Transient Hypogammaglobulinemia Research Articles

IPINeT Ped-unPAD Study: Goals, Design, and Preliminary Results.

Background: An unclassified primary antibody deficiency (unPAD) is a widely heterogeneous clinical entity, recently identified within the spectrum of Inborn Errors of Immunity (IEIs). Since unPAD has been traditionally considered as a mild condition, it has incorrectly received little attention, resulting in the paucity of extensive and comparable studies describing its natural history. To address the gaps in characterizing, understanding, and managing pediatric unPAD patients, the Italian Primary Immunodeficiency Network (IPINet) Ped-unPAD study has recently been launched. Methods: Seventeen IPINeT Centers have expressed interest to participate, and data collection is still on-going. Hereby, we anticipate preliminary key issues emerging from the first 110 enrolled patients, attending three IPINet Centers. Results: A proportion of unPAD patients have experienced a severe infectious phenotype, which required hospitalization in a quarter of patients and antibiotic prophylaxis or Immunoglobulin Replacement Therapy in approximately 10% of patients. In this partial cohort, a mean follow-up (FU) of 5 years confirmed unPAD diagnosis in fifty percent of cases, with the remaining being reclassified as the Transient Hypogammaglobulinemia of Infancy (25%) and other IEIs (25%), such as a Common Variable Immunodeficiency, Selective IgA deficiency, Selective IgM deficiency, and IgG3 subclass deficiency. Conclusions: Despite a phenotype overlap at diagnosis, clinicians should be aware that unPAD is a mutable condition that deserves comprehensive evaluation and long-term monitoring to dissect the final diagnosis for optimal treatment.

Hypogammaglobulinemia in neonates: illustrative cases and review of the literature.

This article presents a review of causes of hypogammaglobulinemia in neonates utilizing illustrative cases to demonstrate commonly seen conditions. Overall, the causes of low immunoglobulin level can be divided into three main categories: decreased maternal transfer or production (due to physiological nadir, transient hypogammaglobulinemia of infancy, medication effects, or immunodeficiency), increased loss of immunoglobulins (from the gastrointestinal (GI) system, lymphatics, kidneys, skin disease, or blood loss) or destruction/suppression (from medication effects). Treatment of hypogammaglobulinemia is generally tailored to the underlying cause and condition of the patient. This can be through supportive care, prophylactic measures, or with immunoglobulin G (IgG) replacement at the recommendation of an immunologist.

Clinical and experimental treatment of primary humoral immunodeficiencies.

Selective IgA deficiency (sIgAD), common variable immunodeficiency (CVID), and transient hypogammaglobulinemia of infancy (THI) are the most frequent forms of primary antibody deficiencies. Difficulties in initial diagnosis, especially in the early childhood, the familiar occurrence of these diseases, as well as the possibility of progression to each other suggest common cellular and molecular patomechanism and a similar genetic background. In this review, we discuss both similarities and differences of these three humoral immunodeficiencies, focusing on current and novel therapeutic approaches. We summarize immunoglobulin substitution, antibiotic prophylaxis, treatment of autoimmune diseases, and other common complications, i.e. cytopenias, gastrointestinal complications, and granulomatous disease. We discuss novel therapeutic approaches such as allogenic stem cell transplantation and therapies targeting-specific proteins, dependent on the patient's genetic defect. The diversity of possible therapeutics models results from a great heterogeneity of the disease variants, implying the need of personalized medicine approach as a future of primary humoral immunodeficiencies treatment.

Transient hypogammaglobulinemia of infancy and unclassified syndromic immunodeficiencies are highly common in oesophageal atresia patients.

Due to the high rate of post-operative sepsis and other infectious complications, a routine immunological screening protocol has been initiated since 2015 in our paediatric surgery clinic for all patients admitted with oesophageal atresia (EA) and warrant a delayed definitive treatment. In our study, we aimed to evaluate the immunodeficiencies in EA patients, by comparing them to healthy age-matched controls. As a prospective cohort study, EA patients admitted between 2015 and 2022, who had their definitive operation after the newborn period (>28 days of age) were included. On admission, serum concentrations of IgG, IgA, IgM, lymphocyte subset levels, C3 and C4 levels, specific IgG antibody responses against hepatitis B, hepatitis A, measles, varicella zoster were evaluated. The patients were age-matched with healthy controls to compare the results and followed up until three years of age. If a humoral immunodeficiency was detected, intravenous immunoglobulin treatment was administered before major oesophageal surgery and during follow-up. 31 EA patients (18 M/13F) with a mean age of 13.3 ± 9.0 months were compared with 40 age-matched healthy controls. Mean serum IgG levels were found to be statistically lower than controls in all age groups (P < .05). Transient hypogammaglobulinemia of infancy (THI) and unclassified syndromic immunodeficiencies (USI) were found to be strikingly high, accounting for 29.0% and 22.5%, respectively, adding up to 51.5% of EA patients. This is the first study evaluating immunodeficiencies in EA patients found in the reviewed literature. More than half of EA patients that required delayed surgery had humoral immunodeficiency, so preoperative screening and immunology referral may improve patient outcomes.

Transcriptome profiling of regulatory T cells from children with transient hypogammaglobulinemia of infancy.

Transient hypogammaglobulinemia of infancy (THI) is one of the most common forms of hypogammaglobulinemia in the early childhood. THI is usually associated with chronic, recurrent bacterial and viral infections, life-threatening in some cases, yet its pathogenesis is still largely unknown. As our previous findings indicated the possible role of Treg cells in the pathomechanism of THI, the aim of the current study was to investigate gene expression profile of Treg cells isolated from THI patients. The transcriptome-wide gene profiling was performed using microarray technology on THI patients in two time-points: during (THI-1), and in resolution phase (THI-2) of hypogammaglobulinemia. As a result, a total of 1086 genes were differentially expressed in THI-1 patients, when compared to THI-2 as well as control group. Among them, 931 were up- and 155 downregulated, and part of them encodes genes important for Treg lymphocyte biology and function, i.e. transcription factors/cofactors that regulate FOXP3 expression. Thus, we postulate that Treg cells isolated from THI patients during hypogammaglobulinemia display enhanced suppressor transcriptome signature. Treg expression profile of THI children after normalization of Ig levels largely resembles the results obtained in healthy control group, suggesting THI Treg transcriptome seems to return to that observed in healthy children. Taken together, we suggest that THI pathomechanism is associated not only with transiently elevated Treg cell numbers, but also with their enhanced regulatory/inhibitory functions. These findings expand our knowledge of human Treg cells and may be useful for the future diagnosis or management of THI.

A Systematic Review of the Clinical Diagnosis of Transient Hypogammaglobulinemia of Infancy.

Transient hypogammaglobulinemia of infancy (THI) is a primary immunodeficiency caused by a temporary decline in serum immunoglobulin G (IgG) levels greater than two standard deviations below the mean age-specific reference values in infants between 5 and 24 months of age. Preterm infants are particularly susceptible to THI, as IgG is only transferred across the placenta from mother to infant during the third trimester of pregnancy. This study aimed to conduct a systematic review of the diagnostic criteria for transient hypogammaglobulinemia of infancy. Systematic review: Three electronic databases (PubMed, MEDLINE, and Google Scholar) were manually searched from September 2021 to April 2022. Abstracts were screened to assess their fit to the inclusion criteria. Data were extracted from the selected studies using an adapted extraction tool (Cochrane). The studies were then assessed for bias using an assessment tool adapted from Cochrane. Of the 215 identified articles, 16 were eligible for examining the diagnostic criteria of THI. These studies were also assessed for bias in the six domains. A total of five studies (31%) had a low risk of bias, while four studies (25%) had a high risk of bias, and bias in the case of seven studies (44%) was unclear. We conclude that THI is only definitively diagnosed after abnormal IgG levels normalise. Hence, THI is not a benign condition, and monitoring for subsequent recurrent infections must be conducted. The diagnostic criteria should also include vaccine and isohaemagglutinin responses to differentiate THI from other immunological disorders in infants.

Kawasaki Disease and Inborn Errors of Immunity: Exploring the Link and Implications

The exact etiopathogenesis of Kawasaki disease (KD), the most common childhood vasculitis, remains unknown; however, an aberrant immune response, possibly triggered by an infectious or environmental agent in genetically predisposed children, is believed to be the underlying pathogenetic mechanism. Patients with inborn errors of immunity (IEI) are predisposed to infections that trigger immune dysregulation due to an imbalance in various arms of the immune system. KD may develop as a complication in both primary and secondary immunodeficiencies. KD may occur either at disease presentation or have a later onset in IEIs. These include X-linked agammaglobulinemia (XLA), selective IgA deficiency, transient hypogammaglobulinemia of infancy; Wiskott–Aldrich syndrome (WAS), hyper IgE syndrome (HIES); chronic granulomatous disease (CGD), innate and intrinsic immunity defects, and autoinflammatory diseases, including PFAPA. Hitherto, the association between KD and IEI is confined to specific case reports and case series and, thus, requires extensive research for a comprehensive understanding of the underlying pathophysiological mechanisms. IEIs may serve as excellent disease models that would open new insights into the disease pathogenesis of children affected with KD. The current review highlights this critical association between KD and IEI supported by published literature.

The Evolutionary Scenario of Pediatric Unclassified Primary Antibody Deficiency to Adulthood.

Unclassified primary antibody deficiency (unPAD) is a relatively novel inborn error of immunity (IEI) condition that can vary with time to more defined entities. Since long-term follow-up (FU) studies are scarce, we aimed to provide insight into the evolutionary clinical and immunological scenario of unPAD children to adulthood and identification of biomarkers of primary immune deficiency (PID) persistence. A total of 23 pediatric unPAD patients underwent clinical and immunological FU for a mean time of 14 years (range 3-32 years, median 16 years). UnPAD diagnosis may change over time. At the last FU, 10/23 (44%) children matched the diagnosis of transient hypogammaglobulinemia of infancy and 13/23 (56%) suffered from a persistent PID. In detail, an unPAD condition was confirmed in 7/23 (30%) patients, whereas 3/23 (13%), 2/23 (9%), and 1/23 (4%) were reclassified as common variable immunodeficiency, selective IgA deficiency, and isolated IgM deficiency, respectively. Low IgA, low specific antibody response to pneumococcus, and lower respiratory tract infections at diagnosis were independently associated with IEI persistence. Long-term monitoring of unPAD patients is required to define their outcome and possible evolution towards a definitive IEI diagnosis.

A Case Report and Review of Increased IgE in Patients with Transient Hypogammaglobulinemia of Infancy and Atopic Dermatitis after Normalization of IgG

The coexistence of a high IgE level and transient hypogammaglobulinemia of infancy ( THI ) with atopic dermatitis (AD) is well known, but the coexistence with a marked serum IgE level ≥ 1000 IU/mL is a rare finding. Literature is scarce regarding IgE levels in patients with THI and AD after treatment with immunoglobulin (Ig). We reported a female infant 8 months old, with THI and severe AD. She was treated with intravenous immunoglobulin (IVIG) infusion after the failure of conventional therapy. Initially, serum levels of IgE were high, and serum levels of IgG were low. After 4 weeks of treatment with IVIG, patient profile showed normalization of IGE and higher elevation in IgG level. The present article is the first to describe a finding of marked IgE elevation (&gt; 1000 IU/mL) after treatment with IVIG. Furthermore, our finding is supported by our review of increased IgE levels in patients with THI and AD who received IG therapy. According to our review different trend of IgE levels in patients who achieved spontaneous normalization of IgG was found.

Antibodydeficiencies Epidemiology, Clinical manifestation, Diagnostics and Therapy

Antibodydeficiencies Epidemiology, Clinical manifestation, Diagnostics and Therapy Abstract. Primary Immune Deficiencies (PID) are caused by a genetically induced malformation/dysfunction of the immune system. Leading symptoms include susceptibility to infection, autoimmune diseases, lymphoproliferative, allergic as well as malignant diseases. They can be divided into ten main groups, including the primary antibody deficiency syndromes (PAD) in adults. The most well-known PADs include the variable immunodeficiency syndrome (CVID), Bruton's agammaglobulinaemia, IgG subclass deficiencies, immunoglobulin A deficiency, Antibody deficiency and transient childhood hypogammaglobulinaemia. Secondary hypogammaglobulinaemia by medicinal products, haematological diseases, malignancies and infections should be excluded. Delayed diagnosis of CVID is associated with a significant increase in morbidity and an increase in mortality. In addition to vaccinations, immunoglobulin replacement therapy is used therapeutically.

Inborn Errors of Immunity among Egyptian Children with Recurrent Acute Otitis Media

Abstract Objective Our objective was to investigate the relative frequency and pattern of inborn errors of immunity (IEIs) among Egyptian children with recurrent acute otitis media (rAOM). Methods This was a cross-sectional study that included children from the age of 6 months to 16 years with rAOM. Those with structural, functional, and environmental risk factors were excluded. Enrolled children underwent thorough clinical, otorhinolaryngological, and immunological evaluation, including hematological counting, quantitative immunoglobulins assay, lymphocytic flow cytometric immunophenotyping, CH50, and phagocytic function tests. Results The study included 69 children with rAOM (44 boys and 25 girls; median age 30 months). IEIs were identified in 14 children, including transient hypogammaglobulinemia (three cases), selective IgA deficiency (three cases), agammaglobulinemia (two cases), common variable immunodeficiency (two cases), and one case for each of congenital neutropenia, Chediak–Higashi syndrome, hyper IgM syndrome, and Griscelli syndrome. Parental consanguinity and history of unexplained/infection-related siblings' deaths were significantly associated with IEIs (p = 0.018 and 0.003, respectively). AOM and related complications were more frequent among IEI cases (p = 0.018 and 0.032, respectively). IEI cases had lower levels of hemoglobin (10.7 ± 2.80 vs. 12.3 ± 1.64 g/dL; p = 0.002), IgG (203 [78–1,370] vs. 708 [42.3–1,509] mg/dL; p = 0.000), and IgA (24.3 [3–310] vs. 80 [15.6–305] mg/dL; p = 0.009) compared with non-IEI cases. Conclusion The current study identified IEIs in one-fifth of children with rAOM, most of which were predominately antibody deficiencies. An immunological workup for rAOM is particularly important in the presence of certain indicators for IEIs, provided that other more common risk factors are excluded.

Transient hypogammaglobulinaemia of the young in a Thoroughbred yearling

SummaryA 12‐month‐old Thoroughbred colt was presented for chronic recurrent respiratory disease characterised by persistent nasal discharge, intermittent pyrexia and coughing of several months' duration. These episodes were responsive to empirical antimicrobial therapy but returned once therapy was discontinued. History, physical examination and initial diagnostics were suggestive of bacterial pneumonia and possible underlying immunodeficiency. Serum immunoglobulin analysis and peripheral blood lymphocyte phenotyping revealed low serum IgG and IgM concentrations. In this 12‐month‐old colt, low serum IgG concentration was the most diagnostic parameter and supported a presumptive diagnosis of transient hypogammaglobulinaemia of the young. The colt responded favourably to repeated treatment with antimicrobials for bacterial pneumonia, and serial immunologic testing over the following months showed gradual increase in serum IgG and IgM concentrations, supporting the diagnosis of delayed development of humoral immunity in this patient.

Regulatory T and B cells in transient hypogammaglobulinemia of infancy.

Transient hypogammaglobulinemia of infancy (THI) is a heterogeneous disorder caused by an abnormal delay in reaching normal IgG levels in the first three years of life. Although THI is a common primary immune deficiency, its pathogenesis has not been fully elucidated. We aimed to investigate the role of regulatory T cells (Tregs) and B cells (Bregs) in the pathogenesis of THI. T and B cell subsets were evaluated in 40 patients with THI aged 6-41 months and 23 healthy controls aged 6-51 months using flow cytometry. CD4 and interleukin-2 receptor-α alpha (CD25) expression and a lack of interleukin-7 receptor-α (CD127) were used for Treg identification. FoxP3 expression in Tregs was determined as a percentage and mean fluorescence intensity. B cell subsets (plasmablast, mature naive, primarily memory, new memory) and Bregs were defined according to CD19, CD38, and CD24 expressions. Patients with THI (15 females and 25 males; mean age: 18.8 ± 8.6 months) and controls (10 females and 13 males; mean age: 22.6 ± 13.1 months) participated in this study. While the proportion of Tregs of children with THI were significantly increased compared to the controls, primarily memory B cells were reduced. Additionally, the proportions of CD127 in CD3+ and CD3+CD4+ T cells were significantly reduced in the patients with THI compared to the control. No significant difference was detected in the FoxP3 expression of Tregs and the frequency of Bregs in the children with THI. Increased Tregs and decreased primarily memory B cells may cause antibody production delay in children with THI. Changes in the T and B cell compartments may be related to chronic immune activation and affected cellular immunity in THI. Further studies are needed to use T and B cell subsets in the prediction of IgG level recovery.

Incidence and risk factors of rituximab-associated hypogammaglobulinemia in patients with complicated nephrotic syndrome.

Hypogammaglobulinemia is a major adverse event after rituximab treatment; however, the precise incidence and risk factors are unclear in complicated steroid-dependent or frequently relapsing nephrotic syndrome (SDNS/FRNS) patients. This was a single-center, retrospective, observational study. Patients who received a single dose of rituximab for complicated SDNS or FRNS between February 2007 and May 2019 were enrolled. Serum IgG levels were plotted, and their trends were evaluated after rituximab treatment. The incidence of transient and persistent hypogammaglobulinemia was examined, and risk factors were calculated by multivariate analysis using logistic regression. We enrolled 103 patients who received 238 single doses of rituximab. Hypogammaglobulinemia was observed in 58.4% of the patients at least once after a single dose of rituximab treatment and 22.3% developed persistent hypogammaglobulinemia. Serum IgG levels gradually increased during B-cell depletion, and patients with low serum IgG levels at rituximab treatment had persistent hypogammaglobulinemia. Repeated courses of rituximab treatment increased the incidence of hypogammaglobulinemia. A past history of steroid-resistant nephrotic syndrome (SRNS) (odds ratio [OR] = 10.02; 95% confidence interval [CI] = 2.65-37.81; P < 0.001) and low serum IgG levels at rituximab treatment (OR = 7.63; 95% CI = 2.10-27.71; P = 0.002) was significantly associated with hypogammaglobulinemia in multivariate analysis. Hypogammaglobulinemia is a frequent adverse event after rituximab treatment, although IgG levels slightly increase during B-cell depletion. Low serum IgG levels at rituximab treatment and a past history of SRNS are significant risk factors for the development of hypogammaglobulinemia after rituximab treatment.

Особенности иммунного статуса детей с разной тяжестью атопического дерматита

Актуальность. Атопический дерматит (АД) — наиболее распространенное атопическое заболевание среди детей, характеризующееся поражением кожи с выраженным зудом. Развитие АД связывают с генетической предрасположенностью, влиянием эпигенетических факторов, которые приводят к нарушению эпидермальной барьерной функции, иммунодисрегуляцией и IgE-опосредованной сенсибилизацией к наиболее распространенным аллергенам. Особое значение исследователи придают не только поляризации Th2-иммунного ответа, но и особенностям работы врожденного звена иммунитета. Целью исследования было изучить особенности иммунного статуса у детей с учетом тяжести течения атопического дерматита. Материалы и методы. Основную группу составили 85 детей в возрасте от 3 месяцев до 3 лет с верифицированным диагнозом АД, группу контроля — 20 детей без проявлений атопии в анамнезе. Для оценки тяжести кожных проявлений использовали шкалу SCORAD. Дети, которые принимали участие в исследовании, были разделены на группы по тяжести АД. Всем детям проводился общий клинический анализ крови. Изучение иммунного статуса у детей основной группы включало типирование лимфоцитарной популяции по CD-маркерам (C3, C4–2, CD3+, CD19–, CD4+, CD8–, CD4–, CD8+, CD3–, CD56+, CD19+, CD14, CD45), измерение уровней IgA, IgM, IgG, IgE, исследование системы комплемента (С3, С4–2), фагоцитарной активности нейтрофилов и пролиферативной активности лимфоцитов проводилось методом проточной цитометрии в ООО «Синэво». Метод иммуноферментного анализа использовался для выявления уровней интерлейкина (ИЛ)-13 (ELISA Kit, Thermo Fisher Scientific, Австрия), исследование проводилось на базе Учебного медико-лабораторного центра Запорожского государственного медицинского университета. Статистическую обработку результатов проводили с помощью официального программного пакета Statistica 13.0. Результаты. У детей с тяжелым течением АД и уровнями ИЛ-13 ниже уровней контрольной группы и групп детей с тяжелым и среднетяжелым течением наблюдалась эозинофилия периферической крови, прирост CD4+, CD8– с одновременным снижением уровней CD4–, CD8+, дисиммуноглобулинемия и низкие уровни С3 по сравнению с другими группами исследования (р &lt; 0,05). Выводы. Полученные результаты позволяют предположить, что у детей тяжелое течение АД было связано с изменениями системы комплемента и низкими уровнями цитотоксических клеток, транзиторной гипогаммаглобулинемией, что, в свою очередь, требует более детального изучения каскадов иммунологических реакций у детей с АД.

One-year intravenous immunoglobulin replacement therapy: efficacy in reducing hospital admissions in pediatric patients with Inborn Errors of Immunity

ObjectivesTo compare the frequency of hospitalization in children with Inborn Errors of Immunity with antibody deficiency previous to intravenous immunoglobulin (pre- IVIG) with a one-year period after initial IVIG (post-IVIG). MethodsMedical reports of 45 patients during an eight-year period were reviewed from 2018 to 2019. Wilcoxon-test was used for related samples. ResultsForty-five children were included in the study, aged 29–249 months of age, and most of them (64.4%) were males. Median ages at onset symptoms and at diagnosis were 6 and 73 months old, respectively. Specific antibody deficiency and unclassified hypogammaglobulinemia were the predominant diagnoses (31.1% and 17.8%, respectively). X-linked agammaglobulinemia, Hyper IgE syndrome, Hyper IgM, transient hypogammaglobulinemia of infancy, and Common Variable Immunodeficiency (CVID) were also reported, in a low frequency. Forty-four (97.8%) patients were hospitalized before IVIG, and 10 patients (22.2%) after. Annual mean hospital admission reduced from 2.5 to 0.5, pre and post-IVIG, respectively (p < 0.0001). Mean length of stay (LOS) reduced from 71 to 4.7 days/year (p < 0.0001) in general ward and in the PICU from 17.2 days/year to zero (p < 0.0002). Pneumonia was the main cause of hospital admission with a reduction in the number of episodes per patient from an average of 2.2–0.1 per year (p < 0.001). Concomitant use of antibiotic prophylaxis did not influence the number of hospital admission. ConclusionOne-year intravenous IVIG significantly decreased the number of hospitalizations and length of stay in children with impaired antibody production. Social and economic impacts would be required.

Vaccination in PADs.

Primary antibody deficiencies (PADs) are the most common primary immunodeficiencies (PIDs). They can be divided into the following groups, depending on their immunological features: agammaglobulinemia; common variable immunodeficiency (CVID) isotype; hyper IgM isotype; light chain or functional deficiencies with normal B cell count; specific antibody deficiency with normal Ig concentrations and normal numbers of B cells and transient hypogammaglobulinemia of infancy. The role of vaccination in PADs is recognized as therapeutic, diagnostic and prognostic and may be used in patients with residual B-cell function to provide humoral immunity to specific infective agents. According to their content and mechanisms, vaccines are grouped as live attenuated, inactivated (conjugated, polysaccharide), mRNA or replication-deficient vector vaccines. Vaccination may be unsafe or less effective when using certain vaccines and in specific types of immunodeficiency. Inactivated vaccines can be administered in PAD patients even if they could not generate a protective response; live attenuated vaccines are not recommended in major antibody deficiencies. From December 2020, European Medicines Agency (EMA) approved vaccines against COVID-19 infection: according to ESID advises, those vaccinations are recommended in patients with PADs. No specific data are available on safety and efficacy in PAD patients.

Selective IgM deficiency: Follow-up and outcome.

Selective IgM deficiency (sIgMD) is classified under primary immunodeficiencies (PID). This study aimed to define the clinical and immunologic features of sIgMD. We assessed a retrospective medical record of patients who fulfilled the diagnostic criteria for sIgMD in a pediatric immunology department. There were 55 patients with sIgMD. Out of 55 patients, 13 (23.6%) patients, diagnosed with a well-defined PID disease, and nine, evaluated as transient hypogammaglobulinemia, were excluded in the follow-up. The ratio of the sIgMD was %0.12 in the outpatient clinic of pediatric immunology (33/27,000). Out of 33 patients, eight (24,2%) were asymptomatic during the follow-up period. Fifteen (45.4%) patients presented with upper/lower respiratory and skin infections. Six patients (18%) had chromosomal anomaly, or syndrome (trisomy 21, 22q11.2 deletion 1p deletion, CHARGE syndrome, and Cohen syndrome). Six (18%) had autoimmune/inflammatory diseases, such as Behcet's disease, immune thrombocytopenic purpura, Crohn's disease, Guillain-Barre syndrome, and diabetes mellitus. Five (15%) had allergic disorders. Three patients (9%) developed malignancy. The PID diagnoses were combined immunodeficiency, common variable immunodeficiency, chronic granulomatous disease, adenosine deaminase deficiency, and congenital neutropenia. Genetic disorders, autoimmune/inflammatory, and allergic diseases may accompany sIgMD. Approximately 25% of the patients were asymptomatic in our series. Patients had increased malignancy risk. We diagnosed about 25% of the patients having low IgM with a specific PID in the follow-up period. Thus, patients with sIgMD should be followed up regularly in immunology clinics.

Infection Phenotypes Among Patients with Primary Antibody Deficiency Mined from a US Patient Registry.

Primary immunodeficiency disorders (PIDs) affect immune system development and/or function, increase infection susceptibility, and cause dysregulation or both. Recognition of PID requires assessment about the normal state of infection frequency and microbiology. To help clarify infection characteristics, we use data mined from the US Immunodeficiency Network (USIDNET) registry among primary antibody deficiency (PAD) patients before diagnosis. We analyzed PAD patient data from the USIDNET registry prior to ultimate diagnosis. Our analysis included basic descriptive statistics for 8 major infection subtypes and significance testing for comparing infection rate by specific organisms across 7 distinct PAD subtypes. Of 2038 patients reviewed, 1259 (61.8%) had infections reported prior to diagnosis. Most (77.4%) had four or less reported infections prior to diagnosis; however, some suffered up to 16 infections. Infection patterns differed across the PAD subtypes. Patients with agammaglobulinemia differed significantly from patients with all other forms of PAD studied in at least one infection category, whereas patients with CVID differed from 3 other PAD categories in at least one infection category. Patterns of infections in patients with hypogammaglobulinemia, specific antibody deficiency, and transient hypogammaglobulinemia were less unique. For each of the infection types, bacteria were the most prevalent cause of disease. Our data shows that distinct subtypes of PAD display unique infection patterns. We also show that patients with agammaglobulinemia suffer more invasive infections and differ most significantly from all other forms of PAD studied. Our analysis has broad implications about infection surveillance, progression, and vulnerability by PAD subtype.

Real-World IgG Testing Frequency and Characteristics Associated with Hypogammaglobulinemia after Anti-CD20 Exposure in Patients with Chronic Lymphocytic Leukemia (CLL)

Introduction: Hypogammaglobulinemia is a known potential adverse event in patients with CLL receiving anti-CD20 monoclonal antibody (mAb) therapy. However, real-world immunoglobulin G (IgG) testing rates have not been extensively studied. We used a real-world database to investigate IgG testing rates in patients with CLL before and after anti-CD20 exposure. We further examined factors that increased the likelihood of new onset hypogammaglobulinemia following anti-CD20 therapy. Methods: The Flatiron Health EHR-derived de-identified database was used to select patients with abstraction-confirmed CLL diagnosed before 6/1/2020 with: (1) Exposure to an anti-CD20 mAb, (2) At least one IgG lab within 180 days prior to first anti-CD20 line start, and (3) No evidence of hypogammaglobulinemia (IgG &amp;lt; 7g/L) within 6 months prior to first anti-CD20 line start. A "hypogammaglobulinemia detection window" was defined for each patient as the time between first anti-CD20 administration through to 365 days thereafter. Patients were grouped into 3 categories: (A) "Unknown status": those with no IgG testing during the window, (B) "Confirmed hypogam": those with hypogammaglobulinemia detected on any test during the window, and (C) "No detected hypogam": those tested for IgG during the window with 0 tests meeting the hypogammaglobulinemia threshold. Demographic and clinical baseline characteristics were compared across the groups. A logistic regression was performed to compare factors associated with higher likelihood of detecting hypogammaglobulinemia among patients with an IgG test in the detection window. Factors included were: patient age at start of detection window, exposure to chemotherapy before detection window (Y/N), concurrent chemotherapy to anti-CD20 during the detection window (Y/N), and whether anti-CD20 was given in the first line (1L) setting (Y/N). We also performed a separate scenario analysis with outcome of severe hypogammaglobulinemia (IgG &amp;lt; 5 g/L, compared to &amp;lt; 7 g/L in primary analysis). Results: We found 5,838 anti-CD20 mAb-exposed patients with CLL, of which 1,927 (33%) had at least 1 IgG lab within 180 days of anti-CD20 start. Of those, 922 (48%) had hypogammaglobulinemia within 6 months prior to starting anti-CD20 therapy, leaving 1,005 patients in the cohort. 526 patients (52%) fell into the 'unknown status' category. 182 (18%) patients fell into the 'confirmed hypogam' category, and 297 (30%) fell into the 'no hypogam detected' category. Patients across these 3 categories had similar baseline characteristics (Table 1). Among the patients with an IgG test in the detection window (N=479), patients with 'confirmed hypogam' had more IgG tests during the window than the patients with 'no detected hypogam' (mean 3.9 vs. 2.8 tests, p&amp;lt;0.001). Results of the logistic regression for IgG &amp;lt; 7 g/L did not yield any factors significantly associated with higher likelihood of hypogammaglobulinemia (Table 2). However, the regression at IgG &amp;lt; 5 g/L (incl. changing cohort inclusion criteria 3, N=703) found that concurrent exposure to chemotherapy was associated with higher likelihood of severe documented hypogammaglobulinemia (odds ratio 1.89; 95% CI 1.23-2.96; p = 0.004). Conclusions: In this real-world cohort of patients with CLL with at least one IgG test within 6 months prior to anti-CD20 mAb initiation, hypogammaglobulinemia was common. A majority of the cohort was not tested for IgG post anti-CD20 mAb initiation, which likely reflects clinical practice of infrequently obtaining IgG levels in patients with normal pre-treatment IgG levels. As clinically expected, patients with hypogammaglobulinemia were tested for IgG more frequently than those who were not. This hypothesis-generating study suggests that administering chemotherapy concurrently to anti-CD20 mAbs increases the likelihood of documented severe hypogammaglobulinemia (IgG &amp;lt; 5g/L) in patients with CLL. Further research should confirm this. Our analyses did not account for patients who may have had transient hypogammaglobulinemia during anti-CD20 treatment, and did not stratify by intravenous immunoglobulin (IVIG) usage in this population. Further research should examine the effect of anti-CD20-associated hypogammaglobulinemia on outcomes, and determine if IgG surveillance should be standardized as part of clinical guidelines. Disclosures Hooley: Flatiron Health Inc: Current Employment, Research Funding; Roche Group: Current equity holder in publicly-traded company. Maignan:Flatiron Health Inc: Current Employment, Research Funding; Roche Group: Current equity holder in publicly-traded company. Jacob:Flatiron Health Inc: Current Employment, Research Funding; Roche Group: Current equity holder in publicly-traded company. Medina:Flatiron Health Inc: Current Employment, Research Funding; Roche Group: Current equity holder in publicly-traded company. Benderoff:Roche Group: Current equity holder in publicly-traded company; Flatiron Health Inc: Current Employment, Research Funding. Chen:Flatiron Health Inc: Current Employment, Research Funding; Roche Group: Current equity holder in publicly-traded company. Huntington:AbbVie: Consultancy; Astrazeneca: Honoraria; Bayer: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; DTRM: Research Funding; Genentech: Consultancy; Novartis: Consultancy; Pharmacyclics: Honoraria; TG Therapeutics: Research Funding.