Manish Butte

J Allergy Clin Immunol Pract. 2021 May 22:S2213-2198(21)00582-1. doi: 10.1016/j.jaip.2021.05.004. Online ahead of print.

ABSTRACT

Knowledge related to the biology of inborn errors of immunity (IEI) and associated laboratory testing methods continue to expand at a tremendous rate. Despite this, many patients with IEI suffer for prolonged periods of time prior to identification of their underlying condition, thereby delaying appropriate care. Understanding that test selection and optimal evaluation for patients with recurrent infections or unusual patterns of inflammation can be unclear, we present a document which distills relevant clinical features of immunological disease due to IEI and related appropriate and available test options. This document is intended to serve the practicing clinical immunologist and, in turn, patients by describing best available test options for initial and expanded immunological evaluations across the disease spectrum. Our goal is to demystify the process of evaluating patients with suspected immune dysfunction and to enable more rapid and accurate diagnosis of such individuals.

PMID:34033983 | DOI:10.1016/j.jaip.2021.05.004

J Allergy Clin Immunol. 2021 May 22:S0091-6749(21)00809-5. doi: 10.1016/j.jaci.2021.05.007. Online ahead of print.

ABSTRACT

BACKGROUND: Rubella virus-induced granulomas have been described in patients with various inborn errors of immunity. Most defects impair T-cell immunity, suggesting a critical role of T cells in rubella elimination. However, the molecular mechanism of virus control remains elusive.

OBJECTIVE: To understand the defective effector mechanism allowing rubella vaccine virus persistence in granulomas.

METHODS: Starting from an index case with Griscelli syndrome type 2 and rubella skin granulomas, we combined an international survey with a literature search to identify patients with cytotoxicity defects and granuloma. We performed rubella virus immunohistochemistry and PCR and T-cell migration assays.

RESULTS: We identified 21 patients with various genetically confirmed cytotoxicity defects, who presented with skin and visceral granulomas. Rubella virus was demonstrated in all 12 accessible biopsies. Granuloma onset was typically before age 2 years and lesions persisted from months to years. Granulomas were particularly frequent in MUNC13-4 and RAB27A deficiency, where 50% of patients at risk were affected. Although these proteins have also been implicated in lymphocyte migration, 3D migration assays revealed no evidence of impaired migration of patient T cells. Notably, patients showed no evidence of reduced control of concomitantly given measles, mumps or varicella live-attenuated vaccine or severe infections with other viruses.

CONCLUSIONS: We identify lymphocyte cytotoxicity as a key effector mechanism for control of rubella vaccine virus, without evidence for its need in control of live measles, mumps or varicella vaccines. Rubella vaccine-induced granulomas are a novel phenotype with incomplete penetrance of genetic disorders of cytotoxicity.

PMID:34033843 | DOI:10.1016/j.jaci.2021.05.007

J Allergy Clin Immunol. 2021 May 22:S0091-6749(21)00810-1. doi: 10.1016/j.jaci.2021.04.036. Online ahead of print.

ABSTRACT

BACKGROUND: Activated phosphoinositide 3-kinase (PI3K) delta syndrome (APDS) is a combined immunodeficiency with a heterogeneous phenotype considered reversible by allogeneic hematopoietic cell transplantation (HCT).

OBJECTIVE: We sought to characterize HCT outcomes in APDS.

METHODS: Retrospective data was collected on 57 APDS1/2 patients (median age 13 years, range 2-66) who underwent HCT.

RESULTS: Pre-HCT comorbidities such as lung, gastrointestinal, and liver pathology were common, with hematologic malignancy in 26%. With 2.3 years median follow-up, 2-year overall and graft failure-free survival probabilities were 86% and 68%, respectively, and did not differ significantly by APDS1 vs 2, donor type, or conditioning intensity. The 2-year cumulative incidence of graft failure following first HCT was 17% overall but 42% if mTOR inhibitors (mTORi) were used in the first year post-HCT, compared to 9% without mTORi. Similarly, 2-year cumulative incidence of unplanned donor cell infusion was overall 28%, but 65% in the context of mTORi receipt and 23% without. Phenotype reversal occurred in 96% of evaluable patients, of whom 17% had mixed chimerism. Vulnerability to renal complications continued post-HCT, adding new insights into potential non-immunologic roles of PI3K not correctable through HCT.

CONCLUSIONS: Graft failure, graft instability and poor graft function requiring unplanned donor cell infusion were major barriers to successful HCT. Post-HCT mTORi use may confer an advantage to residual host cells, promoting graft instability. Longer term post-HCT follow-up of more patients is needed to elucidate the kinetics of immune reconstitution and donor chimerism, establish approaches that reduce graft instability, and assess the completeness of phenotype reversal over time.

PMID:34033842 | DOI:10.1016/j.jaci.2021.04.036

Arch Argent Pediatr. 2021 Jun;119(2):202-207. doi: 10.5546/aap.2021.eng.202.

ABSTRACT

A case series of primary immunodeficiencies is presented and outcome measures associated with survival among patients ≤ 16 years old are described. Diagnoses were made based on the criteria by the International Union of Immunological Societies. Survival was analyzed using Kaplan-Meier curves. Between 2004 and 2019, 40 patients were diagnosed with primary immunodeficiencies. The most common were immunodeficiencies affecting humoral and cell-mediated immunity (32.5 %) and predominantly antibody deficiencies (32.5 %). The median age at the onset of symptoms and at the time of diagnosis was 3.01 and 10.4 months, respectively. Thirty-five percent of patients died, and the risk was higher among those with immunodeficiencies affecting humoral and cell-mediated immunity and those who developed clinical manifestations and were diagnosed in the first 6 months of life.

PMID:34033421 | DOI:10.5546/aap.2021.eng.202

Vet Dermatol. 2021 May 25. doi: 10.1111/vde.12969. Online ahead of print.

ABSTRACT

BACKGROUND: Persian cats are predisposed to chronic and severe dermatophytosis. Alterations to the cutaneous microbiota are one potential contributor to this predisposition.

OBJECTIVES: To characterise the cutaneous and environmental fungal microbiota of Persian cats with chronic, severe dermatophytosis, and to compare the fungal microbiota of cats with and without dermatophytosis.

ANIMALS: Thirty-six client-owned cats, including 26 Persian cats and 10 domestic long hair (DLH) cats.

METHODS AND MATERIALS: Skin and home environment swabs were collected from Persian cats with severe, chronic dermatophytosis as well as groups of healthy control cats (Persian and DLH). Sequencing of the internal transcribed spacer 1 (ITS1) region was performed in addition to ITS1 quantitative PCR and fungal culture.

RESULTS: Next-generation sequencing (NGS) targeting the fungal ITS region detected Microsporum sp. DNA from all Persian cats diagnosed with dermatophytosis and from environmental samples of their homes. A significant difference in community structure was identified between cases and controls, largely resulting from the Microsporum spp. DNA in samples from affected cats. Persian cats with dermatophytosis do not exhibit decreased fungal diversity. NGS failed to identify dermatophyte DNA on two culture-positive asymptomatic Persian controls and identified Trichophyton rubrum DNA from a culture-negative asymptomatic Persian control.

CONCLUSIONS: Aside from M. canis, our results indicate that an underlying fungal dysbiosis is not likely to play a role in development of dermatophytosis in Persian cats. Other explanations for predisposition to this disease, such as a primary immunodeficiency, ineffective grooming or unique features of Persian cat hair should be investigated.

PMID:34033174 | DOI:10.1111/vde.12969

J Allergy Clin Immunol Pract. 2021 May 21:S2213-2198(21)00579-1. doi: 10.1016/j.jaip.2021.04.070. Online ahead of print.

ABSTRACT

BACKGROUND: X-linked agammaglobulinemia (XLA) is an inherited primary immunodeficiency which usually manifests clinically with recurrent sinopulmonary infections. Gastrointestinal manifestations are mostly driven by acute infections and disturbed mucosal immunity, but there is a notable prevalence of inflammatory bowel disease (IBD). Differentiating between XLA-associated enteritis, which can originate from recurrent infections, versus IBD can be diagnostically and therapeutically challenging.

OBJECTIVES: This study presents a critical appraisal of the clinical, radiologic, endoscopic, and histologic features associated with XLA-associated Crohn’s-like enteritis.

METHODS: We report three cases and performed a systematic review of the literature describing the diagnoses and outcomes.

RESULTS: XLA-related enteropathy presented in adolescence with an ileocolonic Crohn’s disease (CD)-like phenotype without perianal disease. Abdominal pain, non-infectious diarrhea, and weight loss were the most common symptoms. Imaging and endoscopic findings closely resemble CD. However, histologically, it presents without nodular lymphoid hyperplasia and only two studies reported the presence of granulomas. Additionally, in XLA-associated enteritis, immunohistochemistry showed the absence or marked reduction in B cells and plasma cells.

CONCLUSION: XLA-associated enteritis is a distinct pathologic process that presents clinically in a manner similar to ileocolonic CD. It is important to evaluate for infectious diarrhea, which is common in XLA and can mimic IBD clinically. Complete multidisciplinary evaluation is therefore recommended for XLA patients with persistent gastrointestinal symptoms. While more research is needed, therapeutic selection for XLA-associated enteritis is like that of IBD, though the possible risk of drug interactions and complications from increasing immunosuppression should be considered.

PMID:34029777 | DOI:10.1016/j.jaip.2021.04.070

J Neuromuscul Dis. 2021 May 18. doi: 10.3233/JND-200616. Online ahead of print.

ABSTRACT

Stiff Person Syndrome (SPS), a rare autoimmune neurologic disorder characterized by fluctuating muscle spasms and rigidity, is mediated by autoantibodies to glutamic acid decarboxylase (GAD) antibodies. Symptoms of SPS have been shown to improve after administration of intravenous immunoglobulin (IVIG) however, there is a paucity of information regarding use of SCIg in SPS. Four patients with Stiff Person Syndrome were treated with SCIgPro20 for a period between 31 to 101 months. Most reactions were local and mild. All patients reported improvement in spasticity, and 2 patients reported improvement in seizure frequency. SCIgPro20 was well tolerated in patients with SPS and was associated with improvement in symptoms.

PMID:34024772 | DOI:10.3233/JND-200616

Turk J Med Sci. 2021 May 23. doi: 10.3906/sag-2010-82. Online ahead of print.

ABSTRACT

BACKGROUND AND AIM: Common variable immunodeficiency (CVID) characterized by defective immunoglobulin production is the most prevalent form of symptomatic primary immunodeficiency (PID) in adults. We aimed to reveal the clinical features of adults with CVID and to evaluate the effects of immunoglobulin replacement treatment (IRT) on hemato-immunological findings.

MATERIALS AND METHODS: This study included 26 adult patients receiving IRT. Two measurements of complete blood counts and major immunoglobulin levels measured at the beginning-end of follow-up period were used for comparisons. Lymphocyte subsets and B-cell subgroups were measured only at the time of presentation.

RESULTS: The most common complications were related to respiratory and digestive systems, and organomegaly. Chronic diarrhoea and low body weight were positively correlated with the percentage of CD8+ T cells (P=0.019 and P=0.003 respectively) but negatively correlated with the CD4/CD8 ratio and the percentage of CD19+ B cells (P=0.019 and P=0.005 for both parameters, respectively). At the end of period, the distribution of haematological parameters significantly improved, and immunoglobulin M (IgM) level increased to detectable levels (P=0.035).

CONCLUSIONS: There are apparent relationships among chronic diarrhoea and low body weight, and deterioration of T and B cell immunity in adults with CVID. IRT improves the whole blood parameters and stimulates IgM production. The later effect supports the immunomodulatory feature of this therapy.

PMID:34022776 | DOI:10.3906/sag-2010-82

Chest. 2021 Apr;159(4):e181-e184. doi: 10.1016/j.chest.2020.11.042. Epub 2021 Apr 6.

ABSTRACT

Some severe asthmatic patients experience frequent bacterial respiratory tract infections, which contribute significantly to their disease burden, and often are attributed to their use of systemic corticosteroids and comorbid bronchiectasis. We report a case of a 58-year-old woman who had prednisone-dependent asthma and exacerbations with intense mixed eosinophilic and neutrophilic bronchitis. Autosomal dominant hyper-IgE syndrome, which is a primary immunodeficiency characterized by elevated IgE, eosinophilia, and recurrent infections, caused by a novel pathogenic mutation in STAT3 was identified as the cause of her airway disease. We believe that this is the first report of the demonstration of an IL-5 driven eosinophilia that is associated with a STAT3 mutation that was treated successfully with an anti-IL5 biological.

PMID:34022014 | DOI:10.1016/j.chest.2020.11.042

Blood. 2021 May 21:blood.2021011005. doi: 10.1182/blood.2021011005. Online ahead of print.

ABSTRACT

Inborn errors of immunity that present with concomitant immunodeficiency and auto-inflammation are therapeutically challenging; furthermore, complexity is added when they are caused by mutations in genes that encode for proteins expressed beyond immune cells. The ubiquitin-proteasome system is the main intracellular proteolytic machinery and participates in most cellular processes by degrading ubiquitinated proteins. Mutations in proteasome subunits resulting in proteasome deficiency cause a severe auto-inflammatory disease characterized by chronic auto-inflammation neutrophilic dermatosis and fever, collectively referred to as Proteasome Associated Auto-inflammatory Syndromes (PRAAS). POMP is a chaperone for proteasome assembly and AD mutations in POMP cause a form of PRAAS with prominent immunodeficiency referred to as POMP-related auto-inflammation and immune dysregulation (PRAID) manifesting with recurrent, severe and opportunistic infections in addition to inflammatory features that are characteristic for all PRAAS disorders, most importantly early-onset neutrophilic dermatosis. JAK inhibitors partially control the disease in individuals with PRAAS, however life-threatening, recurrent and opportunistic infections in patients with POMP mutations limit immunosuppressive therapies and prompted consideration of hematopoietic stem cell transplant (HSCT). We describe successful HSCT in two patients with POMP deficiency. Despite POMP being ubiquitously expressed, the immunologic and auto-inflammatory phenotype were both ameliorated through HSCT which suggests that the clinical and immunological features of PRAID are predominantly derived from a proteasome defect in hematopoietic cells. To our knowledge, these are the first patients with a form of PRAAS cured by HSCT, opening new therapeutic possibilities for these diseases.

PMID:34019630 | DOI:10.1182/blood.2021011005