Barmettler, Sara

Introduction Individuals with inborn errors of immunity (IEI) are increasingly reaching reproductive age, yet guidance on fertility preservation, genetic counseling, medication adjustments in pregnancy and breastfeeding, monitoring for complications, and multidisciplinary coordination is lacking. This joint effort between two committees of the Clinical Immunology Society (CIS), the Women of the Clinical Immunology Society (WCIS) and the Adult Immune Deficiency Committee (AID) survey aimed to characterize current reproductive care practices for IEI patients. Methods A survey was disseminated to 809 CIS members. The response rate was 6.43% (52 respondents). The 24-item questionnaire addressed management of pregnancy in IEI, medications adjustment, participation in hematopoietic stem cell transplant (HSCT) care and fertility preservation, and maternal/neonatal outcomes. Results Because survey items were optional, the number of respondents varies by question. Forty-two participants completed core items: 64% (27/42) allergists/immunologists, 71% (30/42) practicing at academic centers, and 48% (20/42) with >50% immunology-focused practices. Most respondents (78%, 41/52) currently or previously cared for pregnant/planning IEI patients. Preconception counseling was common (90%, 37/41), yet only 2% (1/41) have access to a formal reproductive multidisciplinary team. Among clinicians involved in HSCT care, 45% (13/29) referred patients for fertility preservation. More than half, 52% (22/42), observed reduced fertility in IEI patients, and 56% (20/36) observed adverse maternal outcomes. Medication management varied: 61% (24/39) discontinued known teratogenic medications, and 64% (25/39) adjusted dosing during pregnancy. Regarding immunoglobulin replacement therapy, 79% adjusted dosing based on IgG levels and 42% increased dosing by trimester. Conclusions This CIS survey reveals practice variability and notable gaps in reproductive health support for individuals with IEIs. Due to the relatively low response rate, generalizability across providers and practice settings is challenging. However, the results of this survey suggest that although most clinicians provide preconception counseling and manage IgG and immunomodulatory therapy during pregnancy, formal multidisciplinary structures are rare. High rates of reported fertility concerns and maternal complications underscore the need for enhanced collaboration with obstetrics/gynecology and the development of structured, evidence-based, multidisciplinary guidelines for reproductive care in IEI. Tabular data are included as downloadable supplement files.

Background Non-invasive biomarkers of immune checkpoint inhibitor-associated acute tubulointerstitial nephritis (ICI-nephritis) are urgently needed. Because ICIs block immune checkpoint pathways that include cytotoxic T lymphocyte antigen 4 (CTLA4), we hypothesized that biomarkers of immune dysregulationpreviously defined in patients with congenital CTLA4 deficiency, including elevated soluble interleukin-2 receptor alpha (sIL-2R) and flow cytometric cell-based markers of B and T cell dysregulation in peripheral blood may aid the diagnosis of ICI-nephritis. Methods A retrospective cohort of patients diagnosed with ICI-nephritis was compared with three prospectively enrolled control cohorts: ICI-treated controls without immune-related adverse events, patients not on ICIs with hemodynamic acute kidney injury (hemodynamic AKI), and patients not on ICIs with biopsy proven acute interstitial nephritis from other causes (non-ICI-nephritis). sIL-2R level and flow cytometric parameters were compared between groups using Wilcoxon rank sum test or Kruskal-Wallis test. Receiver operating characteristic curves were generated to define the accuracy of sIL-2R and flow cytometric biomarkers in diagnosing ICI-nephritis. The downstream impact of T cell activation in the affected kidney was investigated using archived biopsy samples to evaluate the gene expression of IL2RA, IL-2 signaling, and T cell receptor signaling in patients with ICI-nephritis compared with other causes of drug-induced nephritis, acute tubular injury, and histologically normal controls. Results sIL-2R level in peripheral blood was significantly higher in patients with ICI-nephritis (N=24) (median 2.5-fold upper limit of normal (ULN), IQR 1.9–3.3), compared with ICI-treated controls (N=10) (median 0.8-fold ULN, IQR 0.5–0.9, p<0.001) and hemodynamic AKI controls (N=6) (median 0.9-fold-ULN, IQR 0.7–1.1, p=0.008). A sIL-2R cut-off point of 1.75-fold ULN was highly diagnostic of ICI-nephritis (area under the curve >96%) when compared with either ICI-treated or hemodynamic AKI controls. By peripheral blood flow cytometry analysis, lower absolute CD8+T cells, CD45RA+CD8+ T cells, memory CD27+B cells, and expansion of plasmablasts were prominent features of ICI-nephritis compared with ICI-treated controls. Gene expressions for IL2RA , IL-2 signaling, and T cell receptor signaling in the kidney tissue with ICI-nephritis were significantly higher compared with controls. Conclusion Elevated sIL-2R level and flow cytometric markers of both B and T cell dysregulation may aid the diagnosis of ICI-nephritis.