Secondary Hypogammaglobulinemia Research Articles

110 Patient with Trisomy 21 and Congenital Chylothorax with Secondary Hypogammaglobulinemia

110 Patient with Trisomy 21 and Congenital Chylothorax with Secondary Hypogammaglobulinemia

Early Chimeric Antigen Receptor T Cell Expansion Is Associated with Prolonged Progression-Free Survival for Patients with Relapsed/Refractory Multiple Myeloma Treated with Ide-Cel: A Retrospective Monocentric Study

The outcomes of patients with relapsed and refractory multiple myeloma (RRMM) previously treated with the 3 main classes of myeloma therapy-immunomodulatory drugs, proteasome inhibitors, and anti-CD38 antibodies-remain poor. Recently, based on the phase II pivotal KarMMa trial showing prolonged overall survival (OS) and progression-free survival (PFS) in heavily treated patients, idecabtagene vicleucel (ide-cel), a B cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell therapy (CAR-T) product, was approved in the United States for the treatment of RRMM. In France, since June 2021, an early access program has authorized the use of ide-cel in the setting of RRMM (defined as progressive myeloma after at least 3 previous regimens, including the 3 main antimyeloma therapies). We report the first French experience through this early access program in a retrospective study of 24 consecutive patients treated with ide-cel at our institution. The patients were evaluated according to International Myeloma Working Group criteria and by positron emission tomography computed tomography (PET-CT) at 1, 3, 6, 9, and 12 months after ide-cel infusion. Most patients had adverse cytogenetic abnormalities, and RRMM with triple-refractory drugs were seen in 79%. Bridging therapy was required for 19 of 24 patients. Before CAR-T cell infusion, lymphodepletion with fludarabine and cyclophosphamide was systematically performed. The median follow-up was 15.2 months. At 3 months after ide-cel infusion, 92% of patients achieved at least a partial response, and 50% achieved a complete response or better (≥CR). At 6 months, 70% of patients had a persistent ≥CR. At 3 and 6 months, bone marrow minimal residual disease (10-6 level) was undetectable in 79% and 75% of patients, respectively. At 6 months, CR as assessed by PET-CT was achieved in 15 of 20 patients (75%). The median PFS was 14.8 months, and median OS was not reached. Notably, an expansion of circulating CAR-T cells to >180/mm3 after infusion was strongly associated with prolonged PFS. Additionally, the level of soluble BCMA measured before infusion was identified as a prognostic factor for PFS, likely correlated to the tumor burden. Grade 1-2 cytokine release syndrome (CRS) occurred in 22 of 24 patients (92%). Only 1 patient (4%) experienced grade ≥3 CRS. The occurrence of neurologic toxicity was infrequent (12.5%) and reversible in all cases. Hematologic toxicity was relatively common, and secondary hypogammaglobulinemia occurred in most patients. Infections (mostly viral) were frequent but most often nonsevere. This study echoes the promising results of the KarMMa trial and identifies possible prognostic indicators in RRMM patients treated with ide-cel, potentially refining treatment strategies and improving outcomes in this challenging context.

Secondary hypogammaglobulinemia in adults—A large retrospective cohort study

Background and objectiveIgG replacement therapy (IgG-RT) has radically changed the clinical evolution of primary immunodeficiencies, yet the information regarding secondary hypogammaglobulinemia (SHG) is insufficient or conflicting. We aim to describe clinical features, evolution and treatment of SHG patients in our center. MethodsDynamic retrospective cohort between January 2001 and July 2021 of adults with gamma globulin fraction <0.6g/dL in a serum protein electrophoresis and a coincident decrease of IgG levels – with a disease-related SHG or treatment that reduces serum immunoglobulins. ResultsWe included 1012 patients with SHG with a median follow-up of 5 years (IQR 2–8). Hematological diseases were identified in 95% of the patients and 61% received drugs related to SHG. Sixty five percent had more than one etiological factor associated with SHG. Infectious diseases were present in 69% of the patients, 48% had respiratory infections and 17% had severe infections. There was statistical association between respiratory and severe infections with multiple myeloma (MM), lymphoma and rituximab. MGUS had less infections and death compared with other etiologies. IgG-RT was indicated in 18.7% of the patients and 4.6% received it for more than 6 months with variable intervals. Among the latter group, there was a significant reduction of all-type infections and respiratory infections with IgG-RT (p<0.001), and it was consistent with similar findings in lymphoma, MM and all IgG levels subgroups. ConclusionSHG was associated with more than one etiological factor and a high frequency of infections. IgG-RT indication was irregular yet still effective. It is relevant to consider IgG levels screening, monitoring and accurate indication of IgG-RT.

Secondary hypogammaglobulinemia in adults—A large retrospective cohort study

Background and objectiveIgG replacement therapy (IgG-RT) has radically changed the clinical evolution of primary immunodeficiencies, yet the information regarding secondary hypogammaglobulinemia (SHG) is insufficient or conflicting. We aim to describe clinical features, evolution and treatment of SHG patients in our center. MethodsDynamic retrospective cohort between January 2001 and July 2021 of adults with gamma globulin fraction <0.6g/dL in a serum protein electrophoresis and a coincident decrease of IgG levels – with a disease-related SHG or treatment that reduces serum immunoglobulins. ResultsWe included 1012 patients with SHG with a median follow-up of 5 years (IQR 2–8). Hematological diseases were identified in 95% of the patients and 61% received drugs related to SHG. Sixty five percent had more than one etiological factor associated with SHG. Infectious diseases were present in 69% of the patients, 48% had respiratory infections and 17% had severe infections. There was statistical association between respiratory and severe infections with multiple myeloma (MM), lymphoma and rituximab. MGUS had less infections and death compared with other etiologies. IgG-RT was indicated in 18.7% of the patients and 4.6% received it for more than 6 months with variable intervals. Among the latter group, there was a significant reduction of all-type infections and respiratory infections with IgG-RT (p<0.001), and it was consistent with similar findings in lymphoma, MM and all IgG levels subgroups. ConclusionSHG was associated with more than one etiological factor and a high frequency of infections. IgG-RT indication was irregular yet still effective. It is relevant to consider IgG levels screening, monitoring and accurate indication of IgG-RT.

Immunoglobulin replacement vs prophylactic antibiotics for hypogammaglobulinemia secondary to hematological malignancy

AbstractImmunoglobulin replacement and prophylactic antibiotics are commonly used to prevent infections in patients with secondary hypogammaglobulinemia due to hematological malignancies but have never been directly compared. In this randomized controlled feasibility trial conducted in 7 hospitals in Australia and New Zealand, we enrolled patients with secondary hypogammaglobulinemia with either a history of recurrent/severe infection or an immunoglobulin G level <4 g/L. Participants were randomized in a 1:2 ratio to immunoglobulin (0.4 g/kg per 4 weeks IV) or daily antibiotics (trimethoprim-sulfamethoxazole 160 mg/800 mg or, if contraindicated, 100 mg doxycycline) for 12 months. Participants allocated to antibiotics were allowed to crossover after grade ≥3 infections. The primary outcome was proportion of patients alive on the assigned treatment 12 months after randomization. Between August 2017 and April 2019, 63 patients were randomized: 42 to antibiotics and 21 to immunoglobulin. Proportion of participants alive on allocated treatment at 12 months was 76% in the immunoglobulin and 71% in the antibiotic arm (Fisher exact test P=.77; odds ratio, 0.78; 95% CI, 0.22-2.52). The lower quartile for time to first major infection (median, not reached) was 11.1 months for the immunoglobulin and 9.7 months for the antibiotic arm (log-rank test, P=.65). Three participants in the immunoglobulin and 2 in the antibiotic arm had grade ≥3 treatment-related adverse events. A similar proportion of participants remained on antibiotic prophylaxis at 12 months to those on immunoglobulin, with similar rates of major infections. Our findings support the feasibility of progressing to a phase 3 trial. Trial registration #ACTRN12616001723471.

Secondary hypogammaglobulinemia in patients with multiple sclerosis on anti-CD20 therapy: Pathogenesis, risk of infection, and disease management.

Hypogammaglobulinemia is characterized by reduced serum immunoglobulin levels. Secondary hypogammaglobulinemia is of considerable interest to the practicing physician because it is a potential complication of some medications and may predispose patients to serious infections. Patients with multiple sclerosis (MS) treated with B-cell-depleting anti-CD20 therapies are particularly at risk of developing hypogammaglobulinemia. Among these patients, hypogammaglobulinemia has been associated with an increased risk of infections. The mechanism by which hypogammaglobulinemia arises with anti-CD20 therapies (ocrelizumab, ofatumumab, ublituximab, rituximab) remains unclear and does not appear to be simply due to the reduction in circulating B-cell levels. Further, despite the association between anti-CD20 therapies, hypogammaglobulinemia, and infections, there is currently no generally accepted monitoring and treatment approach among clinicians treating patients with MS. Here, we review the literature and discuss possible mechanisms of secondary hypogammaglobulinemia in patients with MS, hypogammaglobulinemia results in MS anti-CD20 therapy clinical trials, the risk of infection for patients with hypogammaglobulinemia, and possible strategies for disease management. We also include a suggested best-practice approach to specifically address secondary hypogammaglobulinemia in patients with MS treated with anti-CD20 therapies.

Newly identified common variable immunodeficiency in an elderly patient with rheumatoid arthritis

Common variable immunodeficiency is a group of heterogeneous diseases that are primary immunodeficiencies with a predominant lack of antibody synthesis. The most common manifestation is chronic infectious pathology of the respiratory tract, less often of the gastrointestinal tract, as well as septic arthritis. Non-infectious manifestations include autoimmune diseases, non-infectious diarrhea, cancer, benign lymphoid hyperplasia. In one patient, a combination of several syndromes is possible. Unlike most other primary immunodeficiencies that debut in early childhood, this pathology often manifests in the third or fourth decade of life, and sometimes later in apparently healthy people. Although the routine laboratory method for determining the concentration of the main classes of immunoglobulins makes it quite easy to identify patients with common variable immunodeficiency, often the diagnosis is made many years after the onset of the first clinical symptoms, when serious complications have already developed. The disease is characterized by a gradual onset, chronic progressive course and ineffectiveness of standard therapy. The main method of treatment is lifelong replacement therapy with intravenous immunoglobulins. The article considers a clinical case when an elderly patient with seronegative rheumatoid arthritis with a juvenile onset was diagnosed many years later. The results of immunological studies, including immunophenotyping of peripheral blood and bone marrow lymphocytes, are presented. Issues of differential diagnosis with secondary hypogammaglobulinemia and lymphoproliferative diseases are highlighted. It has been stated that until now, doctors of various specialties are not sufficiently familiar with the problem of primary immunodeficiencies, especially when it comes to adults, and non-infectious manifestations dominate in the clinical picture.

Clinical outcomes following cessation of parenteral immunoglobulin therapy following lung transplantation

Broad use of parenteral immunoglobulin (IgG) therapy in lung transplant (LTx) patients occurs without robust clinical evidence or guidelines. Main indications include secondary hypogammaglobulinemia, antibody-mediated rejection (AMR), and treatment or prevention of graft rejection where the use of conventional immunosuppressive therapies is contraindicated. As part of routine auditing of IgG use in our LTx service, we assessed for adverse clinical outcomes related to IgG therapy cessation between November 2017 and February 2022. Of 220 LTx recipients receiving IgG therapy at our center during this period (approximately 20% of our total LTx cohort), 48 patients ceased therapy. No adverse outcomes were experienced in 83.3% patients. About 10.4% recommenced therapy for the same indication within 6months with no longer term sequelae. One AMR patient developed progressive Chronic lung allograft dysfunction and died within 12months, where therapy cessation was patient-initiated and associated with general noncompliance. These data provide reassurance that physician-directed cessation of IgG therapy is safe when based on sound clinical information and part of a robust clinical auditing process.

Thawed plasma (TP) as a substitute for intravenous immune globulin (IVIG) to prevent hypogammaglobulinemia post-therapeutic plasma exchange

Intravenous immune globulin (IVIG) is a common treatment given after plasma exchange procedures to either prevent secondary hypogammaglobulinemia or as an adjunctive treatment for organ transplant rejection. However, side-effects are relatively common with this medication during and after infusion. This case-report describes our alternative to IVIG infusions post-plasma exchange. We hypothesize that in patients unable to tolerate IVIG, using thawed plasma as a replacement fluid provides a suitable increase in the patients post procedure immunoglobulin G (IgG) levels for patients with secondary hypogammaglobulinemia that are unable to tolerate IVIG infusions.

IgG Replacement Therapy Use in Patients with Hypogammaglobulinemia after Lung Transplant

BackgroundSecondary hypogammaglobulinemia (HG) occurs in up to 73% of patients in the first year post-lung transplant (LT). Severe HG (sHG) with immunoglobulin (Ig)G levels <400 mg/dL is associated with increased infections and mortality. Although IgG replacement therapy (IGRT) may mitigate adverse outcomes associated with HG, further investigation is needed to understand the optimal role for IGRT in HG management. MethodsData were reviewed for 191 patients who underwent first LT before 11/30/2021 with HG (at least one IgG < 600 mg/dL) post-transplant. Bacterial and fungal microbiology results (bronchoalveolar lavage, induced sputum culture, bronchial lavage), IGRT prescriptions, and IgG levels were chart-reviewed. Antimicrobial prescriptions were extracted from electronic medical records. Active infection (AI) was defined as prescription of a non-prophylactic antimicrobial; severe AI (SAI) as inpatient or intravenous prescription of a non-prophylactic antimicrobial. Positive microbiology results, AI, and SAI were reported in patient-years for the one year after first IgG < 600 mg/dL in 141 patients who never received IGRT (No-IGRT), and for the time between LT and IGRT initiation (Pre-IGRT) as well as the one year after IGRT initiation (Post-IGRT) in 50 patients who received IGRT. ResultsIGRT was initiated for secondary HG 82% (41/50), donor specific antibodies 12% (6/50), cytomegalovirus 2% (1/50), and both secondary HG and donor specific antibodies 4% (2/50). Thirty-seven patients started intravenous-IGRT (IVIG), of whom 5 switched to subcutaneous-IGRT (SCIG) during the course of treatment. Thirteen started SCIG, of whom 2 switched to IVIG. IVIG was administered for 18 ± 18 (mean ± standard deviation) doses of 41 ± 22 grams/month over 71 ± 74 weeks. SCIG was administered for 74 ± 53 doses of 27 ± 20 grams/month over 86 ± 64 weeks.There were more AI and SAI per patient-year Pre-IGRT (15.8 and 11.7, respectively) than No-IGRT (4.9 and 2.6) and Post-IGRT (8.3 and 5.8). Positive microbiology results per patient-year were 3.8 Pre-IGRT, 3.3 Post-IGRT, and 2.3 No-IGRT. Among 29 patients with sHG, positive microbiology results per patient-year were 4.8 Pre-IGRT, 4.3 Post-IGRT, and 3.1 No-IGRT.Table 1Infectious Agents Detected on Pulmonary MicrobiologyOrganism (n, %)No-IGRT (n = 318)Pre-IGRT (n = 251)Post-IGRT (n = 166)Penicillium spp.52 (16)36 (14)13 (8)Aspergillus spp.59 (18)34 (13)28 (17)Staphylococcus epidermidis8 (3)21 (9)7 (4)Pseudomonas aeruginosa20 (7)17 (7)18 (11)Staphylococcus aureus2 (1)15 (6)12 (7)Enterococcus spp.0 (0)10 (4)3 (2)Mycobacterium spp.7 (2)12 (5)4 (2)Sterile mycelium8 (3)9 (3)3 (2)Stenotrophomonas maltophilia3 (1)9 (3)8 (5)Enterobacter cloacae complex1 (<1)8 (3)3 (2)Escherichia coli4 (1)7 (3)7 (4)Haemophilus parainfluenzae44 (13)4 (2)9 (5)Klebsiella pneumoniae11 (3)2 (1)8 (5)Other99 (31)67 (27)43(26)Legend: The 735 specific microorganisms detected on bronchoalveolar lavage, sputum culture and bronchial lavage are shown. Abbreviation: Species (spp.) ConclusionThese findings suggest that IGRT was utilized for patients who presented with infections in addition to HG, with a possible decrease in antimicrobial use after initiation.

An updated perspective on immunoglobulin replacement in chronic lymphocytic leukaemia in the era of targeted therapies.

Chronic lymphocytic leukaemia (CLL) is a malignancy of clonally expanded antigen-switched, neoplastic, mature B cells. CLL is characterised by a variable degree of immunosuppression and secondary hypogammaglobulinemia. B-cell depleting therapies have historically been deployed with a proportion of patients becoming resistant to multiple lines of treatment with an associated worsening of immunosuppression and heightened infection risk. Advances in molecular diagnostics and the development of new therapies targeting Bruton's tyrosine kinase and B-cell lymphoma-2 have resulted in novel insights into the cellular mechanisms associated with an increased infection risk and T-cell escape from the complex tumour environment found in CLL. Generally, immunoglobulin replacement therapy with polyvalent human immunoglobulin G (IgG) is indicated in patients with recurrent severe bacterial infections and low IgG levels, but there is no consensus on the threshold IgG level for initiation of such therapy. A proportion of CLL patients have residual IgG production, with preserved quality of the immunoglobulin molecules, and therefore a definition of 'IgG quality' may allow for lower dosing or less frequent treatment with immunoglobulin therapy in such patients. Immunoglobulin therapy can restore innate immunity and in conjunction with CLL targeted therapies may allow T-cell antigen priming, restore T-cell function thereby providing an escape from tumour-associated autoimmunity and the development of an immune-mediated anti-tumour effect. This review aims to discuss the mechanisms by which CLL-targeted therapy may exert a synergistic therapeutic effect with immunoglobulin replacement therapy both in terms of reducing tumour bulk and restoration of immune function.

Hypogammaglobulinemia secondary to B-cell depleting therapies in neuroimmunology: Comparing management strategies.

Anti-CD20 agents are commonly used in MS, NMOSD, and MOGAD. Few studies have compared strategies to address hypogammaglobulinemia. To compare strategies to manage secondary hypogammaglobulinemia in neuroimmunology patients, including reducing anti-CD20 dose and dosing frequency, IVIG/SCIG, anti-CD20 cessation, and DMT switches. All MS, NMOSD, and MOGAD patients at our institution with hypogammaglobulinemia on anti-CD20 agents from 2001 to 2022 were analyzed. The median change in IgG, infection frequency, and infection severity before and after the treatment was calculated. In total, 257 patients were screened, and 30 had a treatment for hypogammaglobulinemia. IVIG/SCIG yielded the largest increase in IgG per year (674.0 mg/dL), followed by B-cell therapy cessation (34.7 mg/dL), and DMT switch (5.9 mg/dL). Dose reduction had the largest decrease in yearly infection frequency (2.7 fewer infections), followed by IVIG/SCIG (2.5 fewer), DMT switch (2 fewer), and reduced dosing frequency (0.5 fewer). Infection grade decreased by 1.9 for reduced dosing frequency (less severe infections), by 1.3 for IVIG/SCIG, and by 0.6 for DMT switch. This data suggests that IVIG/SCIG may yield the greatest recovery in IgG while also reducing infection frequency and severity. Stopping anti-CD20 therapy and/or switching DMTs also increase IgG and may lower infection risk.

Bortezomib is efficacious in the treatment of severe childhood-onset neuropsychiatric systemic lupus erythematosus with psychosis: a case series and mini-review of B-cell immunomodulation in antibody-mediated diseases.

Childhood-onset neuropsychiatric systemic lupus erythematosus (cNPSLE) with psychosis is a challenging manifestation of SLE. Pathogenic long-lived plasma cells (LLPCs) are not specifically targeted by standard immunosuppression and their persistence contributes to chronic autoimmunity. Bortezomib is approved for the treatment of multiple myeloma and has shown benefits in a variety of other antibody-mediated diseases. Bortezomib may be efficacious for severe or treatment-refractory cNPSLE through eradication of LLPCs, decreasing autoantibody production. We describe the first pediatric case series of five patients with unrelenting cNPSLE with psychosis who were treated safely and effectively with bortezomib between 2011 and 2017. Most patients had persistent cNPSLE with psychosis despite aggressive immunosuppression with methylprednisolone, cyclophosphamide, rituximab, and usually plasmapheresis. All patients demonstrated rapid clinical improvement in their psychotic manifestations with the ability to quickly taper immunosuppression after the introduction of bortezomib. No patient had a recurrence of overt psychosis during a follow-up period of 1-10years. Secondary hypogammaglobulinemia developed in all five patients and required immunoglobulin replacement. No other severe side effects or adverse events were observed. Bortezomib-mediated LLPC depletion is a promising therapy for severe recalcitrant cNPSLE with psychosis when used as adjunctive therapy to conventional immunosuppression, B-cell, and antibody-depleting therapies. After initiation of bortezomib, patients had rapid, demonstrable improvement in psychosis as well as reduction in glucocorticoids and antipsychotics. Further investigation is needed to determine the therapeutic role of bortezomib in severe cNPSLE and cSLE. We present a mini-review of the rationale for bortezomib use and novel B-cell immunomodulation in rheumatic disease.

Les déficits immunitaires communs variables : définition, physiopathologie et diagnostic biologique

AbstractCommon variable immunodeficiency (CVID) is a primary immunodeficiency characterized by a defect in the production of immunoglobulins, it is the most frequent of the primary immunodeficiencies. It mainly affects humoral immunity and results, among other biological signs, in severe hypogammaglobulinemia with a decrease in IgG associated with a decrease in IgA and more rarely IgM. Clinical manifestations are recurrent respiratory and digestive infections, frequently associated with autoimmune diseases and lymphoproliferative syndromes. In most cases, this hypogammaglobulinemia is linked to a decrease in switched memory B lymphocytes, and abnormalities of other element in the immune response (T lymphocytes, cytokines, dendritic cells, etc.). Genetic abnormalities affecting genes coding for many proteins involved in the immune response are described in about 35 % of patients. The diagnosis is a diagnosis of exclusion, by ruling out all other causes of secondary hypogammaglobulinemia. The treatment is injection of polyvalent immunoglobulins, and prophylactic treatment such as antibiotics and vaccinations.

ADVERSE REACTION TO TIXAGEVIMAB AND CILGAVIMAB (EVUSHELD): ANAPHYLAXIS OR NOT?

<h3>Introduction</h3> Tixagevimab and cilgavimab (Evusheld) are long-acting monoclonal antibodies indicated for COVID-19 pre-exposure prophylaxis. Although multiple endotypes of hypersensitivity reactions to monoclonal antibodies have been described, including type I (IgE and non-IgE-mediated) reactions, cytokine release, mixed reactions, and type IV delayed reactions, serious hypersensitivity reactions to Evusheld are rare. We present a case of Evusheld adverse reaction, potentially consistent with anaphylaxis. <h3>Case Description</h3> 72-year-old female with Sjogren's syndrome, rheumatoid arthritis, secondary hypogammaglobulinemia from rituximab, interstitial lung disease, and laryngospasm received intramuscular Evusheld in clinic. Forty minutes later, the patient developed throat pain, throat fullness, difficulty swallowing, and dyspnea without wheezing or hypoxia. Documentation noted an unspecified rash. Vitals were stable. The patient was administered epinephrine, diphenhydramine, and steroids and transferred to the emergency department where symptoms resolved. However, five hours later, she developed recurrent throat fullness and difficulty swallowing, resulting in repeat Epinephrine. Flexible laryngoscopy was unremarkable. She had two additional self-resolving episodes of throat tightness at 12 and 24 hours. Labs drawn 24 hours after the initial reaction demonstrated IgE <2 kU/L, tryptase <2 ug/L, and IL-6 <2 pg/mL. The patient was discharged with 5-days of antihistamines and steroids. <h3>Discussion</h3> This case highlights the difficulty in diagnosing anaphylaxis. While certain features of the patient's clinical symptoms were suggestive of anaphylaxis (rash, dyspnea, and throat symptoms), her long-standing history of laryngospasm, unremarkable laryngoscopy, undetectable serum IgE, and non-elevated tryptase suggest against an immediate IgE-mediated type I hypersensitivity reaction to Evusheld. A detailed risk-benefit discussion with the patient is warranted before consideration of future Evusheld doses.

HYPOGAMMAGLOBULINEMIA AS A PRESENTING FINDING OF DGAT1 DEFICIENCY

<h3>Introduction</h3> The constellation of failure to thrive, chronic intractable diarrhea, and hypogammaglobulinemia should prompt the clinician to consider inborn errors of immunity (IEI), including defects in cellular and humoral immunity, immune dysregulatory disorders, and autoinflammatory disorders. However, the differential diagnosis should remain broad to include secondary causes of hypogammaglobulinemia, such as congenital diarrhea and enteropathies (CODEs). <h3>Case Description</h3> A two-week-old, full-term male presented with persistent diarrhea and failure to thrive. Endoscopic evaluation of the bowel showed active duodenitis and active colitis. Food protein-induced enterocolitis syndrome (FPIES) was considered due to transient improvement in stool output on an elemental formula; however, diarrhea recurred after advancing enteral feeds. Newborn screen was normal. Laboratory evaluation showed normal lymphocyte subpopulations, hypogammaglobulinemia (IgG < 108 mg/dL with normal IgA, IgM, IgE), hypoalbuminemia, and an elevated stool alpha-1 antitrypsin. Genetic testing revealed a compound heterozygous mutation in DGAT1 (c.1183C>T, c.329+6T>G). He received two doses of intravenous immunoglobulin; however, the stool output and IgG level resolved after starting a low-fat elemental formula. The patient remains on a low-fat diet with normal growth parameters and no recurrent infections with a normal IgG level. <h3>Discussion</h3> DGAT1 (diacylglycerol acyltransferase 1) deficiency is a protein-losing enteropathy due to defective lipid metabolism that is treated with a low-fat diet. Protein-losing conditions can cause hypoalbuminemia and hypogammaglobulinemia due to enteral loss of plasma proteins. It is important for clinicians to consider both primary hypogammaglobulinemia due to IEI and other conditions associated with secondary hypogammaglobulinemia when evaluating a patient with hypogammaglobulinemia.

RECURRENT CRYPTOCOCCAL MENINGITIS IN PATIENT WITH ANTI-GM-CSF AUTOANTIBODIES

<h3>Introduction</h3> Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic growth factor and pro-inflammatory cytokine. The involvement of anti-GM-CSF autoantibodies in the development of protein alveolar proteinosis (PAP) has been previously elucidated, however its role in increasing susceptibility to opportunistic infections remains less clear. <h3>Case Description</h3> A 33 year-old previously healthy man developed recurrent disseminated cryptococcal infections. He was hospitalized several times due to severe headaches and detection of cryptococcal antigen in his serum and CSF. He underwent multiple courses of antifungal induction therapy followed by antifungal prophylaxis and dexamethasone taper, yet remained symptomatic with persistent cryptococcal antigen in his CSF. Blood work was notable for the presence of anti-GM-CSF autoantibodies, low IgG (463), low IgM (26), normal IgA (69), 3/23 protective pneumococcal titers, and normal tetanus/diphtheria antibodies. Flow cytometry is currently pending. <h3>Discussion</h3> Anti-GM-CSF autoantibodies neutralize cell signaling resulting in impaired phagocytosis and host immune responses. Autoantibodies against GM-CSF increase susceptibility to opportunistic infections, particularly cryptococcal meningitis, in otherwise immunocompetent patients via the inhibition of GM-CSF STAT5 phosphorylation and GM-CSF-induced MIP-1alpha protein production. This is a rare case of a patient who developed recurrent cryptococcal meningitis in the setting of anti-GM-CSF autoantibodies and hypogammaglobulinemia. Further workup is underway to explore the possibility of concurrent CVID versus secondary hypogammaglobulinemia due to prolonged dexamethasone tapers. Patients with recurrent cryptococcal infections should be screened for anti-GM-CSF autoantibodies, which can help tailor treatment including GM-CSF therapy and anti-CD20 therapy. Patients would also benefit from a basic immunologic workup and routine screening for PAP.

Do the Benefits of Subcutaneous Immunoglobulin Therapy for Secondary Hypogammaglobulinemia in ANCA Vasculitis Extend Beyond Infection Prevention?

Do the Benefits of Subcutaneous Immunoglobulin Therapy for Secondary Hypogammaglobulinemia in ANCA Vasculitis Extend Beyond Infection Prevention?

Lymphoma as an Exclusion Criteria for CVID Diagnosis Revisited.

Hypogammaglobulinemia in a context of lymphoma is usually considered as secondary and prior lymphoma remains an exclusion criterion for a common variable immunodeficiency (CVID) diagnosis. We hypothesized that lymphoma could be the revealing symptom of an underlying primary immunodeficiency (PID), challenging the distinction between primary and secondary hypogammaglobulinemia. Within a French cohort of adult patients with hypogammaglobulinemia, patients who developed a lymphoma either during follow-up or before the diagnosis of hypogammaglobulinemia were identified. These two chronology groups were then compared. For patients without previous genetic diagnosis, a targeted next-generation sequencing of 300 PID-associated genes was performed. A total of forty-seven patients had developed 54 distinct lymphomas: non-Hodgkin B cell lymphoma (67%), Hodgkin lymphoma (26%), and T cell lymphoma (7%). In 25 patients, lymphoma developed prior to the diagnosis of hypogammaglobulinemia. In this group of patients, Hodgkin lymphoma was overrepresented compared to the group of patients in whom lymphoma occurred during follow-up (48% versus 9%), whereas MALT lymphoma was absent (0 versus 32%). Despite the histopathological differences, both groups presented with similar characteristics in terms of age at hypogammaglobulinemia diagnosis, consanguinity rate, or severe T cell defect. Overall, genetic analyses identified a molecular diagnosis in 10/47 patients (21%), distributed in both groups and without peculiar gene recurrence. Most of these patients presented with a late onset combined immunodeficiency (LOCID) phenotype. Prior or concomitant lymphoma should not be used as an exclusion criteria for CVID diagnosis, and these patients should be investigated accordingly.

Hypogammaglobulinemia and Multiple Sclerosis - An Overlooked Correlation?

Hypogammaglobulinemia and Multiple Sclerosis - An Overlooked Correlation? Abstract. Hypogammaglobulinemias occur in people with multiple sclerosis (MS) without immunotherapy in 8.1% of patients and with immunotherapy (not drug-specific) in up to 26.4% of affected individuals. This is thus significantly higher than the expected incidence in the general population. In MS patients it is also relevant to differentiate between primary and secondary hypogammaglobulinemia. In particular, anti-CD20 therapies are mainly underlying for the secondary forms in MS patients. With this article, we aim to provide a "spotlight" on hypogammaglobulinemia with a focus on the clinical consequence of these phenomena in people with MS.