglobulins evaluated prior to therapy, 35 (35%) had hypogammaglobulinemia: 27/35 (77%) mild, 6/35 (17%) moderate, and 2/35 (6%) severe. Following CAR T-cells, 72/81(89%) patients with immunoglobulins evaluated had hypogammaglobulinemia: 22/72 (31%) mild, 41/72 (57%) moderate, and 9/72 (13%) severe. The median time to nadir IgG levels was 2 months (interquartile range 1-6 months) post-CAR T-cell therapy. In the 46 patients who had both pre- and post-CAR T-cell therapy immunoglobulins evaluated, immunoglobulin levels decreased significantly post therapy (692mg/dL pre- vs. 392mg/dL post-; p <0.0001). Following CAR T-cell therapy, most patients were found to have hypogammaglobulinemia. Future studies are needed to evaluate if hypogammaglobulinemia is associated with worse clinical outcomes including excess infections and mortality.

NRH has been correlated with increased morbidity and mortality in CVID patients. Liver biopsy is the gold standard for NRH diagnosis, however, ideal would be an earlier, noninvasive diagnostic technique. We hypothesized that Fibroscan® (vibration controlled transient liver elastography) may facilitate the diagnosis of NRH in CVID patients. Using a published MGH CVID cohort, we identified CVID patients with biopsy-confirmed NRH ('NRH'), elevated liver biochemistries without biopsy-confirmed NRH ('at risk for NRH'), and non-elevated liver biochemistries ('control'). Patients with chronic viral hepatitis, non-alcoholic steatohepatitis, chronic alcohol use, and/or primary biliary cirrhosis were excluded. We reviewed both clinical Fibroscans, from the electronic medical record, and research-based Fibroscans. Fibroscan-obtained liver stiffness measurements (LSM, kPa) were compared using a two-tailed Student's t-test. Within the MGH CVID cohort, 'control' patients (n=3) had a median LSM of 4.9 kPa (range 4.1 – 5.8 kPa), 'NRH' patients (n=4) had a median LSM of 11.2 kPa (range 7.0 – 26.1 kPa), and 'at risk for NRH' patients (n=2) had a median LSM of 11.5 kPa (range 9.8-13.1 kPa). Compared to control CVID, LSMs were significantly elevated in CVID patients with known or suspected NRH (P = 0.031). These preliminary data suggest the diagnostic utility of Fibroscan in CVID patients with known or suspected NRH. Elevated liver biochemistries and LSMs may prompt liver biopsy and immediate immunosuppressive intervention. Further studies will extend these findings to the full CVID cohort, correlate Fibroscan reads with NRH disease severity on biopsy, and increase monitoring of liver stiffness following immunosuppressive therapy.

Common variable immunodeficiency (CVID) is a heterogeneous collection of disorders characterized by impaired B-cell differentiation and defective immunoglobulin production. It is the most common symptomatic primary immunodeficiency worldwide, with an estimated incidence of 1 in 25,000 to 30,000 people.1