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Objective To uniquely classify children with microscopic polyangiitis (MPA), to describe their demographic characteristics, presenting clinical features, and initial treatments in comparison to patients with granulomatosis with polyangiitis (Wegener's) (GPA). Methods The European Medicines Agency (EMA) classification algorithm was applied by computation to categorical data from patients recruited to the ARChiVe (A Registry for Childhood Vasculitis: e-entry) cohort, with the data censored to November 2015. The EMA algorithm was used to uniquely distinguish children with MPA from children with GPA, whose diagnoses had been classified according to both adult- and pediatric-specific criteria. Descriptive statistics were used for comparisons. Results In total, 231 of 440 patients (64% female) fulfilled the classification criteria for either MPA (n = 48) or GPA (n = 183). The median time to diagnosis was 1.6 months in the MPA group and 2.1 months in the GPA group (ranging to 39 and 73 months, respectively). Patients with MPA were significantly younger than those with GPA (median age 11 years versus 14 years). Constitutional features were equally common between the groups. In patients with MPA compared to those with GPA, pulmonary manifestations were less frequent (44% versus 74%) and less severe (primarily, hemorrhage, requirement for supplemental oxygen, and pulmonary failure). Renal pathologic features were frequently found in both groups (75% of patients with MPA versus 83% of patients with GPA) but tended toward greater severity in those with MPA (primarily, nephrotic-range proteinuria, requirement for dialysis, and end-stage renal disease). Airway/eye involvement was absent among patients with MPA, because these GPA-defining features preclude a diagnosis of MPA within the EMA algorithm. Similar proportions of patients with MPA and those with GPA received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%, respectively) or both drugs in combination with plasmapheresis (19% and 22%, respectively). Other treatments administered, ranging in decreasing frequency from 13% to 3%, were rituximab, methotrexate, azathioprine, and mycophenolate mofetil. Conclusion Younger age at disease onset and, perhaps, both gastrointestinal manifestations and more severe kidney disease seem to characterize the clinical profile in children with MPA compared to those with GPA. Delay in diagnosis suggests that recognition of these systemic vasculitides is suboptimal. Compared with adults, initial treatment regimens in children were comparable, but the complete reversal of female-to-male disease prevalence ratios is a provocative finding.

BACKGROUND: Diffuse alveolar hemorrhage (DAH) is a devastating clinical syndrome characterized by a falling hematocrit, respiratory insufficiency, and radiographic evidence of pulmonary infiltrates. Literature regarding management of DAH in childhood-onset SLE (cSLE) is limited. METHODS: We reviewed the presentation, management, and outcome of DAH in a pediatric tertiary medical center with one of the largest cSLE cohorts in North America. During a 10 year period 7 of 410 children with cSLE had DAH. RESULTS: The majority of cSLE patients with DAH were male (71%) and Hispanic (57%). The median age at the time of DAH diagnosis was 14 years (range 3 -15 years). DAH was the presenting manifestation of cSLE in 29% of children; 71% presented with DAH within 3 months of their diagnosis. All patients had cough, 86% had dyspnea, and 29% had hemoptysis. All patients had anemia and 71% had thrombocytopenia. Eighty-six percent had hematuria/proteinuria, and a positive anti-double stranded DNA antibody. Chest imaging showed diffuse ground glass opacities in all events. All patients developed respiratory insufficiency (29% supplemental oxygenation and 71% mechanical ventilation). Transfusions were required in 57% of cases. All patients received corticosteroids and additional immunomodulation to achieve disease control. Eighty-six percent of our DAH/cSLE cohort survived their initial event (median follow-up 2.5 years). No survivor required supplemental oxygen or had a DAH recurrence. CONCLUSIONS: SLE should be in the hospitalist's differential diagnosis for any child with respiratory insufficiency, cytopenias, and/or urinary abnormalities. Once cSLE is identified, initiation of aggressive immune suppression with multiple agents may enhance outcomes.

Background/Aims: There is a critical need for more noninvasive biomarkers to identify nephritis in patients with systemic lupus erythematosus (SLE). Recent studies in a model mouse and an adult SLE patient cohort suggest that anti-basement membrane antibody levels correlate well with lupus activity and kidney injury. The purpose of this study was to assess the anti-basement membrane reactivity in pediatric SLE (pSLE) patients with or without nephritis. Methods: Auto-antibodies to basement membrane antigens were assessed using an anti-matrigel ELISA. Endpoint titers were measured in pSLE patients and healthy children, as well as in autoimmune and non-immune mice, with good reproducing capabilities. Findings were also analyzed with respect to the presence or absence of nephritis, dsDNA antibodies, and other manifestations of pSLE. Results: MRL/lpr mice developed high-titer anti-matrigel antibodies, whereas C57BL/6 mice did not. In a cohort of 21 pSLE patients and 22 pediatric controls, high-titer anti-matrigel IgG, IgM and IgA antibody levels were specific for pSLE. High-titer anti-matrigel IgG3 levels could distinguish with good sensitivity the 13 pSLE patients with a history of nephritis from the 8 non-renal pSLE patients. High-titer anti-matrigel IgG, IgA, IgM or IgG3 did not correlate with positive anti-double stranded DNA, but defined an overlapping subset of patients. Conclusion: The addition of anti-basement membrane antibody testing to serologic testing in pSLE may help to monitor disease activity or to define important subsets of patients with risks for specific disease manifestations.

WOS: 000393996800025, PubMed: 27577878, Background: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. Methods: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. Results: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/ 110) and management was directly altered in nearly a quarter (26/ 110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. Conclusion: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes., South-Eastern Norway Health Authority; American Women's club of Oslo; National Human Genome Research InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI); National Heart, Lung, and BloodUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [U54HG006542]; Jeffrey Modell Foundation; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [AI-120989], Funding for the work performed in Oslo was provided by the South-Eastern Norway Health Authority, and A. S.-P. received research scholarship from the American Women's club of Oslo. The BHCMG is supported by the National Human Genome Research Institute and the National Heart, Lung, and Blood (U54HG006542). Funding was also provided by the Jeffrey Modell Foundation and NIH AI-120989 (to J.S.O.).

Inherently defective immunity typically results in either ineffective host defense, immune regulation, or both. As a category of primary immunodeficiency diseases, those that impair immune regulation can lead to autoimmunity and/or autoinflammation. In this review we focus on one of the most recently discovered primary immunodeficiencies that leads to immune dysregulation: "Copa syndrome". Copa syndrome is named for the gene mutated in the disease, which encodes the alpha subunit of the coatomer complex-I that, in aggregate, is devoted to transiting molecular cargo from the Golgi complex to the endoplasmic reticulum (ER). Copa syndrome is autosomal dominant with variable expressivity and results from mutations affecting a narrow amino acid stretch in the COPA gene-encoding COPα protein. Patients with these mutations typically develop arthritis and interstitial lung disease with pulmonary hemorrhage representing a striking feature. Immunologically Copa syndrome is associated with autoantibody development, increased Th17 cells and pro-inflammatory cytokine expression including IL-1β and IL-6. Insights have also been gained into the underlying mechanism of Copa syndrome, which include excessive ER stress owing to the impaired return of proteins from the Golgi, and presumably resulting aberrant cellular autophagy. As such it represents a novel cellular disorder of intracellular trafficking associated with a specific clinical presentation and phenotype.

Background Generic health status quality of life (QoL) instruments have been used in patients with common variable immune deficiency (CVID). However, by their nature, these tools may over- or underestimate the impact of diseases on an individual's QoL. Objective The objective of this study was to develop and validate a questionnaire to measure specific-health-related QoL for adults with CVID (CVID_QoL). Methods The 32-item content of the CVID_QoL questionnaire was developed using focus groups and individual patient interviews. Validation studies included 118 adults with CVID who completed Short Form-36, Saint George Respiratory Questionnaire, General Health Questionnaire-12, and EuroQol-5D questionnaire in a single session. Principal component and factor analysis solutions identified 3 scores to be similar in number and content for each solution. Validation of 3 factor scores was performed by construct validity. Reproducibility, reliability, convergent validity, and discriminant validity were evaluated. Matrices consisting of correlations between the 32 items in the CVID_QOL were calculated. Results Factor analysis identified 3 dimensions: emotional functioning (EF), relational functioning (RF), and gastrointestinal and skin symptoms (GSS). The instrument had good internal consistency (Cronbach's alpha, min. 0.74 for GSS, max. 0.84 for RF, n = 118) and high reproducibility (intraclass correlation coefficient, min. 0.79 for RF, max 0.90 for EF, n = 27). EF and RF scores showed good convergent validity correlating with conceptually similar dimensions of other study scales. Acute and relapsing infections had a significant impact on EF and RF. Conclusions This study provides evidence of the reliability and construct validity of the CVID_QoL to identify QoL issues in patients with CVID that may not be addressed by generic instruments.

Background: Kawasaki disease is the leading cause of acquired heart disease in children in the US. While it remains a rare disease, the purpose of this study is to evaluate the incidence of KD Methods: To evaluate our hypothesis we used the Pediatric Health Information Systems (PHIS), 2004-2013, including all discharges at 44 of the largest freestanding children’s hospitals in the US. Results: Between 2004-2013, there were 16,417 hospitalizations for KD, 10,388 (61%) were male. The race of patients admitted with KD showed 5276 (31%) Caucasian, 2370 (14%) African American, 1586 (9.3%) Other, and 941 (5.5%) Asian. The average length of stay 3.9 days. The number of patients with KD increased annually for the past decade, Figure 1. The largest proportion of the increase was from those children between 1 and 5 years of age, Figure 2. Most children were only hospitalized once (14,231, 84%) however some children required subsequent hospitalization (1,291,8%). Conclusions: There has been a steady increase in the number of admissions per year for Kawasaki disease predominately for those patients ages 1-5 years.

Kawasaki disease (KD) is the leading cause of acquired heart disease in children with a subset presenting in shock. We sought to describe the incidence and outcomes of KD shock in the US. Methods: The Pediatric Health Information Systems (PHIS), 1/2004-12/2013, dataset including all hospitalizations at 44 of the largest freestanding children’s hospitals in the US was used. We assumed KD shock patients were admitted to the ICU. Results: KD admissions included 16,417 patients, 1,179 requiring ICU care, KD shock, with an annual incidence of 8 - 13%, Figure 1. Among KD shock admissions (versus non-ICU KD), the length of stay (10 vs 4 days, P Conclusions: KD shock may not be an uncommon presentation given 8-13% of KD admissions required ICU care. KD shock patients are more likely to have complications including coronary artery changes, mechanical ventilation, ECMO, and longer hospitalizations than non-ICU admissions.

Advances in genomics have allowed unbiased genetic studies of human disease with unexpected insights into the molecular mechanisms of cellular immunity and autoimmunity1. We performed whole exome sequencing (WES) and targeted sequencing in patients with an apparent Mendelian syndrome of autoimmune disease characterized by high-titer autoantibodies, inflammatory arthritis and interstitial lung disease (ILD). In five families, we identified four unique deleterious variants in the Coatomer subunit alpha (COPA) gene all located within the same functional domain. We hypothesized that mutant COPA leads to a defect in intracellular transport mediated by coat protein complex I (COPI)2–4. We show that COPA variants impair binding of proteins targeted for retrograde Golgi to ER transport and demonstrate that expression of mutant COPA leads to ER stress and the upregulation of Th17 priming cytokines. Consistent with this pattern of cytokine expression, patients demonstrated a significant skewing of CD4+ T cells toward a T helper 17 (Th17) phenotype, an effector T cell population implicated in autoimmunity5,6. Our findings uncover an unexpected molecular link between a vesicular transport protein and a syndrome of autoimmunity manifested by lung and joint disease. These findings provide a unique opportunity to understand how alterations in cellular homeostasis caused by a defect in the intracellular trafficking pathway leads to the generation of human autoimmune disease.

Natural killer (NK) cells possess an array of germline-encoded activating, inhibitory and adhesion receptors, the balance of which in concert with their developmental stage, determine their cytotoxic and cytokine-producing potential. Although NK cells develop in the bone marrow and secondary lymphoid tissues, substantive differentiation is apparent in the peripheral blood including known age-related variation. In order to gain greater insight into phenotypic and functional variation within peripheral blood NK cells across age groups, we used multi-parameter, polyfunctional flow cytometry to interrogate the NK cell variability in 20 healthy adults and 15 5–10, 11–15 and 16–20 year-old children. We found that the normative ranges in both adults and children displayed great inter-individual variation for most subsets. Children possessed >76% unstimulated NK subsets coexpressing perforin and granzyme B as opposed to >65% in adults. Children also had >28% NK subsets expressing all adhesion receptors in our panel compared to half of that in adults. As examples, terminally differentiated CD16+CD57+CD11b+ NK cells were reduced after 16 years of age as well as NKp46, 2B4, CD107a and newly-synthesized perforin in adults. Although CD107a intensity and new perforin synthesis was lower in adults, induced levels of IFNγ (by intensity) was higher. Despite most receptors not differing in their overall expression levels, major phenotypic differences were revealed in the combinatorial expression of NK receptors between adults and children. Our findings identify previously unappreciated NK cell subsets potentially distinguishing children from adults and suggest functional correlates that may have relevance in age-specific host defense.

Methods TNPB, Ped-ANAM, quality of life (PedsQL), and depression scales (CDI-S) were administered by psychology associates blinded to clinical status at two research visits. Differences in mean TNPB standardized scores, PedANAM throughput scores (raw Throughput=correct responses/minute), and clinical variables between visits were compared using paired Student t-tests. Multi-variable linear regression analysis was used to assess the influence of initial test performance, aPL/LAC status, disease duration, and cumulative prednisone dosing on composite TNPB or Ped-ANAM scores at a second visit.

Background/Purpose: Males represent 4–22% of all SLE patients, but it is unclear if gender should influence management. A number of studies of mostly adult patients suggest genetic, hormonal and environmental aspects of gender differences contribute to differences in presentation, clinical course and outcome, including a positive association between male gender and nephritis and a negative association with disease activity and outcome. While differences may exist, these findings are supported by limited evidence, particularly for children and adolescents with SLE. Methods: We retrospectively reviewed records of the nearly 200 pediatric SLE patients actively followed in the TCH rheumatology and renal clinics between 2011 and 2013 to identify males with SLE. Characteristic autoantibody features and renal disease were defined. Results: We identified 25 males (48% Hispanic, 16% Black, 16% Asian). The mean age of onset of disease was 11.5 ± 0.6 yo. Comorbid autoimmune diseases were identified in 46% of patients and 31% had a positive family history of autoimmune disease. Hypocomplementemia was seen at least once in 54% of patients. The cumulative incidence of positive autoantibodies included 50% anti-dsDNA, 54% with antiphospholipid abs, 42% with anti-RNP, 38% with anti-Ro (SS-A), 19% with anti-Smith, 15% with anti-La (SS-B), and 8% with RF. Only 35% (9) of male SLE patients developed lupus nephritis (LN), the majority of whom had class IV lesions (77%). Class V lesions were seen in 3 patients, including one with mixed histopathology (IV/V). LN was a presenting symptom in all 9 patients. Of these, 33% had acute kidney injury and 22% had crescentic disease on biopsy. The proportion of boys with LN and anti-dsDNA antibodies was not significantly different from boys without LN (66% vs. 50%, p = 0.67); however, a significantly higher proportion of boys with LN had anti-RNP abs (77% vs. 29%, p = 0.04). Conclusion: Although SLE predominately affects females, males with SLE represent an important subset of patients about which little is known. In our male cohort, rates of autoantibody positivity were similar to those published for females, but rates of kidney invovlement seem lower than expected. In addition, autoantibody profiling may not be as useful in predicting kidney involvement in boys. Additional research is of upmost importance to improve the diagnosis, quality of care, and outcomes of male SLE patients.

Background/Purpose: In 1998, Sorof et al. reported 28% of 60 pediatric SLE patients had class V lesions on their first biopsy and 37% had class V lesions on their most recent biopsy. Although 19% of patients with LN transformed from other classes to class V, there were no patients with repeat biopsies who showed complete resolution of their class V lesions. The prognosis of the patients with class V LN was better than those with non-class V LN (only 5% vs. 21% developed renal dysfunction or died). Methods: We retrospectively reviewed pathology records of pediatric lupus nephritis patients who underwent renal biopsies at Texas Children's Hospital between 1990 and 2013. Results: A total of 321 biopsies were performed on 174 patients with SLE. The cumulative incidence of class V histopathology was 50% (160/321). Upon initial biopsy, 93/174 (53%) patients had Class II, III or IV LN without class V lesions, and 81/174 (47%) patients had class V lesions, either alone (n = 38), or associated with class II, III or IV LN (n = 43). Repeat biopsies were obtained in 97 cases. The median interval between first and second biopsies was 11 months (IQR 9–19m, range 3–110 m). Of the 97 patients with at least 2 renal biopsies, 36 (37%) had class V lesions on the initial biopsy, and 61 (63%) did not have class V lesions on the initial biopsy. Although transformation between classes was common, the initially non-class V LN patients frequently remained free of class V lesions at follow up (n = 42, 70%). Of the 18/61 initially non-class V LN patients who did later develop class V lesions, 6% initially had pure class II LN, 61% pure class III, and 33% pure class IV. Repeat biopsies revealed mixed class V LN in 16/18 patients, with subsequent resolution of class V lesions or transformation to pure class V in 4. Six (17%) of the 36 patients with class V lesions on the initial biopsy had pure class V lesions, and 30 (83%) had mixed class II, III or IV LNThree (50%) of the 6 patients with initially pure class V lesions showed evolution to mixed class III/V LN, and evolution to class IV with sustained absence of class V lesions in 1 (17%). Of the 30 patients with initially mixed class V LN, repeat biopsies revealed persistent mixed class V LN in 22 (73%), transformation to pure class V in 4 (13%) and sustained resolution of class V lesions in 4 (13%). Conclusion: A comparison of the WHO classification of initial and repeat biopsies showed evolution to pure class V LN, or more commonly, development of a mixed class including class V LN. Although the vast majority of patients with class V LN showed persistence of this histopathology, sustained resolution of class V lesions may be possible.

Background/Purpose: Pulmonary hemorrhage (PH) is a rare and devastating manifestation of SLE, occurring in 1–5% of adult cohorts with mortality rates ranging from 70%-90%. The majority of PH reported in SLE refers to the adult population, and there is a paucity of data in pediatrics. Therefore, we describe our experience with PH in pediatric SLE, outlining disease presentation, treatment, and outcomes. Methods: We reviewed records of pediatric SLE patients who presented with pulmonary involvement diagnosed between January 2000 and August 2010. Inclusion criteria included > 4 SLE classification criteria and PH based on pulmonary evaluation by BAL, lung biopsy and/or characteristic imaging with worsening anemia. We describe our pediatric cohort, presenting symptoms, diagnostic modalities, various interventions and overall outcomes. Results: Seven of 401 (1.7%) SLE patients met inclusion criteria for PH. Patients were predominantly male (71.4%) and Hispanic (57.1%). Median age of PH presentation was 13.5 years (range 2.0–15.2). Episodes were primarily within the first 3 months of SLE diagnosis (71.4%) and were a presenting manifestation for SLE in 28.6% of our patients. All patients presented with a new cough, dyspnea, hypoxemia, anemia and abnormal CXR. Hemoptysis was present in 28.6%. Four out of 6 children had chest CT findings with diffuse ground glass opacities (66.6%) and 3 with nodules (50%). Additional non-pulmonary features included fever (71.4%), renal disease (57.1%), cytopenias (71.4%), cardiac disease (50.0%), and positive antiphospholipid antibodies (85.7%). Eighty-five percent required supplemental oxygen and 57.1% required mechanical ventilation. Hemosiderin-laden macrophages without infection were observed in 3 BAL's. Out of the two lung biopsies performed, both revealed diffuse hemorrhage and one demonstrated immunoglobulin and complement deposition. All were treated with pulse doses of methylprednisolone infusions. Other therapeutic interventions included cyclophosphamide (42.8%), plasma exchange (42.8%), rituximab (85.7%) and IVIG (14.2%). Survival rate was 87.5%. All patients were maintained on corticosteroids and 66.6% received monthly cyclophosphamide infusions. Subsequent outpatient therapies included IVIG (33.3%), azathioprine (16.6%) or rituximab (16.6%). No patients had recurrences of PH. No survivors required supplemental oxygen nor developed interstitial lung disease (median follow-up 2.6 years, range 1.5–5.0). Conclusion: In our review of pSLE patients with PH, the prevalence of this complication approximated that of adult SLE cohorts. However, in contrast to the adult population, PH presented earlier in the course of SLE in children. Additionally, outcomes were favorable with initiation of aggressive, multi-modal immunosuppressive therapy with no recurrences. The mortality rate was much lower than described in adult cohorts.