Inborn errors of immunity: Recent progress.

Recent advances in the field of inborn errors of immunity (IEIs) have been wide in scope, including progress in mechanisms of disease, diagnosis, and management. New gene defects affecting the immune response continue to be reported, as many as 26 in the year 2020. It was noted that the presentation of IEIs might not include recurrent infections in 9% of cases, and that current diagnostic methods can identify molecular causes in 92% of patients with severe combined immunodeficiency. Progress in immunopathogenesis explained mechanisms leading to symptoms of autosomal-recessive hyper-IgE syndrome. There was an emphasis on research in primary antibody deficiencies. The benefit of antibiotic prophylaxis to reduce the frequency of infections was demonstrated in these patients. The regimen of rituximab and azathioprine or mycophenolate was proven effective for chronic granulocytic interstitial pneumonia. The efficacy and adverse events of hematopoietic stem cell transplant in different IEI conditions were reported, as well as different strategies to improve outcomes, supporting its use in immunodeficiency and immunodysregulatory syndromes. The recent pandemic of coronavirus disease 2019 affected patients with IEIs, in particular those with deficiency in the interferon-mediated activation of the immune response. Initial data suggest that coronavirus disease 2019 vaccines might elicit anti-coronavirus disease 2019-neutralizing antibody responses in some patients with IEI conditions.

Secondary immunodeficiencies: An overview.

OBJECTIVE: To review the different causes of secondary immunodeficiencies and provide clinicians with an updated overview of potential factors that contribute to immunodeficiency. DATA SOURCES: Recent published literature obtained through PubMed database searches, including research articles, review articles, and case reports. STUDY SELECTIONS: PubMed database searches were conducted using the following keywords: immunodeficiency, antibody deficiency, immunosuppressive drugs, genetic syndrome, malignancy, HIV infection, viral infection, secondary immunodeficiency, nutrition, prematurity, aging, protein-losing enteropathy, nephropathy, trauma, space travel, high altitude, and ultraviolet light. Studies published in the last decade and relevant to the pathogenesis, epidemiology, and clinical characteristics of secondary immunodeficiencies were selected and reviewed. RESULTS: Researchers continue to investigate and report abnormal immune parameters in the different entities collectively known as secondary immunodeficiencies. Immunodeficiency might occur as a consequence of malnutrition, metabolic disorders, use of immunosuppressive medications, chronic infections, malignancies, severe injuries, and exposure to adverse environmental conditions. The neonate and the elderly may have decreased immune responses relative to healthy adults. Each of these conditions may present with different immune defects of variable severity. The acquired immunodeficiency syndrome results from infections by the human immunodeficiency virus, which targets CD4 T cells leading to defective immune responses. Rituximab is a monoclonal antibody that targets CD20 B cells, and its use might result in persistent hypogammaglobulinemia. CONCLUSION: Clinicians should consider secondary immunodeficiencies in the differential diagnosis of a patient with recurrent infections and abnormal immunologic evaluation. The use of biological agents for the treatment of inflammatory conditions and malignancies is an increasingly important cause of secondary immunodeficiency.

Combination Steroid and Test-based Food Elimination for Eosinophilic Esophagitis: A Retrospective Analysis.

OBJECTIVES: Eosinophilic esophagitis (EoE) is a clinicopathologic disorder characterized by infiltration of eosinophils into the esophagus. Primary treatment approaches include topical corticosteroids and/or food elimination. The aim of the present study was to compare the effectiveness of combination therapy (topical corticosteroid plus test-based food elimination [FS]) with single therapy (topical corticosteroid [S] or test-based food elimination [F]). METHODS: Chart review of patients with EoE at Texas Children's Hospital (age <21 years) was performed. Clinical and histological statuses were evaluated after a 3-month treatment with either single or combination therapy. Comparisons were analyzed using Fisher exact test, Kruskal-Wallis tests, and multiple logistic regression models. RESULTS: Among 670 charts, 63 patients (1-21 years, median 10.3 years) with clinicopathologic diagnoses of EoE were identified. Combination FS therapy was provided to 51% (n = 32) and single treatment (S, F) to 27% (n = 17) or 22% (n = 14) of patients, respectively. Clinical responses were noted in 91% (n = 29), 71% (n = 12), and 64% (n = 14) of patients in the FS, S, and F groups, respectively. The odds of clinically improving were 4.6 times greater (95% confidence interval: 1.1-18.8) with combination versus single therapy. The median peak number of eosinophils per high-power field after 3-month therapy was not significantly different in the S, F, and FS groups. CONCLUSIONS: The combination of topical corticosteroids with specific food elimination is as effective in achieving clinical and histological remissions as the single-treatment approaches. Responses were achieved with the combination in patients who had previously failed single-agent therapy. Prospective research of this combination approach in young patients with EoE is needed.

Utility of FLAER and CD157 in a five-color single-tube high sensitivity assay, for diagnosis of Paroxysmal Nocturnal Hemoglobinuria (PNH)-A standalone flow cytometry laboratory experience.

BACKGROUND: FLAER-based flow cytometry assay is considered the gold standard for diagnosis of paroxysmal nocturnal hemoglobinuria (PNH). CD157 is a recently reported marker for GPI-anchored protein found both on neutrophils and monocytes. This study highlights the robustness of FLAER and CD157 combination to identify PNH clones in a high sensitivity assay. Though rare, the data shown highlight the presence of CD157 negativity in few cases re-emphasizing the importance of FLAER for PNH diagnosis. METHODS: A single 5-color tube-FLAER Alexa488/ CD157PE/ CD15PECy5/ CD64PE-Cy7 & CD45APCH7-was used for a high sensitivity PNH assay. RESULTS: Of 364 cases, 59(16.2%) cases had PNH clone in both granulocytes and monocytes. PNH clone sizes ranged from 0.02% to 96.6% in granulocytes and 0.07% to 96.3% in monocytes based on their FLAER-negative, CD157-negative phenotype. Twenty-two of the 59 PNH cases (37.3%) had WBC clone size of <1%. In addition, there were 10 cases which showed absence of CD 157 expression on both granulocytes and monocytes but on FLAER staining showed normal staining patterns. Three of these ten cases also showed a PNH clone based on absence of FLAER expression on both granulocytes and monocytes. CONCLUSION: FLAER and CD157 is a robust combination for diagnosis of clinical and subclinical PNH. Absence of CD157 expression in normal WBCs, though rare, should be kept in mind and re-emphasizes the importance of FLAER for the high sensitivity PNH assay.

Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder characterized by deficient synthesis of dopamine and serotonin. It presents in early infancy, and causes severe developmental disability and lifelong motor, behavioral, and autonomic symptoms including oculogyric crises (OGC), sleep disorder, and mood disturbance. We investigated the safety and efficacy of delivery of a viral vector expressing AADC (AAV2-hAADC) to the midbrain in children with AADC deficiency (ClinicalTrials.gov Identifier NCT02852213). Seven (7) children, aged 4-9 years underwent convection-enhanced delivery (CED) of AAV2-hAADC to the bilateral substantia nigra (SN) and ventral tegmental area (VTA) (total infusion volume: 80 µL per hemisphere) in 2 dose cohorts: 1.3 × 1011 vg (n = 3), and 4.2 × 1011 vg (n = 4). Primary aims were to demonstrate the safety of the procedure and document biomarker evidence of restoration of brain AADC activity. Secondary aims were to assess clinical improvement in symptoms and motor function. Direct bilateral infusion of AAV2-hAADC was safe, well-tolerated and achieved target coverage of 98% and 70% of the SN and VTA, respectively. Dopamine metabolism was increased in all subjects and FDOPA uptake was enhanced within the midbrain and the striatum. OGC resolved completely in 6 of 7 subjects by Month 3 post-surgery. Twelve (12) months after surgery, 6/7 subjects gained normal head control and 4/7 could sit independently. At 18 months, 2 subjects could walk with 2-hand support. Both the primary and secondary endpoints of the study were met. Midbrain gene delivery in children with AADC deficiency is feasible and safe, and leads to clinical improvements in symptoms and motor function.

Nasopharyngeal carcinoma with unusual metastasis to urinary bladder.

Nasopharyngeal carcinoma (NPC) metastasizing to urinary bladder is an uncommon site. We report an interesting case of NPC, on follow-up, presenting with unusual urinary symptoms and mimicking a primary bladder cancer. Subsequent bladder cold cup biopsy and immunohistochemistry unfolded a metastasis of NPC, highlighting unexpected and a rare presentation.

Weaker ERG expression in patients with ERG-positive prostate cancer is associated with advanced disease and weaker androgen receptor expression: An Indian outlook.

INTRODUCTION: Gene fusion between TMPRSS2 and ERG has a causal role in prostate cancer initiation. However, studies evaluating its role clinically have shown conflicting results. We investigated simultaneously multiple aspects of ERG, namely, "presence" and "strength" of ERG expression and "correlation" of ERG with other common clinicopathological parameters. MATERIALS AND METHODS: From January 2012 to November 2013, the status of ERG, androgen receptor (AR), and p53 was prospectively determined by immunohistochemistry unselectively in all types of specimens positive for prostate cancer. "Strength" of expression was measured in terms of "intensity" as well as "percentage positivity," with each parameter given a score from 0 to 3 based on fixed protocol, which was tested for interrater variability as well as test-retest reliability. Data were collected for age, Gleason score, prostate specific antigen levels, presence of perineural invasion and lymphovascular invasion, high-grade prostatic intraepithelial neoplasia, and cancer stage. RESULTS: In total, 100 specimens were analyzed, and overall 51 patients had ERG-positive immunostaining. ERG-positive tumors had lower presence of high-grade prostatic intraepithelial neoplasia and p53 positivity, with no significant difference in prostate specific antigen levels, Gleason scores, and presence of lymphovascular invasion. Moreover, 54 patients had complete stage information, and the absolute number of patients with ERG positivity increased with increasing clinical stage. Among these, 30 patients were ERG positive, and ERG score had strong positive correlation with AR expression (Spearman correlation coefficient 0.677). However, median ERG scores showed a significant decline (consistent across percentage positivity and intensity) in patients with stage 4 disease, and score ≤ 2 had 88.2% specificity in identifying patient with stage 4 disease. Cohen׳s κ = 0.81, whereas intraclass correlation coefficient was 0.95, indicating substantial agreement and near-perfect reproducibility of scoring scheme for immunohistochemistry. CONCLUSION: ERG-positive tumors increase in proportion with increasing stage of disease, but strength of ERG expression in ERG-positive patients shows a significant decline, or "loss," in patients with stage 4 disease. This may have potential therapeutic implications as ERG expression score showed strong positive correlation with AR expression score.