The common variable immunodeficiency IgM repertoire narrowly recognizes erythrocyte and platelet glycans.

BACKGROUND: Autoantibody-mediated cytopenias (AICs) regularly occur in profoundly IgG-deficient common variable immunodeficiency (CVID) patients. The isotypes, antigenic targets, and origin(s) of their disease-causing autoantibodies are unclear. OBJECTIVE: To determine reactivity, clonality and provenance of AIC-associated IgM autoantibodies in CVID patients. METHODS: We utilized glycan arrays, patient erythrocytes, and platelets to determine targets of CVID IgM autoantibodies. Glycan binding profiles were used to identify auto-reactive clones across B cell subsets, specifically circulating marginal zone-like (MZ) B cells, for sorting and IGH sequencing. The locations, transcriptomes and responses of tonsillar MZ B cells to different T helper cell subsets were determined by confocal microscopy, RNA-sequencing, and co-cultures, respectively. RESULTS: Autoreactive IgM coated erythrocytes and platelets from many CVID patients with AICs (CVID+AIC). On glycan arrays, CVID+AIC plasma IgM narrowly recognized erythrocytic i antigens and platelet i-related antigens and failed to bind hundreds of pathogen- and tumor-associated carbohydrates. Polyclonal i antigen-recognizing B-cell receptors were highly enriched among CVID+AIC circulating marginal zone (MZ) B cells. Within tonsillar tissues, MZ B cells secreted copious IgM when activated by the combination of IL-10 and IL-21 or when cultured with IL10/IL-21 secreting FOXP3-CD25hiTfh cells. In lymph nodes from immunocompetent controls, MZ B cells, plentiful FOXP3+ regulatory T cells, and rare FOXP3-CD25+ cells that represented likely CD25hiTfh cells, all localized outside of GCs. In CVID+AIC lymph nodes, cellular positions were similar but CD25hiTfh cells greatly outnumbered regulatory cells. CONCLUSIONS: Our findings indicate glycan-reactive IgM autoantibodies produced outside of GCs may contribute to the autoimmune pathogenesis of CVID.

Immune urinary biomarkers predict infant cardiac surgery-associated acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) occurs frequently after infant cardiac surgery and is associated with poor outcomes, including mortality and prolonged length of stay. AKI mechanisms are poorly understood, limiting therapeutic targets. Emerging data implicates dysregulated immune activation in post-cardiac surgery AKI development. We sought to identify immune-mediated AKI biomarkers after infant cardiopulmonary bypass (CPB)-assisted cardiac surgery. METHODS: A single-center prospective study of 126 infants less than 1 year old undergoing CPB-assisted surgery enrolled between 10/2017 and 6/2019. Urine samples were collected before CPB and at 6, 24, 48, and 72 h after surgery. Immune-mediated biomarkers were measured using commercial ELISA and Luminex™ multiplex kits. Based on subject age, neonatal KDIGO (< 1 month) or KDIGO criteria defined AKI. The Kruskal-Wallis rank test determined the relationship between urinary biomarker measurements and AKI. RESULTS: A total of 35 infants (27%) developed AKI. AKI subjects were younger, underwent more complex surgery, and had longer CPB time. Subjects with AKI vs. those without AKI had higher median urinary chemokine 10 (C-X-C motif) ligand levels at 24, 48, and 72 h, respectively: 14.3 pg/ml vs. 5.3 pg/ml, 3.4 pg/ml vs. 0.8 pg/ml, and 1.15 pg/ml vs. 0.22 pg/ml (p < 0.05) post-CPB. At 6 h post-CPB, median vascular cell adhesion protein 1 (VCAM) levels (pg/mL) were higher among AKI subjects (491 pg/ml vs. 0 pg/ml, p = 0.04). CONCLUSIONS: Urinary CXCL10 and VCAM are promising pro-inflammatory biomarkers for early AKI detection and may indicate eventual AKI therapeutic targets. A higher resolution version of the Graphical abstract is available as Supplementary information.

Rubella virus chronic inflammatory disease and other unusual viral phenotypes in inborn errors of immunity.

Infectious susceptibility is a component of many inborn errors of immunity. Nevertheless, antibiotic use is often used as a surrogate in history taking for infectious susceptibility, thereby disadvantaging patients who present with viral infections as their phenotype. Further complicating clinical evaluations are unusual manifestations of viral infections which may be less familiar that the typical respiratory viral infections. This review covers several unusual viral phenotypes arising in patients with inborn errors of immunity and other settings of immune compromise. In some cases, chronic infections lead to oncogenesis or tumor-like growths and the conditions and mechanisms of viral-induced oncogenesis will be described. This review covers enterovirus, rubella, measles, papillomavirus, and parvovirus B19. It does not cover EBV and hemophagocytic lymphohistiocytosis nor lymphomagenesis related to EBV. EBV susceptibility has been recently reviewed. Our goal is to increase awareness of the unusual manifestations of viral infections in patients with IEI and to describe treatment modalities utilized in this setting. Coincidentally, each of the discussed viral infections can have a cutaneous component and figures will serve as a reminder of the physical features of these viruses. Given the high morbidity and mortality, early recognition can only improve outcomes.

Respiratory Comorbidities Associated with Bronchiectasis in Patients with Common Variable Immunodeficiency in the USIDNET Registry.

BACKGROUND: Bronchiectasis is a major respiratory complication in patients with common variable immunodeficiency (CVID) and is associated with recurrent pulmonary infections. However, it is unclear whether other infections or non-infectious respiratory conditions are related to its development. OBJECTIVE: To identify respiratory comorbidities associated with bronchiectasis in patients with CVID. METHODS: A total of 1470 CVID patients enrolled in the USIDNET registry were included in a cross-sectional analysis. The primary outcome of our study was to determine the clinical characteristics and other respiratory conditions associated with respiratory comorbidities and physician-reported bronchiectasis. RESULTS: One hundred ninety-seven CVID patients were noted to have bronchiectasis (13.4%). Affected patients were significantly older than patients without bronchiectasis (median age 54 years vs. 49 years, p = 0.0004). These patients also had lower serum IgA (13 mg/dL IQR 60 mg/dL vs. 28.4 mg/dL IQR 66 mg/dL, p = 0.000). Notably, chronic rhinosinusitis (OR = 1.69 95%CI 1.05-2.75), sinusitis (OR = 2.06 95%CI 1.38-3.09), pneumonia (OR = 2.70 95%CI 1.88-3.88), COPD (OR = 2.66 95%CI 1.51-4.67), and interstitial lung disease (OR = 2.34 95%CI 1.41-3.91) were independently associated with the development of bronchiectasis in this population. CONCLUSION: These data suggest that lower and upper respiratory infections, chronic lower airway disease, and interstitial lung diseases are independently associated with bronchiectasis in CVID patients. Further study into predisposing conditions related to the development of bronchiectasis in CVID patients may allow prediction and early intervention strategies to prevent the development of this complication.

Who's your data? Primary immune deficiency differential diagnosis prediction via machine learning and data mining of the USIDNET registry.

PURPOSE: There are currently more than 480 primary immune deficiency (PID) diseases and about 7000 rare diseases that together afflict around 1 in every 17 humans. Computational aids based on data mining and machine learning might facilitate the diagnostic task by extracting rules from large datasets and making predictions when faced with new problem cases. In a proof-of-concept data mining study, we aimed to predict PID diagnoses using a supervised machine learning algorithm based on classification tree boosting. METHODS: Through a data query at the USIDNET registry we obtained a database of 2396 patients with common diagnoses of PID, including their clinical and laboratory features. We kept 286 features and all 12 diagnoses to include in the model. We used the XGBoost package with parallel tree boosting for the supervised classification model, and SHAP for variable importance interpretation, on Python v3.7. The patient database was split into training and testing subsets, and after boosting through gradient descent, the predictive model provides measures of diagnostic prediction accuracy and individual feature importance. After a baseline performance test, we used the Class Weighting Hyperparameter, or scale_pos_weight to correct for imbalanced classification. RESULTS: The twelve PID diagnoses were CVID (1098 patients), DiGeorge syndrome, Chronic granulomatous disease, Congenital agammaglobulinemia, PID not otherwise classified, Specific antibody deficiency, Complement deficiency, Hyper-IgM, Leukocyte adhesion deficiency, ectodermal dysplasia with immune deficiency, Severe combined immune deficiency, and Wiskott-Aldrich syndrome. For CVID, the model found an accuracy on the train sample of 0.80, with an area under the ROC curve (AUC) of 0.80, and a Gini coefficient of 0.60. In the test subset, accuracy was 0.76, AUC 0.75, and Gini 0.51. The positive feature value to predict CVID was highest for upper respiratory infections, asthma, autoimmunity and hypogammaglobulinemia. Features with the highest negative predictive value were high IgE, growth delay, abscess, lymphopenia, and congenital heart disease. For the rest of the diagnoses, accuracy stayed between 0.75 and 0.99, AUC 0.46-0.87, Gini 0.07-0.75, and LogLoss 0.09-8.55. DISCUSSION: Clinicians should remember to consider the negative predictive features together with the positives. We are calling this a proof-of-concept study to continue with our explorations. A good performance is encouraging, and feature importance might aid feature selection for future endeavors. In the meantime, we can learn from the rules derived by the model and build a user-friendly decision tree to generate differential diagnoses.

Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium.

BACKGROUND: Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010-18. METHODS: We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982-89, 1990-99, 2000-09, and 2010-18. Categorical variables were compared by χ2 test and continuous outcomes by the Kruskal-Wallis test. Overall survival was estimated by the Kaplan-Meier method. A multivariable analysis using Cox proportional hazards regression models examined risk factors for HCT outcomes, including the variables of time interval of HCT, infection status and age at HCT, trigger for diagnosis, SCID type and genotype, race and ethnicity of the patient, non-HLA-matched sibling donor type, graft type, GVHD prophylaxis, and conditioning intensity. FINDINGS: For 902 children with confirmed SCID, 5-year overall survival remained unchanged at 72%-73% for 28 years until 2010-18, when it increased to 87% (95% CI 82·1-90·6; n=268; p=0·0005). For children identified as having SCID by newborn screening since 2010, 5-year overall survival was 92·5% (95% CI 85·8-96·1), better than that of children identified by clinical illness or family history in the same interval (79·9% [69·5-87·0] and 85·4% [71·8-92·8], respectively [p=0·043]). Multivariable analysis demonstrated that the factors of active infection (hazard ratio [HR] 2·41, 95% CI 1·56-3·72; p<0·0001), age 3·5 months or older at HCT (2·12, 1·38-3·24; p=0·001), Black or African-American race (2·33, 1·56-3·46; p<0·0001), and certain SCID genotypes to be associated with lower overall survival during all time intervals. Moreover, after adjusting for several factors in this multivariable analysis, HCT after 2010 no longer conveyed a survival advantage over earlier time intervals studied (HR 0·73, 95% CI 0·43-1·26; p=0·097). This indicated that younger age and freedom from infections at HCT, both directly driven by newborn screening, were the main drivers for recent improvement in overall survival. INTERPRETATION: Population-based newborn screening has facilitated the identification of infants with SCID early in life, in turn leading to prompt HCT while avoiding infections. Public health programmes worldwide can benefit from this definitive demonstration of the value of newborn screening for SCID. FUNDING: National Institute of Allergy and Infectious Diseases, Office of Rare Diseases Research, and National Center for Advancing Translational Sciences.

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

PURPOSE: To 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. METHODS: The 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. RESULTS: Data 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. CONCLUSIONS: Current 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.

Urine biomarker score captures response to induction therapy with lupus nephritis.

BACKGROUND: The Renal Activity Index for Lupus (RAIL) consists of urine protein assessment of neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, monocyte chemotactic protein 1, adiponectin, hemopexin, and ceruloplasmin, which non-invasively identifies lupus nephritis (LN). We aimed to delineate RAIL scores with inactive versus active LN and changes over time with response to LN induction therapy. METHODS: There were 128 pediatric patients with systemic lupus erythematosus (SLE) and age-matched healthy controls recruited in a prospective case control study, with kidney biopsy confirmation of LN. Laboratory and clinical information was recorded and urine collected at diagnosis and end of induction and during maintenance therapy. Response to therapy was assessed by repeat kidney biopsy or laboratory parameters. Urine was assayed for RAIL biomarkers and the RAIL score calculated. RESULTS: Pediatric RAIL (pRAIL) scores from 128 children and young adults with SLE (with/without LN: 70/38) including 25 during LN induction therapy, differentiated clinically active LN from inactive LN or without LN, and controls (all p < 0.0017). pRAIL scores significantly decreased with complete LN remission by 1.07 ± 1.7 (p = 0.03). CONCLUSIONS: The RAIL biomarkers differentiate LN patients based on activity of kidney disease, with decreases of ≥ 1 in pRAIL scores indicating complete response to induction therapy. Significantly lower RAIL scores in healthy controls and in SLE patients without known LN raise the possibility of subclinical kidney disease. A higher resolution version of the Graphical abstract is available as Supplementary information.

Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome.

BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.

Metagenomic sequencing of the bronchoalveolar lavage extracellular virome and cellular transcriptome of sarcoidosis patients does not detect rubella virus.

BACKGROUND:   Sarcoidosis is a multisystem granulomatous inflammatory disease of unclear etiology that involves the lung, skin and other organs, with an unknown antigenic trigger. Recently, evidence has been found in both immune deficient and immune competent patients for rubella virus in cutaneous granulomas. These granulomatous lesions share overlapping features with cutaneous sarcoidosis, raising the question of rubella virus in sarcoidosis. OBJECTIVE: To investigate the presence of rubella virus in sarcoidosis lung samples. METHODS: We employed metagenomic sequencing to interrogate extracellular virome preparations and cellular transcriptomes from bronchoalveolar lavage (BAL) of 209 sarcoidosis patients for rubella virus sequences. RESULTS: We found no evidence for rubella virus genomes in acellular fluid or rubella virus gene expression in BAL cells of sarcoidosis patients. CONCLUSIONS: These findings argue against rubella virus infection or persistence within the lung at time of sampling as a sarcoidosis trigger.

Canakinumab for the treatment of autoinflammatory very early onset- inflammatory bowel disease.

Introduction: Therapeutic options are critically needed for children with refractory very early onset inflammatory bowel disease (VEO-IBD). Our aim was to evaluate clinical response to canakinumab, an anti-IL-1ß monoclonal antibody, in patients with VEO-IBD whose phenotype resembles those with monogenic autoinflammatory disease. Methods: This is a single center retrospective study of patients with VEO-IBD with autoinflammatory phenotype (AIP) in the absence of identified monogenic disease treated with canakinumab for >6 months. AIP was defined as confirmed IBD with associated signs of systemic inflammation in the absence of infection, including leukocytosis, markedly elevated inflammatory markers, and extraintestinal manifestations (recurrent fevers, oral ulcers, arthritis). Primary outcomes included clinical response in disease activity indices after 6 months of therapy. Secondary outcomes included rate of AIP signs and symptoms, growth, surgery, steroid use, hospitalizations, and adverse events. Results: Nineteen patients were included: 47% with infantile onset, 58% classified as IBD-U, and 42% classified as CD. At baseline, 37% were biologic naïve, and canakinumab was used as dual therapy in 74% of patients. Clinical response was achieved in 89% with statistically significant improvement in PCDAI and PUCAI. Clinical remission was achieved in 32% of patients. There was significant improvement in the clinical manifestations of AIP and the biochemical markers of disease. Number of hospitalizations (p<0.01) and length of stay (p<0.05) decreased. Growth improved with median weight-for-length Z-score increasing from -1.01 to 1.1 in children less than 2 years old. There were minimal adverse events identified during the study period. Conclusion: Canakinumab may be an effective and safe treatment for a subset of children with VEO-IBD with AIP, as well as older patients with IBD. This study highlights the importance of a precision medicine approach in children with VEO-IBD.

Eosinophilic gastrointestinal disorders in patients with inborn errors of immunity: Data from the USIDNET registry.

Rationale: Eosinophilic gastrointestinal disorders (EGID), including eosinophilic esophagitis (EoE), are inflammatory disorders of the gastrointestinal mucosa mediated by complex immune mechanisms. Although there have been initial reports of EGID in patients with inborn errors of immunity (IEI), little is known about the presentation of EGID in immunodeficient individuals. Methods: We queried the U.S. Immunodeficiency Network (USIDNET) for patient records including the terms eosinophilic esophagitis, gastritis, enteritis, or colitis. We analyzed 74 patient records from the database, including diagnoses, demographics, infectious history, laboratory findings, genetic studies, therapeutic interventions, and clinical outcomes. Results: We examined 74 patient records. A total of 61 patients had isolated EoE, and 13 had distal gastrointestinal involvement consistent with EGID. The most common IEI were common variable immunodeficiency (43.2%), some form of combined immunodeficiency (21.6%), chronic granulomatous disease (8.1%), hyper-IgE syndrome (6.8%), and autoimmune lymphoproliferative syndrome (6.8%). The median age at presentation with IEI was 0.5 years (IQR 1.725, max 39 years) and 56.76% were male. Approximately 20% of the patients in the cohort received a hematopoietic stem cell transplantation for treatment of IEI, but the timing of the HSCT in relationship to the EGID diagnosis was unknown. Conclusions: Here, we report EGID in a diverse cohort of IEI patients, suggesting that both non-EoE EGID and EoE can be seen as comorbid conditions with a variety of IEI. Our data suggests that EGID may be more common in patients with IEI than would be expected based on estimates of EGID in the general population.

The 2022 Update of IUIS Phenotypical Classification for Human Inborn Errors of Immunity.

The International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) reports here the 2022 updated phenotypic classification, which accompanies and complements the most-recent genotypic classification. This phenotypic classification is aimed for clinicians at the bedside and focuses on clinical features and laboratory phenotypes of specific IEI. In this classification, 485 IEI underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity and auto-inflammation are described, including 55 novel monogenic defects and 1 autoimmune phenocopy. Therefore, all 485 diseases of the genetic classification are presented in this paper in the form of colored tables with essential clinical or immunological phenotype entries.

Urinary HER2, TWEAK and VCAM-1 levels are associated with new-onset proteinuria in paediatric lupus nephritis.

OBJECTIVE: Lupus nephritis is a key driver of morbidity and mortality in SLE. Detecting active nephritis on a background of pre-existing renal damage is difficult, leading to potential undertreatment and accumulating injury. An unmet need is a biomarker that distinguishes active lupus nephritis, particularly important in paediatrics where minimising invasive procedures is desirable. METHODS: This was a multicentre, prospective study of 113 paediatric patients with biopsy-proven lupus nephritis. Clinical data and urine were obtained every 3-4 months and patients averaged 2 years on study with seven time points. Urine was analysed for human epidermal growth factor receptor 2 (HER2), tumour necrosis factor-like weak inducer of apoptosis and vascular cell adhesion molecule-1 (VCAM-1) by ELISA. We defined active disease as either a rise in serum creatinine ≥0.3 mg/dL from baseline or a rise in renal Systemic Lupus Erythematosus Disease Activity Index score from the previous visit. These markers were also studied in patients with acute kidney injury, juvenile idiopathic arthritis (JIA), amplified pain syndrome and healthy controls. RESULTS: The rate of active disease was 56% over an average of 2 years of follow-up. HER2 and VCAM-1 were significantly elevated at time points with active disease defined by increased serum creatinine compared with time points with inactive disease or patients who never flared. All three biomarkers were associated with new-onset proteinuria and VCAM-1 was elevated at time points preceding new-onset proteinuria. These biomarkers were not increased in acute kidney injury or JIA. CONCLUSION: All three biomarkers were associated with new onset proteinuria and increased VCAM-1 may predict impending proteinuria. These biomarkers provide potential non-invasive measures for monitoring that may be more sensitive to impending flare than conventional measures.

Safety and efficacy of a novel iron chelator (HBED; (N,N'-Di(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid)) in equine (Equus caballus) as a model for black rhinoceros (Diceros bicornis).

While iron overload disorder (IOD) and related disease states are not considered a common occurrence in domestic equids, these issues appear prevalent in black rhinoceroses under human care. In addressing IOD in black rhinos, altering dietary iron absorption and excretion may be the most globally practical approach. A main option for treatment used across other species such as humans, is chelation therapy using iron-specific synthetic compounds. As horses may serve as an appropriate digestive model for the endangered rhinoceros, we evaluated the potential use of the oral iron chelator N,N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid (HBED) in horses for safety and efficacy prior to testing in black rhinoceros. Health and iron digestibility and dynamics were assessed in horses (n = 6) before, and after treatment with HBED (50 mg/kg body weight) for 8 days using a crossover design with serum, faecal and urine collection. A preliminary pharmacokinetic trial was also performed but no trace of HBED was found in serially sampled plasma through 8 h post-oral dosing. HBED increased urinary iron output in horses compared to control by 0.7% of total iron intake (p < 0.01), for an average of 27 mg urinary iron/day, similar to human chelation goals. Blood chemistry, blood cell counts and overall wellness were not affected by treatment. As healthy horses are able to regulate iron absorption, the lack of change in iron balance is unsurprising. Short-term HBED administration appeared to be safely tolerated by horses, therefore it was anticipated it would also be safe to administer to black rhinos for the management of iron overload.

Clinical and laboratory predictors of monogenic very early onset inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract. Treatment for patients who have a monogenic cause of their IBD, often the youngest children, known as very early onset IBD (VEO-IBD), can be different from standard treatment for polygenic cases. Yet, ascertainment of these patients is difficult. METHODS: We analyzed cases of VEO-IBD to understand the breadth of monogenic etiology and to identify clinical, laboratory, and flow cytometric correlates of this subpopulation. RESULTS: Genetic causes of very early onset inflammatory bowel disease are highly diverse ranging from pure epithelial defects to classic T cell defects. Flow cytometry, other than testing for chronic granulomatous disease, has a low sensitivity for monogenic etiologies. Poor growth was a clinical feature associated with monogenic causality. CONCLUSIONS: Genetic testing is, at this moment, the most robust method for the identification of monogenic cases of very early onset IBD.

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

BACKGROUND: Few published studies address eye disease in primary immunodeficiency (PID) despite ocular infections and autoimmune disease being known manifestations of immunodeficient states. OBJECTIVE: Data from the USIDNET Registry provide a resource to study ocular ailments in subjects with PID. METHODS: Ocular manifestations and patient characteristics were determined using data from 4624 patients with PID enrolled in the US Immunodeficiency Network (USIDNET) Registry. RESULTS: 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. CONCLUSIONS: 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.