United States Immunodeficiency Network Research Articles

Renal complications in patients with predominantly antibody deficiency in the United States Immune Deficiency Network (USIDNET)

BackgroundPrior studies have reported that renal insufficiency occurs in a small percentage of patients with predominantly antibody deficiency (PAD) and in about 2% of patients with common variable immunodeficiency (CVID). ObjectiveThe goal of our study was to understand and evaluate the prevalence and type of renal complications in PAD patients in the United States Immunodeficiency Network (USIDNET) cohort. We hypothesized there is an association between certain renal complications and severity of immunophenotype in patients with PAD. MethodsWe performed a query of patients with PAD from the USIDNET cohort with renal complications. Patients with documented renal disease such as chronic kidney disease (CKD), nephrolithiasis, nephritis, and renal failure syndrome were included. We compared immunophenotype, flow cytometry and immunoglobulin (Ig) levels of PAD patients with renal complications to the total PAD USIDNET cohort. ResultsWe identified that 140/2071 (6.8%) of PAD patients had renal complications. Of these 50 (35.7%) had CKD, 46 (32.9%) had nephrolithiasis, 18 (12.9 %) had nephritis, and 50 (35.7%) had other renal complications. Compared to the total USIDNET cohort of patients with PAD, patients with CKD had lower ALCs, CD3+ T-cells, CD4+ T-cells, CD19+ B-cells, CD20+ B-cells and CD27+IgD- B-cells (p<0.05 for all). Patients with nephritis had lower ALCs, CD19+ B-cells, CD27+ B-cells and IgE levels (p<0.05 for all) compared to PAD patients without renal disease. ConclusionsWe identified that 6.8% of PAD patients in the USIDNET cohort had a documented renal complication. The patients with nephritis and CKD had a more severe immunophenotype compared to the overall PAD cohort.

CVID-Associated Intestinal Disorders in the USIDNET Registry: An Analysis of Disease Manifestations, Functional Status, Comorbidities, and Treatment.

Common variable immunodeficiency (CVID) has been subdivided into five phenotypes, including one marked by non-infectious enteropathies that lead to significant morbidity and mortality. We examined a large national registry of patients with CVID to better characterize this population and understand how the presence of enteropathy influences nutritional status, patient function, and the risk of additional non-infectious disorders in CVID patients. We also sought to illustrate the range of treatment strategies for CVID-associated enteropathies. We extracted patient data from the United States Immunodeficiency Network (USIDNET) database, which included 1415 patients with CVID, and compared those with and without intestinal disorders. Demographic and genetic profiles, functional status, and treatments targeting intestinal disorders are reported. Intestinal disorders were present in 20% of patients with CVID, including chronic diarrhea, inflammatory bowel disease, malabsorption, and others. Compared to those without enteropathies, this patient subset exhibited significantly lower Karnofsky-Lansky functional scores, greater reliance on nutritional support, higher rates of vitamin deficiencies, and increased prevalence of hematologic disorders, liver disease, pulmonary disease, granulomatous disease, and lymphoma. Genetic data were reported for only 5% of the cohort. No mutations segregated significantly to patients with or without intestinal disease. Corticosteroids were most frequently used for treatment. Patients with CVID-associated intestinal disorders exhibit higher rates of autoimmune and inflammatory comorbidities, lymphoma, malnutrition, and debility. We review recent studies implicating specific pathways underlying this immune dysregulation. Further studies are needed to evaluate the role of targeted immunomodulatory therapies for CVID-associated intestinal disorders.

A Registry Study of 240 Patients with X-Linked Agammaglobulinemia Living in the USA

PurposeTo understand the natural history and clinical outcomes for patients with X-linked agammaglobulinemia (XLA) in the United States utilizing the United States Immunodeficiency Network (USIDNET) patient registry.MethodsThe USIDNET registry was queried for data from XLA patients collected from 1981 to 2019. Data fields included demographics, clinical features before and after diagnosis of XLA, family history, genetic mutation in Bruton’s tyrosine kinase (BTK), laboratory findings, treatment modalities, and mortality.ResultsData compiled through the USIDNET registry on 240 patients were analyzed. Patient year of birth ranged from 1945 to 2017. Living status was available for 178 patients; 158/178 (88.8%) were alive. Race was reported for 204 patients as follows: White, 148 (72.5%); Black/African American, 23 (11.2%); Hispanic, 20 (9.8%); Asian or Pacific Islander, 6 (2.9%), and other or more than one race, 7 (3.4%). The median age at last entry, age at disease onset, age at diagnosis, and length of time with XLA diagnosis was 15 [range (r) = 1–52 years], 0.8 [r = birth–22.3 years], 2 [r = birth–29 years], and 10 [r = 1–56 years] years respectively. One hundred and forty-one patients (58.7%) were < 18 years of age. Two hundred and twenty-one (92%) patients were receiving IgG replacement (IgGR), 58 (24%) were on prophylactic antibiotics, and 19 (7.9%) were on immunomodulatory drugs. Eighty-six (35.9%) patients had undergone surgical procedures, two had undergone hematopoietic cell transplantation, and two required liver transplantation. The respiratory tract was the most affected organ system (51.2% of patients) followed by gastrointestinal (40%), neurological (35.4%), and musculoskeletal (28.3%). Infections were common both before and after diagnosis, despite IgGR therapy. Bacteremia/sepsis and meningitis were reported more frequently before XLA diagnosis while encephalitis was more commonly reported after diagnosis. Twenty patients had died (11.2%). The median age of death was 21 years (range = 3–56.7 years). Neurologic condition was the most common underlying co-morbidity for those XLA patients who died.ConclusionsCurrent therapies for XLA patients reduce early mortality, but patients continue to experience complications that impact organ function. With improved life expectancy, more efforts will be required to improve post-diagnosis organ dysfunction and quality of life. Neurologic manifestations are an important co-morbidity associated with mortality and not yet clearly fully understood.

Interstitial cystitis in common variable immunodeficiency: Could it be another autoimmune complication? A descriptive report

IntroductionCommon variable immunodeficiency (CVID) is considered the most common Human Inborn Error of Immunity (HIEI) and involves low IgG and susceptibility to infections. ESID 2014 criteria has expanded diagnostic criteria to include autoimmunity and lymphoproliferation. One less common and not well understood noninfectious complication of CVID is interstitial cystitis (IC), which may be caused by immune dysregulation. We hypothesized that patients with both CVID and IC may have reduced switched memory B cells. We conducted this study using data from United States Immunodeficiency Network (USIDNET) and compared results to patients at our institution to see if there were any variables of interest. Results and DiscussionSeventeen of 1446 patient (1.2%) with CVID in the USIDNET database had a diagnosis of possible interstitial cystitis and all were females. Patients in this group had normal average range for IgG (798 mg/dL) with IVIG replacement, along with normal WBC, platelet, IgM and basic T cell enumeration. B cell phenotyping data was available for only one patient, showing normal memory and switched memory B cells. Data from our institution showed similar normal ranges for all the above labs except one female patient who had low memory and switched memory B cell population and had the mildest IC-related disease course. One male patient had normal memory and switched memory B cell population with mild Tcell lymphopenia, however had the worst IC-related clinical outcome. ConclusionWe failed to observe a strong correlation between low switched memory B cells and IC in patients with CVID. IVIG, despite its immunomodulating effects, also appeared to lack any association. While the severity of IC and male gender for one of our patients may be coincidental, it does raise the suspicion that the phenotype of IC in male CVID patients may be different from their female counterparts. IC may be underreported in USIDNET, leading to limited data and prohibiting any clear causative conclusions we may draw this study. Nevertheless, we believe it is important to raise the awareness of this rare disease, so that we can be cognizant of its heterogeneous manifestations and impacts on morbidity and mortality.

Renal Complications in Patients with Predominant Antibody Deficiency in the United States Immune Deficiency Network (USIDNET)

Prior studies have reported that renal insufficiency occurs in a small percentage of patients with predominant antibody deficiency (PAD), and in ∼2% of patients with common variable immunodeficiency (CVID). We sought to understand the epidemiologic and clinical characteristics of renal complications in PAD patients in the United States Immunodeficiency Network (USIDNET) cohort and hypothesized that there is an association between certain renal complications and severity of immunophenotype in PAD patients.

Allergic manifestations of inborn errors of immunity and their impact on the diagnosis: A worldwide study

BackgroundAllergies have long been observed in Inborn Errors of Immunity (IEI) and might even be the first presentation resulting in delayed diagnosis or misdiagnosis in some cases. However, data on the prevalence of allergic diseases among IEI patients are limited and contradictory. ObjectiveTo provide a worldwide view of allergic diseases, across a broad spectrum of IEI, and their impact on the timely diagnosis of IEI. MethodsThis is a worldwide study, conceived by the World Allergy Organization (WAO) Inborn Errors of Immunity Committee. A questionnaire was developed and pilot-tested and was sent via email to collect data from 61 immunology centers known to treat pediatric and/or adult IEI patients in 41 countries. In addition, a query was submitted to The United States Immunodeficiency Network (USIDNET) at its website. ResultsThirty centers in 23 countries caring for a total of 8450 IEI patients responded. The USIDNET dataset included 2332 patients. Data from responders showed that a median (IQR) of 16.3% (10–28.8%) of patients experienced allergic diseases during the course of their IEI as follows: 3.6% (1.3–11.3%) had bronchial asthma, 3.6% (1.9–9.1%) atopic dermatitis, 3.0% (1.0–7.8%) allergic rhinitis, and 1.3% (0.5–3.3%) food allergy. As per the USIDNET data, the frequency of allergy among IEI patients was 68.8% (bronchial asthma in 46.9%). The percentage of IEI patients who presented initially with allergic disorders was 8% (5–25%) and diagnosis delay was reported in 7.5% (0.9–20.6%). Predominantly antibody deficiencies had the highest frequency of allergic disease followed by combined immunodeficiency with a frequency of 40.3% (19.2–62.5%) and 20.0% (10–32%) respectively. As per the data of centers, anaphylaxis occurred in 25/8450 patients (0.3%) whereas per USIDNET dataset, it occurred in 249/2332 (10.6%); drugs and food allergy were the main causes in both datasets. ConclusionsThis multinational study brings to focus the relation between allergic diseases and IEI. Major allergies do occur in IEI patients but were less frequent than the general population. Initial presentation with allergy could adversely affect the timely diagnosis of IEI. There is a need for policies to raise awareness and educate primary care and other referring specialties on the association of allergic diseases with IEI. This study provides a network among centers for future prospective studies in the field.

Ocular Manifestations in Primary Immunodeficiency Disorders: A Report From the United States Immunodeficiency Network (USIDNET) Registry

Few published studies address eye disease in primary immunodeficiency (PID) despite ocular infections and autoimmune disease being known manifestations of immunodeficient states. Data from the USIDNET Registry provide a resource to study ocular ailments in subjects with PID. Ocular manifestations and patient characteristics were determined using data from 4624 patients with PID enrolled in the US Immunodeficiency Network (USIDNET) Registry. A total of 519 (11.2%) patients had recorded ocular diseases. Those with autoinflammatory disorders (n= 4 of 7 [57.1%]), intrinsic and innate immunity defects (n= 9 of 44 [20.5%]), and immune dysregulation (n= 27 of 142 [19.0%]) had the highest percentage of ocular diseases for the PID diagnosis category. Of the 67.6% with infections, 85.5% had conjunctivitis. Bacteria (56.2%) and viruses (27.4%) were the most common microorganisms reported, with Staphylococcus (31.7%), Haemophilus (26.8%), and Streptococcus (22.0%) being the most common bacteria isolated. Those with a history of eye infections had lower immunoglobulin levels, lower CD19 B-cell percentages, and a lower number of protective pneumococcal titers. In patients with noninfectious ocular complications, 30.8% had vision changes, with retina (n= 20 [8.0%]), cataract (n= 16 [6.4%]), and nerve diseases (n= 16 [6.4%]) also being common. Many patients with ocular disease had serious sequelae, with 12.7% undergoing eye surgery and 10.6% having a vision-based disability. Vision loss and conjunctivitis were the most commonly reported ocular complications and pose large quality-of-life issues. Learning more about ocular disease in PID will increase awareness about the importance of addressing and evaluating for these ailments.

Morbidity, Mortality, and Therapeutics in Combined Immunodeficiency: Data From the USIDNET Registry

Optimal management of patients with combined immunodeficiency, especially pertaining to hematopoietic stem cell transplantation (HSCT), remains unclear. To identify factors influencing HSCT and mortality in the population with combined immunodeficiency in North America. We identified 337 participants in the United States Immunodeficiency Network database with diverse forms of combined immunodeficiency and their characteristics, including demographic characteristics, laboratory values, infectious history, comorbidities, and treatment strategies. Univariate analysis was performed using logistic regression, whereas multivariate analysis was performed using multiple Cox proportional hazards. On univariate analysis, disseminated invasive viral infections and variants in STAT3, GATA2, and, DOCK8 were associated with increased odds of HSCT. Mucocutaneous fungal infections and variants in STAT3 were associated with increased odds of survival, whereas disseminated/invasive fungal infections, disseminated/invasive viral infections, and parasitic infections were associated with decreased odds of survival. On multiple variable Cox proportional hazards analysis, variants in ZAP70, nonspecific bacterial, and disseminated/invasive viral infections were associated with increased hazards of transplantation, whereas variants in multiple genes (RMRP, NEMO, DOCK8, CD40L, and CARD9), disseminated/invasive viral infections, autoimmune disease, and higher absolute lymphocyte count were associated with increased hazards of death. Importantly, demographic characteristics, basic lymphocyte subset counts, and absence of genetic diagnosis were not associated with HSCT or mortality. We determined that specific genetic diagnoses and infection burden impacts the decision to undergo HSCT in this cohort. In addition, certain genetic diagnoses and invasive viral infections carry an increased risk of mortality.

Rheumatologic diseases in patients with inborn errors of immunity in the USIDNET registry.

There is a gap in clinical knowledge regarding associations between specific inborn errors of immunity (IEIs) and rheumatologic diseases. This study reports the frequency of rheumatologic conditions in a large cohort of patients with IEI using the USIDNET (United States Immunodeficiency Network) registry. We used the USIDNET registry to conduct the analysis. We included all IEI patients within the registry for whom a diagnosed rheumatologic disease was reported. The total number of patients with IEI in our query was 5058. Among those, 278 (5.49%) patients had a diagnosis of rheumatologic disease. This cohort included 172 (61.8%) female and 106 (38.2%) male patients. Rheumatologic complications were highest in the interferonopathies (66.6%), autoimmune lymphoproliferative syndrome (ALPS) (13.7%), and immunoglobulin G subclass deficiency (IgGSD) (11.11%). Additionally, disease patterns were noted to be different in various IEI disease groups. Inflammatory myopathies were the most common rheumatologic condition in patients with X-linked agammaglobulinemia (1.65%), Sjogren's syndrome was the most common rheumatologic disease reported in ALPS patients (6.85%), and systemic lupus erythematosus was the most common rheumatologic disease in patients with chronic mucocutaneous candidiasis (CMC) (7.41%). Rheumatoid arthritis (RA) report rate was highest in patients with IgGSD (3.70%), specific antibody deficiency (SAD) (3.66%), and ALPS (2.74%). This study reports that rheumatologic diseases are frequently observed in patients with IEI. The frequency of different rheumatologic conditions was variable based on the underlying diagnosis. Clinicians caring for patients with IEI should be vigilant to monitor for rheumatologic complications. Key Points • The rates of reported rheumatologic diseases in the USIDNET registry are different in individual IEIs. • Further studies are needed to guide clinicians for detecting rheumatologic conditions earlier in patients with IEI.

Clinical Manifestations and Outcomes of Activated Phosphoinositide 3-Kinase δ Syndrome from the USIDNET Cohort

Activated phosphoinositide 3-kinase δ syndrome is a combined primary immunodeficiency characterized by gain-of-function mutations in PIK3CD and PIK3R1. Activated phosphoinositide 3-kinase δ syndrome demonstrates a large range of phenotypes including respiratory and herpesvirus infections, lymphadenopathy, autoimmunity, and developmental delay. To describe clinical phenotypes and disease outcomes of a large activated phosphoinositide 3-kinase δ syndrome cohort from the United States Immunodeficiency Network Registry. A total of 38 patients were enrolled in the United States Immunodeficiency Network Registry, and 2 additional patients were obtained from the Clinical Immunology Division at Mount Sinai Hospital. Each patient's demographic characteristics, disease complications, genetic studies, laboratory data, therapeutic interventions, and clinical outcomes were reviewed. There was a high frequency of respiratory infections (70.0% pneumonia) and herpesvirus infections (37.5%). Bronchiectasis was observed in 45.0% of patients. Lymphadenopathy was common (52.5%), and 12.5% of patients developed lymphoma. Neurological and developmental findings were common: 20.0% had developmental delay, 15.0% had seizures, and 10.0% had dysmorphic features. Asthma was more common in PIK3CD compared with PIK3R1 patients (63.6% vs 14.3%). More subjects with PIK3CD had CD3 lymphopenia compared with the PIK3R1 cohort. Seven patients underwent hematopoietic stem cell transplantation. One patient died from infectious complications. This is the first cohort comparing clinical manifestations in PIK3CD and PIK3R1 patients from the USIDNET Registry. Similar frequencies of respiratory and herpesvirus infections, lymphadenopathy, and developmental delay were observed compared with previous cohort studies. However, a higher frequency of asthma and CD3 lymphopenia in the PIK3CD cohort compared with the PIK3R1 cohort was observed.

Humoral Immunodeficiency and Immune Globulin Replacement Therapy (IGRT) Usage in DiGeorge Syndrome.

An analysis of patients in the United States Immunodeficiency Network (USIDNET) registry previously described a discordance in the reported prevalence of humoral immune deficiency in patients with DiGeorge syndrome (DGS) and its treatment. The primary purpose of this study is to evaluate the rates of humoral immunodeficiency and immune globulin replacement therapy (IGRT) use in patients with DiGeorge syndrome in the USIDNET registry as of September 2016, and to correlate IGRT use with prior infections and laboratory evidence of immune deficiency. Current patients in the USIDNET registry with DGS were identified. Patients who were treated with immune globulin replacement therapy (IGRT) were compared with those who were untreated with respect to their laboratory findings and clinical history. Four hundred seventy-three patients were identified. The use of IGRT in patients with DGS has increased over time from 3 to 6.6%. IGRT was more common in patients with humoral immune deficiency (18.2% of those with hypogammaglobulinemia, 39.1% of those with documented low vaccine titers), but most patients with evidence of humoral immune deficiency remain untreated with IGRT. Patients treated with IGRT were more likely to have experienced episodes of pneumonia, sepsis, and bacterial skin infections (p < 0.01 for all). Humoral immune deficiencies were more common among patients with DGS than previously reported. IGRT was used most commonly in patients with DGS who demonstrated frequent or severe bacterial infections. There is still a significant deficit between those with DGS who have laboratory evidence of a humoral immune deficiency and those being treated for it.

PROMIS-29 survey confirms major impact of fatigue on health-related quality of life in common variable immunodeficiency.

Health-related quality of life (HRQOL) is an emerging topic of interest in patients with immunodeficiency. Information about HRQOL in common variable immunodeficiency (CVID) is limited. The primary objective was to compare primary immunodeficiency disease (PIDD) patients with and without common variable immunodeficiency (CVID) on HRQOL domains using Patient-Reported Outcomes Measurement Information System (PROMIS-29) survey data from the United States Immunodeficiency Network (USIDNET) registry. The primary endpoint variables were scores on 7 HRQOL domains. The USIDNET registry was used to select patients with baseline PROMIS-29 data collected between 2015 and 2018. Descriptive statistics, Fisher's exact test, and Student's two-sample t test were used to compare patients with CVID versus patients with non-CVID on demographic and clinical characteristics. The single-sample t test was used to compare sample means to the normed population mean of 50. A general linear model approach to multiple regression with backward selection was used to remove factors that did not contribute significant information to the multivariable models, while controlling for multiple testing. Potential explanatory variables included group (CVID/non-CVID), sex, age, and BMI. Among 184 PIDD patients, 146 (79%) were diagnosed with CVID. Patients had a mean (SD) age of 53 (13.8), were predominantly female (83%), and were Caucasian (98%). PROMIS-29 results revealed a significant effect of group (CVID/non-CVID) on the anxiety, fatigue, and social participation domains, with fatigue being the most statistically significant. Fatigue, anxiety, and social participation may be key factors influencing HRQOL among patients with CVID. Future prospective longitudinal studies using PROMIS-29 will be needed to confirm these findings and to determine the mechanisms through which these factors develop in CVID, and how they can be improved.

Lymphoproliferative Disease in CVID: a Report of Types and Frequencies from a US Patient Registry

Lymphoproliferative disease in common variable immunodeficiency disease (CVID) is heterogeneous in pathogenesis and ranges from non-malignant lymphoid hyperplasia to lymphoma. The United States Immunodeficiency Network (USIDNET) patient registry was queried for lymphoproliferative diseases reported in CVID patients. Diagnoses included as possible manifestations of lymphoproliferation included lymphadenopathy, lymphoid hyperplasia, lymphocytic inflammation, lymphocytosis, and gammopathy. Among 1091 CVID patients, lymphoproliferative conditions were reported in 17.2% (N = 188). These conditions included lymphadenopathy (N = 192, 12.3%), lymphoid hyperplasia or lymphocytic inflammation (N = 50, 4.6%), lymphocytosis (N = 3, 0.3%), and gammopathies (N = 3, 0.3%). Of the 188 patients with lymphoproliferative conditions, 15 (8%) also had a diagnosis of lymphoma, while the remaining 173 (92%) did not. Nine (4.8%) had a diagnosis of non-lymphomatous malignancy including basal cell carcinoma (N = 3, 1.6%), thyroid carcinoma (N = 2, 1.1%), gynecologic cancer (N = 2, 1.1%), testicular cancer (N = 1), and vocal cord carcinoma (N= 1). CVID patients with lymphoma were older than patients with lymphoproliferative disease who did not have a diagnosis of lymphoma at the time of analysis (median age 49 vs. 35years, p = 0.005). CVID patients with lymphoproliferative disease had 2.5 times higher odds of having chronic lung disease compared with those with lymphoma (OR = 0.4, p = 0.049). There were no significant differences in the frequency of autoimmune, gastrointestinal, hepatic, or granulomatous disease between these populations. While CVID patients are at increased risk for lymphoma, lymphoproliferation may be observed in the absence of a concurrent hematologic or solid tumor malignancy.

Neutropenia Is an Underrecognized Finding in Pediatric Primary Immunodeficiency Diseases: An Analysis of the United States Immunodeficiency Network Registry.

The frequency of neutropenia in pediatric primary immunodeficiency disorders (PIDDs) is unknown and potentially underappreciated. Our study aimed to determine the overall frequency and severity of neutropenia in children diagnosed with a PIDD entered in the United States Immunodeficiency Network (USIDNET) patient registry. Neutropenia data and demographic/clinical information from 1145 patients younger than 21 years of age was obtained from the USIDNET registry. Neutropenia is more common in PIDD patients entered within the USIDNET registry than previously appreciated. There was a >10% occurrence rate of neutropenia in all broad primary immunodeficiency categories as well as in nearly all individual PIDDs. Neutropenia frequency was greater in African American pediatric PIDD patients than in white or Asian patients. The degree of neutropenia did not associate with mortality in pediatric patients with a PIDD. Although our study did not assess the frequency of PIDD in patients presenting with neutropenia, the possibility of a primary immune disorder should be considered in patients with idiopathic neutropenia.

Characteristics of a diverse urban population of primary antibody deficiency patients

Primary antibody deficiency (PAD) disorders are most common primary immunodeficiencies, yet much of the research on these disorders is limited to predominantly Caucasian populations at specialized referral centers. We aimed to explore whether there are clinically important differences within a diverse urban population of PAD patients. Retrospective analysis of electronic medical records at Boston Medical Center (BMC) dating back to 2012 was conducted to identify patients with ICD-9/ICD-10 diagnostic codes for agammaglobulinemia, common variable immunodeficiency, hereditary hypogammaglobulinemia, nonfamilial hypogammaglobulinemia, and IgG deficiency. 57 BMC patients were confirmed to have PAD deficiency upon chart review and included in this study with social demographics, clinical histories, and laboratory characteristics recorded. The PAD cohort at BMC is more diverse than that of the United States Immunodeficiency Network (USIDNET), with 15.8% of BMC subjects identifying as Black/African American compared to 2.8% of USIDNET (P < 0.0001) and 12.3% of BMC subjects identifying as Hispanic compared to 3.5% of USIDNET (P = 0.002). IgG replacement therapy was prescribed less commonly in the BMC cohort (37%) compared to USIDNET (87%, P < 0.0001). Bronchiectasis was more common in Black/African American patients (55.6%, P = 0.043) compared to other PAD patients in the BMC cohort. An urban population of PAD patients that is racially and ethnically more diverse than USIDNET had significantly less usage of IgG replacement therapy. Also, bronchiectasis was more common in Black/African American patients. Further work is needed to explore how social disparities may be influencing treatment and outcomes of PAD patients.

CVID-associated intestinal disorders in the USIDNET registry: An analysis of disease phenotypes, functional status, comorbidities, and treatment

Non-infectious intestinal disorders occur in a substantial proportion of patients with common variable immunodeficiency (CVID). These generally do not improve with immunoglobulin replacement and are linked to higher mortality. Here we report the phenotypic distribution of intestinal disorders, comorbidities, and treatment strategies in a large cohort of patients with CVID. The United States Immunodeficiency Network database included 1415 patients with CVID, of which 290 had intestinal disorders. We compared the prevalence of comorbidities, malignancies, and functional status between patients with and without intestinal disorders, and describe agents used to treat them. Intestinal disorders were present in 20% of patients, with chronic diarrhea (40%) and colitis (21%) being the most common diagnoses. Patients with intestinal disorders were more likely to require enteral or parenteral nutrition (p<0.01) and had lower Karnofsky-Lansky scores (p<0.01) compared to those without. Autoimmune gastritis/pernicious anemia (p<0.01), vitamin D deficiency (p<0.01), hepatic disease (p<0.01), interstitial lung disease (p<0.01), granulomatous disease (p<0.01), lymphoma (p=0.01), autoimmune hematologic disorders (p<0.01) including immune thrombocytopenic purpura (p=0.04), and mutations in CTLA4 (p=0.04) were more prevalent in the intestinal disease cohort. Corticosteroids, followed by azathioprine, rituximab, infliximab, and mesalamine were the most commonly reported pharmacotherapies for intestinal disorders. Patients with CVID who have intestinal disorders are more likely to have other autoimmune/inflammatory comorbidities and lymphoma. This combination of sequelae may explain the lower functional status observed here and the higher mortality reported previously. Corticosteroids were the most commonly employed treatment, yet the optimal therapeutic strategy is unclear.

Pulmonary Disease Burden in Primary Immune Deficiency Disorders: Data from USIDNET Registry.

Pulmonary manifestations are common in patients with primary immunodeficiency disorders (PIDs) but the prevalence, specific diseases, and their patterns are not well characterized. We conducted a retrospective analysis of pulmonary diseases reported in the database of the United States Immunodeficiency Network (USIDNET), a program of the Immune Deficiency Foundation. PIDs were categorized into 10 groups and their demographics, pulmonary diagnoses and procedures, infections, prophylaxis regimens, and laboratory findings were analyzed. A total of 1937 patients with various PIDs (39.3% of total patients, 49.6% male, average age 37.9years (SD = 22.4years)) were noted to have a pulmonary disease comorbidity. Pulmonary diseases were categorized into broad categories: airway (86.8%), parenchymal (18.5%), pleural (4.6%), vascular (4.3%), and other (13.9%) disorders. Common variable immune deficiency (CVID) accounted for almost half of PIDs associated with airway, parenchymal, and other pulmonary disorders. Pulmonary procedures performed in 392 patients were mostly diagnostic (77.3%) or therapeutic (16.3%). These patients were receiving a wide variety of treatments, which included immunoglobulin replacement (82.1%), immunosuppressive (32.2%), anti-inflammatory (12.7%), biologic (9.3%), and cytokine (7.6%)-based therapies. Prophylactic therapy was being given with antibiotics (18.1%), antifungal (3.3%), and antiviral (2.2%) medications, and 7.1% of patients were on long-term oxygen therapy due to advanced lung disease. Pulmonary manifestations are common in individuals with PID, but long-term pulmonary outcomes are not well known in this group of patients. Further longitudinal follow-up will help to define long-term prognosis of respiratory comorbidities and optimal treatment modalities.

Cellular Defects in CVID Patients with Chronic Lung Disease in the USIDNET Registry.

Chronic lung disease is the most common cause of morbidity and mortality in patients with common variable immunodeficiency (CVID). While biomarkers exist to predict non-infectious complications, the unique features that define CVID patients with chronic lung disease are not well understood. We analyzed data from CVID patients from the retrospective USIDNET (United States Immunodeficiency Network) patient database. Patients were categorized into 3 phenotypes for comparison: (1) CVID without chronic lung disease, (2) CVID with bronchiectasis only, and (3) CVID with interstitial lung disease (ILD) with or without bronchiectasis. Among these groups, differences were assessed in demographics, comorbidities, infections, treatments, and peripheral blood immune measures. We analyzed 1518 CVID patients which included 1233 (81.2%) without chronic lung disease, 147 (9.7%) with bronchiectasis only, and 138 (9.1%) with interstitial lung disease. Patients with ILD had lower CD3+ cell counts (P = .001), CD4+ cell counts (P < .05), and CD8+ cell counts (P < .001) compared with patients without lung disease. Additionally, there was significantly more CVID patients with ILD with pneumonia (P < .001), herpes viruses (P = .01) and fungal infections (P < .001) compared with patients with CVID without chronic lung disease. This analysis suggests that patients with chronic lung disease may be more likely to have lower peripheral T cell counts and complications of those defects compared with CVID patients without chronic lung disease.

Role of Allogeneic Hematopoietic Stem Cell Transplant for Chronic Granulomatous Disease (CGD): a Report of the United States Immunodeficiency Network.

Chronic granulomatous disease (CGD) is a primary immunodeficiency for which allogeneic hematopoietic stem cell transplant (HSCT) offers potential cure. Direct comparison of HSCT to non-HSCT management in the North American population was performed to identify clinical factors associated with overall survival (OS) and transplant-related survival (TRS). Retrospective review of CGD subjects enrolled in the United States Immunodeficiency Network. Survival was estimated by the Kaplan-Meier method and modeled by proportional hazards regression. We identified 507 patients (66% CYBB mutants) diagnosed in 1953-2016. Fifty underwent allogeneic HSCT. Median follow-up was 9.1years after diagnosis (0-45.8years). OS was negatively associated with CYBB mutation (HR=6.25; p=0.034) and not associated with HSCT (88% v. 85% ± HCT) (HR=1.26; p=0.65). Transplant at ≤ 14years old was associated with improved TRS (93% v. 82% at T + 60months) (HR=- 4.51; p=0.035). Patients transplanted before 15years old had fewer severe infections pre-HSCT (mean 0.95 v. 2.13; p=0.047). No mortality was reported in patients receiving stem cells from matched siblings. Infection incidence declined post-HSCT in subjects with greater than or equal to four infections pre-HSCT (p=0.0010). Compared to non-HSCT patients ≥ 15years old, post-transplant survivors had higher mean performance score (93.2 v. 85.9; p=0.0039) and lower frequency of disability (11% v. 52%; p=0.014). Allogeneic HSCT was associated with reduced infection incidence and improved functional performance, but not with a change in overall survival. Transplant-related survival was elevated in patients undergoing HSCT before 15years old. Consider HSCT prior to late adolescence in patients with severely diminished reactive oxygen intermediate synthesis, particularly if a matched sibling is available.

Neutropenia Is an Under-Recognized Finding in Pediatric Primary Immunodeficiency Diseases: An Analysis of the United States Immunodeficiency Network Registry

Background: Neutropenia is recognized as a defining or common element in a limited number of primary immunodeficiency diseases (PIDDs) (Dotta L et al. Immunol Let 2014; Cham B et al. Semin Hematol 2002); but, the overall prevalence of neutropenia within the more than 300 known PIDDs is not well described. Many of the PIDDs rely on a high index of clinical suspicion for diagnosis which may not be readily apparent to hematologists evaluating a neutropenic patient, underscoring the importance of understanding the rate of neutropenia in PIDDs and impact on clinical outcomes. The goal of this study was to evaluate the frequency and characteristics of neutropenia in a large registry of patients with primary immunodeficiency (PID).Methods: The United States Immunodeficiency Network (USIDNET) is a research consortium that maintains a national registry for the collection of data on patients with PIDDs. The USIDNET was queried for data regarding patients aged 21 years or less. Data utilized included reported PID diagnosis, gene mutation, gender, race, status of patient (living or deceased), year of birth, age at death, age of disease diagnosis, and results of reported complete blood counts (CBCs). PID diagnoses were grouped according to the 2017 International Union of Immunological Societies (IUIS) Phenotypic Classification for Primary Immunodeficiencies (Bousfiha A et al. J Clin Immunol 2018). Mild, moderate, and severe neutropenia were defined as absolute neutrophil counts of 1000-1499 cells/μL, 500-999 cells/μL, and < 500 cells/μL, respectively. Data are presented with descriptive statistics. The frequency of neutropenia was compared between genders and by race using chi-square test analysis.Results: An initial data request resulted in information on 1577 patients; 384 patients were eliminated from analysis given insufficient recorded registry data due to a lack of a documented absolute neutrophil count. An additional 48 patients were excluded given that complete blood cell counts were only reported following hematopoietic stem cell transplantation. Data was thus available for 1145 pediatric patients with PIDDs. A total of 2058 neutrophil values were analyzed with 62.7% (719) patients having only a single neutrophil value available for review. Overall, 15.8% of PIDD pediatric patients in the USIDNET registry had neutropenia, ranging from 12.01% (combined immunodeficiencies with associated or syndromic features) to 66.67% (defects in intrinsic and innate immunity) in IUIS categories (Table 1) and in USIDNET categories from 2.94% (autoimmune lymphoproliferative syndrome) to 75.00% (susceptibility to mycobacterial infections) (Table 2). Of PID patients with neutropenia, 20.4% had severe neutropenia, 33.1% had moderate neutropenia, and 46.4% had mild neutropenia. Neutropenia was most likely to be severe in patients with predisposition to severe viral infections as well as those with a defect in intrinsic and innate immunity (Tables 1-2). There was no statistically significant difference in neutropenia between genders (p = 0.64). However, females were more likely to have severe neutropenia than males (28% versus 16%; p=0.03). Additionally, 28% of African-American patients had recorded neutropenia while only 17% of Caucasians and 2% of Asian/Pacific Islanders were neutropenic (p=0.005). There was no statistically significant difference in severity of neutropenia and death nor in the rate of bacterial and fungal infections detected between neutropenic and non-neutropenic patients with 93% of patients in the dataset living at the time of data collection.Conclusions: The frequency of neutropenia within pediatric patients diagnosed with PIDD is higher and more ubiquitous than previously suspected. Hematologists should consider a PIDD in the assessment of neutropenia, particularly if other concerning signs or symptoms are present. Although this evaluation did not detect a difference in morbidity or mortality, the data set was constrained by a limited number of CBCs per patient and the rarity of the PIDDs. The impact of neutropenia on PIDD outcomes requires further study, ideally through a prospective longitudinal study.Acknowledgments: The U.S. Immunodeficiency Network (USIDNET), a program of the Immune Deficiency Foundation (IDF), is supported by a cooperative agreement, U24AI86837, from the National Institute of Allergy and Infectious Diseases (NIAID). [Display omitted] DisclosuresDale:Athelas, Inc.: Equity Ownership; Amgen: Consultancy, Research Funding; Sanofi-Aventi: Consultancy, Honoraria; Cellerant: Other: Scientific Advisory Board; Hospira: Consultancy; Prolong: Consultancy; Beheringer-Ingelheim: Consultancy; Coherus: Consultancy.