Chronic Granulomatous Disease-Like Presentation of a Child with Autosomal Recessive PKCδ Deficiency.

BACKGROUND: Autosomal recessive (AR) PKCδ deficiency is a rare inborn error of immunity (IEI) characterized by autoimmunity and susceptibility to bacterial, fungal, and viral infections. PKCδ is involved in the intracellular production of reactive oxidative species (ROS). MATERIAL AND METHODS: We studied a 5-year old girl presenting with a history of Burkholderia cepacia infection. She had no history of autoimmunity, lymphocyte counts were normal, and no auto-antibodies were detected in her plasma. We performed a targeted panel analysis of 407 immunity-related genes and immunological investigations of the underlying genetic condition in this patient. RESULTS: Consistent with a history suggestive of chronic granulomatous disease (CGD), oxidative burst impairment was observed in the patient's circulating phagocytes in a dihydrorhodamine 123 (DHR) assay. However, targeted genetic panel analysis identified no candidate variants of known CGD-causing genes. Two heterozygous candidate variants were detected in PRKCD: c.285C > A (p.C95*) and c.376G > T (p.D126Y). The missense variant was also predicted to cause abnormal splicing, as it is located at the splice donor site of exon 5. TOPO-TA cloning confirmed that exon 5 was completely skipped, resulting in a truncated protein. No PKCδ protein was detected in the patient's neutrophils and monocyte-derived macrophages. The monocyte-derived macrophages of the patient produced abnormally low levels of ROS, as shown in an Amplex Red assay. CONCLUSION: PKCδ deficiency should be considered in young patients with CGD-like clinical manifestations and abnormal DHR assay results, even in the absence of clinical and biological manifestations of autoimmunity.

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.

Improved diagnostic clarity in shrimp allergic non-dust-mite sensitized patients.

BACKGROUND: Allergen specific immunoglobulin E (sIgE) levels predictive of shrimp allergy have not been identified, but these may be helpful in identifying patients at risk for shrimp-induced allergic reactions. OBJECTIVE: This study sought to identify component resolved diagnostic tests useful for diagnosis of shrimp allergy in patients with or without house-dust mite (HDM) sensitization to the major allergen cysteine protease (Der p 1). METHODS: Patients with positive skin-prick test (SPT) results and/or sIgE values were recruited. Shrimp allergy was classified by oral food challenge (OFC) or by a clear history of anaphylaxis after shrimp ingestion. Patients with shrimp allergy and patients who were tolerant were further classified based on HDM sensitivity (Der p 1 > 0.35 kUA/L). Testing for sIgE to total shrimp, and shrimp and HDM components was performed. The Fisher exact test, Wilcoxon sum rank test, and receiver operating characteristics analyses were used to compare sIgE levels in patients with allergy and patients who were tolerant. RESULTS: Of 79 patients recruited, 12 patients with shrimp allergy (7 with positive OFC results and 5 with a history of anaphylaxis) and 18 patients who were shrimp tolerant were enrolled. Of the patients not HDM sensitized, sIgE levels to shrimp (10.5 kUA/L, p = 0.012) and Der p 10 (4.09 kUA/L, p = 0.035) were higher in patients with shrimp allergy. Shrimp sIgE of ≥3.55 kUA/L had 100% diagnostic sensitivity and 85.7% specificity (receiver operating characteristic 0.94 [0.81, 1.0] 95% CI) and Der p 10 sIgE levels of ≥3.98 kUA/L had a diagnostic sensitivity of 80% and specificity of 100% (receiver operating characteristic 0.86 [0.57, 1.0] 95% CI) for prediction of clinical reactivity. CONCLUSION: HDM sensitization influences shrimp and HDM component sIgE levels and, consequently, their diagnostic accuracy in shrimp allergy. In our series, in the patients who were non-HDM sensitized, a shrimp sIgE level of >3.55 kUA/L showed 100% sensitivity and, Der p 10 sIgE of >3.98 kUA/L showed 100% specificity for the diagnosis of shrimp allergy. These levels may not be applicable to every patient and, therefore, may not obviate the need for OFC.

A 15-year-old boy with severe combined immunodeficiency, fungal infection, and weight gain.

Hematopoietic stem cell transplantation (HSCT) outcomes in X-linked severe combined immune deficiency are most effective when performed with patients <3 months of age and without coexisting morbidity, and with donor cells from a matched sibling. Even under such favorable circumstances, outcomes can be suboptimal, and full cellular engraftment may not be complete, which results in poor B or natural killer cell function. Protein losing enteropathies can accompany persistent immune deficiency disorders with resultant low serum globulins (immunoglobulin A [IgA], IgG, IgM) and lymphopenia. Patients with immune disorders acquire infections that can be predicted by their immune dysfunction. Fungal infections are typically noted in neutropenic (congenital or acquired) and T-cell deficient individuals. Coexisting fungal infections are rare, even in hosts who are immunocompromised, and they require careful evaluation. Antifungal treatment may result in drug-drug interactions with significant complications.

Utility of Component-Resolved Diagnostics in Food Allergy.

Allergen component-resolved diagnostic testing (CRD) is a new methodology in clinical food allergy diagnosis, improving the ability to identify specific clinical phenotypes. Instead of relying on the crude allergen extracts used in standard allergy diagnostics, CRD utilizes purified or recombinant allergens for identification of specific molecules causing sensitization or allergy. This method is able to determine risk of the severity of allergic reactions in specific cases, like soy, peanut, and hazelnut allergy. The severity of allergic reaction can be predicted in peanut allergy with Ara h 2, and clinically relevant disease in pollen-allergic patients can be identified. However, age and geographic differences affect CRD results and it should always be utilized in the context of a clinical history. In the future, clinical phenotypes may be differentiated with larger prospective studies utilizing food challenges.