Joshi, Avni Y.

Black race and Hispanic ethnicity are associated with higher mortality in severe combined immunodeficiency (SCID) following hematopoietic cell transplantation (HCT), though mechanisms remain unclear. We evaluated 796 children with SCID who received nonsibling HCT between 1982 and 2020 using data from the Primary Immune Deficiency Treatment Consortium. Overall survival for Black (aHR 2.47, 95%CI 1.64, 3.71) and Asian/Pacific Islander patients (aHR 1.82, 95%CI 1.00, 3.30) was significantly lower compared with non-Hispanic White patients, while Hispanic patients had lower event-free survival (aHR 1.83, 95%CI 1.27, 2.63) compared with non-Hispanic White patients. Even after adjusting for age and infection, Black patients with SCID had more than twofold hazard of death compared with non-Hispanic White patients. NBS was associated with earlier diagnosis, reduced infection at HCT, and elimination of survival disparities between Black and non-Hispanic White patients. These findings suggest that universal, system-level interventions such as NBS can mitigate disparities in outcomes for children with SCID.

Background Granulomatous-lymphocytic interstitial lung disease (GLILD) is a major cause of morbidity and mortality in common variable immunodeficiency (CVID), yet its pathophysiology remains incompletely understood, and no Food and Drug Administration (FDA)-approved therapies exist. Cellular senescence, a state associated with inflammation and fibrosis, has been implicated in chronic lung diseases, including idiopathic pulmonary fibrosis, where senolytic therapies have shown benefit. Cellular senescence has also been described in some cases of GLILD. Objective To evaluate the efficacy of fisetin, a senolytic flavonoid, compared with placebo in adults with CVID-associated GLILD. Methods We conducted a randomized, double-blind, placebo-controlled pilot trial in 10 adults with GLILD (Figure 1). Participants received fisetin 20 mg/kg or placebo on days 0–1 and 28–29, with follow-up over 180 days. Assessments included pulmonary function testing (PFT) and Short Form Health Survey (SF-36). Results Fisetin was well tolerated, with no adverse events. SF-36 Mental Health scores were numerically higher in fisetin participants (day 28: −0.28; day 180: 0.00) than placebo (day 28: −0.56; day 180: −0.28). Mental Component Summary scores remained stable in the fisetin group (−0.65 to −0.70) but declined in the placebo group (−1.09 to −1.94). All other SF-36 domains were comparable between groups. Mean spirometry measures were stable in both groups. With fisetin, lung volumes increased over time, with increases in mean total lung capacity (5.46 to 5.76 L), residual volume (1.69 to 2.09 L), and residual volume (RV)/total lung capacity (TLC) (0.31 to 0.37). In contrast, the placebo group demonstrated decreases in total lung capacity (4.72 to 4.62 L), residual volume (1.89 to 1.72 L), and RV/TLC (0.41 to 0.38). Diffusion capacity corrected increased from baseline to day 90 in the fisetin group (13.9 to 15.9) and remained stable at day 180, whereas it declined in the placebo group by day 180 (19.1 to 17.6). Discussion In this randomized pilot study, fisetin was well tolerated and showed benefit in diffusion capacity, lung volumes, and mental health–related outcomes compared to placebo in GLILD. The temporal pattern of changes suggests that alternative dosing strategies may warrant further evaluation, in addition to potentially larger future studies. Figure 1. CONSORT flow diagram.

Abstract Background Good syndrome (GS) is an under-recognized adult-onset immunodeficiency characterized by the coexistence of thymoma and hypogammaglobulinemia. It is marked by recurrent infections, combined B- and T-cell immunodeficiency, and frequent autoimmune manifestations. Its rarity, unclear pathogenesis, and often delayed diagnosis contribute to its clinical complexity.Distribution of Infections by pathogen type in patients with Good Syndrome: the microbiological spectrumDemographics, clinical characteristics, thymoma classification with staging and management Methods We conducted a retrospective review of adults diagnosed with good syndrome at Mayo Clinic up until 2024. We assessed baseline characteristics, clinical features with a particular focus on infectious complications, immunological lab parameters, thymoma histopathology with staging, and management. Descriptive statistics were utilized for analysis.Immunological lab parameters and management of Good syndrome Results During the study period, Good syndrome was diagnosed in 32 patients; 78% were male, with a median age at diagnosis of 62 years (Table 1). All patients had thymoma, the majority of which were stage I (localized), and most underwent thymectomy as part of management. The median delay in GS diagnosis following thymoma diagnosis was 1,486 days (interquartile range IQR: 406.75–1,992.75). Infectious complications were observed in 30 of 32 patients (97%), most commonly sinopulmonary infections (87%) (Figure 1). Bacterial infections were documented in 29 patients (94%), viral in 14 (45%), fungal in 13 (42%), and mycobacterial in 3 (10%) (Figure 2). Immunologic data were available for 22 patients. Reduced CD4+ T-cell counts and severe B-cell lymphopenia were observed in 77%. IgM and IgG deficiencies were the most prevalent, present in 82% of cases. Most patients received monthly immunoglobulin replacement; additionally, 59% were prescribed oral antimicrobial prophylaxis due to their elevated risk of infections. All-cause mortality was 31% (n=10); among these, 3 deaths (10%) were directly attributable to complications of Good syndrome. Conclusion We observed a significant delay (Median of 4.07 years) in the diagnosis of Good syndrome following thymoma detection. Given the high risk of infectious complications and associated mortality, clinicians should maintain a high index of suspicion and consider early immunologic evaluation in adults with recurrent or opportunistic infections, particularly in the context of a known thymoma. Disclosures All Authors: No reported disclosures

Abstract Wiskott-Aldrich syndrome (WAS), an X-linked disorder characterized by immunodeficiency, thrombocytopenia, autoimmunity, and malignancy, can be effectively treated with allogeneic hematopoietic cell transplantation (HCT). Older age at HCT and mismatched donors are known to affect overall survival (OS). However, the influence of specific clinical manifestations or WAS variant class on OS and factors associated with event-free survival (EFS) remain incompletely defined. We analyzed outcomes of 308 patients with WAS who underwent HCT at 37 institutions of the Primary Immune Deficiency Treatment Consortium from 1990 to 2018. With a median follow-up of 5.3 years, the 5-year OS and EFS were 87.2% and 79.7%, respectively. Age ≥5 years, donor type, and a pre-HCT history of severe infection had a negative impact on OS and EFS, whereas pre-HCT autoimmunity had no impact. Reduced-intensity regimens were associated with lower T-cell and myeloid donor chimerism, particularly when non–busulfan-based regimens were used. Low myeloid donor chimerism was associated with lower platelet counts. Mixed chimerism was not consistently associated with post-HCT autoimmunity. Patients with class I (exon 1-2 missense and intron 5 hot spot variants) and class II variants (all others) had similar pre-HCT clinical symptom severity and no difference in OS, EFS, or platelet recovery post-HCT. In conclusion, our study showed excellent long-term OS and EFS after HCT for WAS, highlighting the importance of early HCT, before the development of severe infections. We confirmed that HCT using busulfan-based conditioning was associated with improved donor chimerism and platelet recovery. This trial was registered at www.clinicaltrials.gov as NCT02064933.

Abstract Description Fungal species, such as Candida albicans, are commonly found as part of the normal microbiota in both the skin and intestine. However, these fungal species, including C. albicans, can also become opportunistic pathogens and have been associated with intestinal and allergic disorders. We hypothesized C. albicans colonization could occur in early life when the neonatal microbiota is permissive to pathogens and lacks colonization resistance compared to later times in life. To investigate this question, we sequenced stool of premature and term infants and frequently found C. albicans colonization, suggesting fungal colonization within the human GI tract. To investigate the impact of long-term C. albicans colonization to the immune system, we established colonization by oral administration of C. albicans to neonatal mice. Colonization of C. albicans was associated with increased diversity of bacterial species in the intestinal microbiota at weaning. Additionally, we observed significant increases of inflammatory cytokines IL-17 and G-CSF in the serum. Future research will expand on the impact of C. albicans colonization on the intestinal microbiota and immune systems. Funding Sources Center for Individualized Medicine Microbiome Program Research Team Science Award, Mayo Clinic NIH, NIDDK R01 DK134366 Topic Categories Mucosal and Regional Immunology (MUC)

We assessed associations of pediatrician demographic characteristics with patient satisfaction (PS) scores. We performed a retrospective analysis of PS scores among pediatricians at a single academic institution and their associations with individual demographic features including gender, race, and geographic location of medical school education. We analyzed PS survey results for 153 pediatricians, 48.4% of whom were female. Males received higher scores in 4 out of 10 questions including “Likelihood of your recommending this care provider to others” ( P = .007). We observed similar findings for white pediatricians compared to Black, Indigenous, and People of Color (BIPOC) ( P = .033) and US medical school graduates compared to international school graduates ( P = .044). Overall, we observed that pediatricians who are female, BIPOC, or international medical school graduates receive lower PS scores than their counterparts. The impact of potential survey responder bias should be acknowledged when interpreting PS scores for pediatricians.

Abstract Introduction: Cystic fibrosis (CF) is a genetic disorder characterized by defective chloride ion transport, leading to thick mucus production, chronic respiratory infections, and other multisystem involvement. Although CF is often diagnosed in childhood, the condition can be missed or misdiagnosed in adults. Description of Case: We present the case of a 60-year-old male from India who was diagnosed with CF after a prolonged period of sinopulmonary symptoms. He initially presented in 2014. His medical history was pertinent for asthma, and multiple episodes of clinically and radiographically confirmed pneumonia and polypoid sinusitis requiring IV antibiotics and sinus surgery. He carried a prior diagnosis of allergic bronchopulmonary aspergillosis treated with itraconazole and steroids, as well as elevated IgE levels. His CT chest was notable for extensive bronchiectasis, bronchial wall thickening, and mucus plugging of both lungs. He had no known family history of CF. Sweat chloride testing was in the intermediate range (44, 47 mmol/L; normal <30 mmol/L, intermediate 30 to 59 mmol/L, abnormal >59 mmol/L). Given high suspicion for CF, cystic fibrosis transmembrane conductance regulator (CFTR) full gene analysis was pursued. Sequence analysis and multiplex ligation-dependent probe amplification of the CFTR gene detected heterozygous sequence changes c.1717-2A>T, classified as likely deleterious, and c.1367T>C (p.V456A), variant of uncertain significance. He was thus initially diagnosed as a CF carrier. He re-presented in 2024 with decline in pulmonary function testing and continued sinopulmonary infections. Genetic testing results from 2014 were re-analyzed. Between initial presentation and present, his V456A variant was upgraded to pathogenic. He met diagnostic criteria for CF with two pathogenic CFTR variants, a repeated intermediate sweat chloride (47 mmol/L) suggestive of CFTR protein dysfunction, and disease that could be attributed to CFTR dysfunction. He subsequently started TRIKAFTA® (elexacaftor/tezacaftor/ivacaftor and ivacaftor) and airway clearance therapy. Discussion: The diagnosis of CF in adults can be challenging, particularly in individuals without a known family history, intermediate sweat chloride testing, and with inconclusive genetic testing. Our understanding of CF in Asian populations is limited. CF is suspected to be underreported in patients with Southeast Asian ancestry in part due to genetic heterogeneity. The interpretation of certain genetic variants can evolve over time. A variant of unknown significance may later be reclassified as pathogenic, revealing its true role in disease development. This highlights the critical importance of regularly re-evaluating genetic test results.

Introduction Loss of interferon-γ (IFN-γ) function through the development of neutralizing autoantibodies results in a late-onset immunodeficiency characterized by disseminated opportunistic infection. While rare, there is a higher prevalence in patients of Southeast Asian ancestry. Treatment is aimed at B cell depletion; however, relapse is common. Here we describe two cases of anti–IFN-γ autoantibody-associated immunodeficiency. Case Descriptions Patient 1: A 42-year-old female originally from Laos presented with a 30-lb weight loss and fatigue over the course of 8 months. Cultures grew Mycobacterium hassiacum. Testing by National Jewish was positive for anti–IFN-γ autoantibody via ELISA and for IFN-γ neutralizing ability via pSTAT1 phosphorylation. Autoantibodies were treated with rituximab 375 mg/m2 weekly for 4 weeks. She had subsequent negative autoantibody levels for 6 months until positive autoantibodies were again detected. She was treated with an additional 3 rituximab 375 mg weekly infusions and maintained remission for an additional 15 months until autoantibody levels were again positive without associated symptoms or infection (see table for timeline). She is currently undergoing additional 4 rituximab infusions. Table Patient 2 A 59-year-old female originally from Laos who presented for an immunodeficiency workup with a history of disseminated Mycobacterium avium infection, with pulmonary, lymph node, and parotid gland involvement. Anti–IFN-γ autoantibody testing from National Jewish was positive. She was treated with rituximab 375 mg/m2 weekly for 4 weeks. Autoantibody levels were negative 3 months later, and she has maintained remission since by serial monitoring. Discussion In our experience, anti–IFN-γ autoantibody-associated secondary immunodeficiency should be suspected in middle-aged patients with disseminated opportunistic infection, especially women of Southeast Asian ancestry. Rituximab rapidly depletes autoantibody levels; however, maintenance of remission is variable. The average duration of response in patient 1 was 10.5 months compared with persistent remission in patient 2. Thus, serial monitoring with autoantibody levels, markers of inflammation, and symptom assessments should be performed with consideration for repeated doses of rituximab.

Introduction STAT1 gain-of-function (GOF) mutations result in a broad clinical spectrum characterized by complex phenotypic manifestations. In addition to the hallmark chronic mucocutaneous candidiasis (CMC), patients are predisposed to bacterial and viral infections, autoimmunity, endocrinopathies, lymphoproliferative disorders, and malignancies. Severe complications, including invasive infections, cerebral aneurysms, and malignancies, are significant predictors of poor outcomes. Understanding genotype–phenotype correlations is critical for optimizing management in this challenging patient population. Methods We conducted a retrospective review of electronic medical records for five patients diagnosed with STAT1 GOF mutations at Mayo Clinic, Rochester, MN. This case series included data on demographics, clinical history, immunologic evaluations, genetic testing results, disease manifestations, treatments, and outcomes. Results The cohort included five patients (1 male, 4 females; mean age at diagnosis: 21.7 years) with heterozygous STAT1 GOF mutations. Three patients had c.1154C>T (p.Thr385Met), one had c.1310C>T (p.Thr437Ile) in the DNA-binding domain (DBD), and one had c.856A>G (p.Lys286Glu) in the coiled-coil domain (CCD). Universal features included CMC and recurrent sinopulmonary infections. Patients with c.1154C>T presented with early-onset infections, severe autoimmunity (e.g., pancytopenia and enteropathy), and bronchiectasis, requiring ruxolitinib in all three cases. The patient with c.1310C>T had a late childhood onset of symptoms, later complicated by persistent histoplasmosis. The c.856A>G case experienced severe multidrug-resistant infections, splenomegaly, coagulopathy, neurological complications, poor response to ruxolitinib, and died from complications of MSSA pneumonia and monkeypox. Conclusion Genotype–phenotype correlations in STAT1 GOF mutations highlight a diverse clinical spectrum driven by mutation-specific mechanisms. DBD mutations are associated with more severe outcomes, including early-onset immunodeficiency, invasive infections, and autoimmunity, due to faster nuclear accumulation and impaired dephosphorylation of STAT1. CCD mutations present with multisystem involvement, further emphasizing the heterogeneity of clinical manifestations. These variations underscore the importance of genetic insights for prognostication and tailored management. Early interventions, including hematopoietic stem cell transplantation for severe cases, and emerging therapies like JAK inhibitors show promise; however, ruxolitinib's need for individualized dosing, vigilant monitoring, continuous treatment to maintain benefits, and lack of epigenetic correction warrant further evaluation.

Background Cytokines play an important role in Th1 and Th2 inflammation. Both Th1 and Th2 cytokines can be utilized for evaluation and treatment response in many different disorders, including inborn errors of immunity. The role of broad cytokine panel testing in inborn errors of immunity is not well described. Objective To analyze broad cytokine panel testing in clinical practice. Methods A retrospective review of cytokine panel testing performed at Mayo Clinic was performed. Data were collected from patients at Mayo Clinic Rochester, Mayo Clinic Jacksonville, and Mayo Clinic Health System. Serum cytokine panel testing included the following cytokines: tumor necrosis factor (TNF), IL-6, IFN-β, IL-10, monocyte chemoattractant protein-1 (MCP-1), IL-1β, IFN-γ, macrophage inflammatory protein-1 alpha (MIP-1α), granulocyte-monocyte colony-stimulating factor (GM-CSF), IL-2 receptor α soluble, IFN-α, and IL-18. Data collection ranged from 03/2021 to 09/2024. The study was funded by Mayo CCaTS grant number UL1TR002377. Results A total of 88 cytokine panel tests were performed during the study period on 80 total patients. There was at least 1 elevated cytokine level in 70/88 (80%) tests performed. There was elevation in each individual cytokine level as follows: TNF (49), IL-2 receptor α soluble (40), IFN-α (0), IL-18 (26), IL-6 (33), IFN-β (4), IL-10 (13), MCP-1 (18), IL-1β, IFN-γ (11), MIP-1α (12), and GM-CSF (6). 18 patients that underwent cytokine panel testing had common variable immune deficiency (CVID), and 10 of those patients had granulomatous lymphocytic interstitial lung disease. 6 patients with early onset inflammatory bowel disease, 5 patients with autoimmune lymphoproliferative syndrome, 2 patients with Myhre syndrome, 2 patients with Hyper IgE syndrome, 1 patient with hypereosinophilic syndrome, 1 patient with autoimmune polyglandular syndrome type 1, 1 patient with XIAP deficiency, 1 patient with X-linked chronic granulomatous disease, and 1 patient with STAT 1 gain of function were tested. Other patients tested had other medical diagnoses or were undergoing immunodeficiency evaluation. There was no significant increase noted in any individual cytokine level when compared with the whole cohort. Conclusion Cytokine panel testing could be a potential diagnostic tool in evaluation of inborn errors of immunity. Further research is needed to better characterize the importance of cytokine panel testing in inborn errors of immunity.