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With the exponential discovery of new inborn errors of immunity (IEI), it is becoming increasingly difficult to differentiate between a number of the more recently defined disorders. This is compounded by the fact that although IEI primarily present with immunodeficiency, the spectrum of disease is broad and often extends to features typical of autoimmunity, autoinflammation, atopic disease, and/or malignancy. Here we use case studies to discuss the laboratory and genetic tests used that ultimately led to the specific diagnoses., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

The differential diagnosis of eosinophilia is broad and includes infections, malignancies, and atopy as well as inborn errors of immunity (IEI). Certain types of IEIs are known to be associated with elevated numbers of eosinophils and frequently elevated serum IgE, whereas for others the degree and frequency of eosinophilia are less established. The molecular defects underlying IEI are heterogeneous and affect different pathways, which highlights the complex regulations of this cell population within the immune system. In this review, we list and discuss clinical manifestations and therapies of immune deficiency or immune dysregulation disorders associated with peripheral blood or tissue eosinophilia with or without raised IgE levels. We present illustrative case vignettes for the most common entities and propose a diagnostic algorithm aiming to help physicians systematically to evaluate patients with eosinophilia and suspicion of an underlying IEI., (Published by Elsevier Inc.)

Background: Biallelic variations in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy. Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease., Objective: To determine outcome of HSCT for DOCK8 deficiency and define possible outcome variables., Methods: We performed a retrospective study of the results of HSCT in a large international cohort of DOCK8-deficient patients., Results: We identified 81 patients from 22 centers transplanted at a median age of 9.7 years (range, 0.7-27.2 years) between 1995 and 2015. After median follow-up of 26 months (range, 3-135 months), 68 (84%) patients are alive. Severe acute (III-IV) or chronic graft versus host disease occurred in 11% and 10%, respectively. Causes of death were infections (n = 5), graft versus host disease (5), multiorgan failure (2), and preexistent lymphoma (1). Survival after matched related (n = 40) or unrelated (35) HSCT was 89% and 81%, respectively. Reduced-toxicity conditioning based on either treosulfan or reduced-dose busulfan resulted in superior survival compared with fully myeloablative busulfan-based regimens (97% vs 78%; P = .049). Ninety-six percent of patients younger than 8 years at HSCT survived, compared with 78% of those 8 years and older (P = .06). Of the 73 patients with chimerism data available, 65 (89%) had more than 90% donor T-cell chimerism at last follow-up. Not all disease manifestations responded equally well to HSCT: eczema, infections, and mollusca resolved quicker than food allergies or failure to thrive., Conclusions: HSCT is curative in most DOCK8-deficient patients, confirming this approach as the treatment of choice. HSCT using a reduced-toxicity regimen may offer the best chance for survival., (Copyright © 2018. Published by Elsevier Inc.)

Background: Autosomal dominant hyper-IgE syndrome (AD-HIES) is a rare condition., Objective: Data from the USIDNET Registry provide a resource to examine the characteristics of patients with rare immune deficiency diseases., Methods: A query was submitted to the USIDNET requesting deidentified data for patients with physician-diagnosed AD-HIES through July 2016., Results: Data on 85 patients diagnosed with AD-HIES (50 males; 35 females) born between 1950 and 2013, collected by 14 physicians from 25 states and Quebec, were entered into the USIDNET Registry by July 2016. Cumulative follow-up was 2157 years. Of these patients, 45.9% had a family history of HIES. The complications reported included skin abscesses (74.4%), eczema (57.7%), retained primary teeth (41.4%), fractures (39%), scoliosis (34.1%), and cancer (7%). Reported allergic diseases included food (37.8%), environmental (18%), and drugs (42.7%). The mean serum IgE level was 8383.7 kU/mL and was inversely correlated to the patient's age. A total of 49.4% had eosinophilia; 56% were known to be on trimethoprim-sulfamethoxazole, 26.6% on antifungal coverage, and 30.6% on immunoglobulin replacement therapy. Pneumonias were more commonly attributed to Staphylococcus aureus (55.3%) or Aspergillus fumigatus (22.4%); 19.5% had a history of lung abscess; these were most often associated with Pseudomonas aeruginosa (P Fisher's exact test = .029) or A. fumigatus (P Fisher's exact test = .016). Lung abscesses were significantly associated with drug reactions (P χ 2  = .01; odds ratio: 4.03 [1.2-12.97]), depression (P Fisher's exact test = .036), and lower Karnofsky index scores (P Mann-Whitney = .007)., Discussion: Data from the USIDNET Registry summarize the currently reported clinical characteristics of a large cohort of subjects with AD-HIES., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. All rights reserved.)