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Usefulness of Gastric Aspirate Culture for Diagnosing Congenital Immunodeficiency in an Infant with Fungal Pneumonia Caused by Rasamsonia piperina.

Tohoku J Exp Med. 2019;247(4):265-269

Authors: Fujita Y, Ishiwada N, Takei H, Suwabe SI, Yarita K, Ohkusu M, Muraosa Y, Kamei K, Shimojo N

Abstract
Chronic granulomatous disease (CGD) is a type of primary immunodeficiency disease, which increases susceptibility to recurrent bacterial and fungal infections. Sputum and bronchoalveolar lavage fluid are often obtained using bronchoscopy from adult patients for pathogenic diagnosis, although this approach is much more invasive for infants. We report the case of a 2-month-old boy with CGD, in which gastric aspirate culture was used to diagnose fungal pneumonia. Rasamsonia piperina was isolated from the gastric aspirate, and the patient was successfully treated with micafungin based on the drug susceptibility test results for the fungal isolate. The acid tolerance test revealed that R. piperina could grow at pH 2, indicating high acid resistance. Although we can only report our experience with a single case, gastric aspirate culture may be a useful tool for detecting fungal respiratory pathogens in children with primary immunodeficiency. Detecting these pathogens may help improve outcomes, as early diagnosis and appropriate treatment are extremely important for immunocompromised patients with respiratory infections.

PMID: 31006737 [PubMed – in process]

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The high mortality of patients with common variable immunodeficiency and small bowel villous atrophy.

Scand J Gastroenterol. 2019 Apr 21;:1-5

Authors: Pensieri MV, Pulvirenti F, Schiepatti A, Maimaris S, Lattanzio S, Quinti I, Klersy C, Corazza GR, Biagi F

Abstract
OBJECTIVES: Common variable immunodeficiency (CVID) is a primary humoral immunodeficiency characterised by reduced serum levels of immunoglobulins, recurrent infections, autoimmune phenomena and lymphoproliferative disorders. Gastrointestinal symptoms are very common in these patients and a coeliac-like villous atrophy was described in some of them. Since mortality in CVID is much higher than in the general population, our aim was to evaluate mortality rates and clinical predictors of survival in patients with both CVID and duodenal villous atrophy.
PATIENTS AND METHODS: Sex, date of diagnosis of villous atrophy, HLA genomic typing, date of death/last follow-up, type of complication were retrospectively collected from medical files. Univariate analysis for each predictor was conducted and Kaplan-Meier curves were generated to evaluate survival.
RESULTS: Twenty-three patients were enrolled (9 females, mean age at diagnosis of villous atrophy 38 ± 13 years) and 8 of them died after a median time of 96 months (25th-75th 60-120 months) corresponding to a mortality rate of 3.9 per 100 person-years (95% CI 1.9-7.7). Mortality was higher in men compared to women (60 vs. 11/1000 person-years), although not statistically significant. Causes of death included onco-haematological disorders and infections.
CONCLUSIONS: Although based on a small cohort, our results confirm that patients with CVID and villous atrophy are burdened by a very high mortality mainly due to onco-immunological disorders and infections. Strict follow-up is required in these patients.

PMID: 31006294 [PubMed – as supplied by publisher]

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Measurement of Typhim Vi IgG as a Diagnostic Tool to Determine Anti-polysaccharide Antibody Production Deficiency in Children.

Front Immunol. 2019;10:654

Authors: Guevara-Hoyer K, Gil C, Parker AR, Williams LJ, Orte C, Rodriguez de la Peña A, Ochoa-Grullón J, Rodriguez De Frias E, García IS, García-Gómez S, Recio MJ, Fernández-Arquero M, Pérez de Diego R, Ramos JT, Sánchez-Ramón S

Abstract
Background: The assessment of specific polysaccharide antibody production plays a pivotal role in the diagnosis of humoral primary immunodeficiencies (PID). The response to 23-valent pneumococcal vaccine (PPV) remains the gold standard for the diagnosis of polysaccharide antibodies. However, in Spain, the interpretation of pure polysaccharide 23-valent immunization is hampered by the high endemicity of pneumococcal disease and the generalization of the 13-valent adjuvant pneumococcal vaccination. Specific Typhim Vi vaccination (TV) immunoglobulin G IgG response to immunization is useful in adult PID, but there is no data regarding children. Objectives: To evaluate the clinical utility of TV IgG production as a diagnostic tool to determine anti-polysaccharide antibody production deficiency in children, when the response to PPV is unclear and isolated determination of serotypes is unfeasible. Methods: We conducted a single-institution prospective observational study on 61 children with recurrent infections. Baseline specific antibodies against PPV and TV were evaluated. In 28 children (46%), the response to the production of antibodies confirmed a clinical suspicion of humoral PID, and they were therefore immunized with 23-valent pneumococcal vaccine and Typhim Vi. Both specific antibody responses were measured by ELISA (The Binding Site Group Ltd, Birmingham, UK) using previously published cut-offs. Results: Seventy percent of the 61 children displayed baseline PPV IgG > 27 mg/L, whereas only 8% showed TV IgG > 28 U/mL (p < 0.0001). Twenty-one of 28 children (75%) achieved a 3-fold increase in post-vaccination TV IgG levels, whereas only 3% achieved a 4-fold increase in PPV IgG post vaccination, mainly due to high baseline PPV IgG titers. When we classified children according to their response to TV as responders or non-responders and compared this with the well-known clinical warning signs of the Jeffrey Modell Foundation. The proportions of children with history of pneumonia and the need for intravenous antibiotics were significantly higher in TV IgG non-responders than in TV IgG responders (p = 0.02 and p = 0.01, respectively). Conclusion: Response to TV can be considered an ancillary diagnostic tool to determine polysaccharide antibodies in children, particularly when isolated determination of pneumococcal serotypes is not feasible. TV provides a useful asset for clinicians in the era of conjugate PPV vaccination, with clinical relevance. Further research is warranted for validation.

PMID: 31001267 [PubMed – in process]

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Three novel compound heterozygous IL12RB1 mutations in Chinese patients with Mendelian susceptibility to mycobacterial disease.

PLoS One. 2019;14(4):e0215648

Authors: Zhou X, Jia W, Ni Z, Wang A, Liu Z, Hou M, Zhou M, Tang Z, Zhang D, Li L, Han T, Tan Y, Luo G, Wang J, Wu Y, Zhang X

Abstract
Mendelian Susceptibility to Mycobacterial Diseases (MSMD) is a primary immunodeficiency disease (PID) characterized by variable susceptibility to weakly virulent mycobacteria (Bacille Calmette-Guerin, BCG) and various intramacrophagic bacteria, fungi, parasites. Mycobacterial disease generally begins in childhood, more rarely during adolescence and adulthood. The pathogenesis of MSMD is the inherited impaired production of interferon gamma (IFN-γ) or inadequate response to it. Autosomal recessive IL12RB1 deficiency is the most common genetic etiology of MSMD. Here we identified three novel compound heterozygous mutations in IL12RB1 gene (c.635G>A, c.765delG; c.632G>C, c.847C>T; c.64G>A, c.1673insGAGCTTCCTGAG) in three Chinese families with MSMD.

PMID: 30998751 [PubMed – in process]

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Acute-onset Autoimmune Hepatitis in a Patient with Selective Immunoglobulin M Deficiency.

Intern Med. 2019 Apr 17;:

Authors: Sano A, Inoue J, Kakazu E, Ninomiya M, Iwata T, Morosawa T, Takai S, Nakamura T, Masamune A

Abstract
Selective immunoglobulin M deficiency (SIGMD) is an uncommon primary immunodeficiency disorder. We herein report an SIGMD patient with autoimmune hepatitis. A 21-year-old Japanese man was transferred to our hospital because of acute liver dysfunction. His serum IgM level was low, whereas those of IgG and IgA were normal, indicating that he had SIGMD. We diagnosed him with acute-onset autoimmune hepatitis, and his liver function test findings gradually recovered with corticosteroid administration. Although SIGMD with autoimmune diseases has been reported, the clinical features and pathogenesis have not yet been clarified. We have summarized previous reports on SIGMD patients with autoimmune diseases.

PMID: 30996186 [PubMed – as supplied by publisher]

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Clinical, immunologic, and molecular spectrum of patients with LPS-responsive beige-like anchor protein (LRBA) deficiency: a systematic review.

J Allergy Clin Immunol Pract. 2019 Apr 14;:

Authors: Habibi S, Zaki-Dizaji M, Rafiemanesh H, Lo B, Jamee M, Gámez-Díaz L, Salami F, Kamali AN, Mohammadi H, Abolhassani H, Yazdani R, Aghamohammadi A, Anaya JM, Azizi G

Abstract
BACKGROUND: LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency and immune dysregulation syndrome caused by biallelic mutations in the LRBA gene. These mutations usually abrogate the protein expression of LRBA, leading to a broad spectrum of clinical phenotypes including autoimmunity, chronic diarrhea, hypogammaglobulinemia and recurrent infections.
OBJECTIVE: Our aim was to systematically collect all studies reporting on the clinical manifestations, molecular and laboratory findings, and management of patients with LRBA deficiency.
METHODS: We searched in PubMed, Web of Science, and Scopus without any restrictions on study design and publication time. A total of 109 LRBA-deficient cases were identified from 45 eligible articles. For all patients, demographic information, clinical records, immunologic and molecular data were collected.
RESULTS: Of the patients with LRBA deficiency, 93 had homozygous and 16 had compound heterozygous mutations in LRBA. The most common clinical manifestations were autoimmunity (82%), enteropathy (63%), splenomegaly (57%) and pneumonia (49 %). Reduction in numbers of CD4+ T cells and regulatory T cells as well as IgG levels were recorded for 21.6%, 65.6% and 54.2% of evaluated patients, respectively. B cell subpopulation analysis revealed low numbers of switched-memory and increased numbers of CD21low B cells in 73.5% and 77.8 % of patients, respectively. Eighteen (16%) patients underwent hematopoietic stem cell transplantation due to the severity of complications and the outcomes improved in 13 of them.
CONCLUSIONS: Autoimmune disorders are the main clinical manifestations of LRBA deficiency. Therefore, LRBA deficiency should be included in the list of monogenic autoimmune diseases and screening for LRBA mutations should be routinely performed for patients with these conditions.

PMID: 30995531 [PubMed – as supplied by publisher]

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X-Linked Lymphoproliferative Syndrome Presenting as Adult-Onset Multi-Infarct Dementia.

J Neuropathol Exp Neurol. 2019 May 01;78(5):460-466

Authors: Blackburn PR, Lin WL, Miller DA, Lorenzo-Betancor O, Edwards ES, Zimmermann MT, Farrugia LP, Freeman WD, Soto AI, Walton RL, Klee EW, Atwal PS, Abraham RS, Billadeau DD, Ross OA, Dickson DW, Meschia JF

Abstract
Pathogenic hemizygous variants in the SH2D1A gene cause X-linked lymphoproliferative (XLP) syndrome, a rare primary immunodeficiency usually associated with fatal Epstein-Barr virus infection. Disease onset is typically in early childhood, and the average life expectancy of affected males is ∼11 years. We describe clinical, radiographic, neuropathologic, and genetic features of a 49-year-old man presenting with central nervous system vasculitis that was reminiscent of adult primary angiitis but which was unresponsive to treatment. The patient had 2 brothers; 1 died of aplastic anemia at age 13 and another died of diffuse large B-cell lymphoma in his sixties. Exome sequencing of the patient and his older brother identified a novel hemizygous variant in SH2D1A (c.35G>T, p.Ser12Ile), which encodes the signaling lymphocyte activation molecule (SLAM)-associated protein (SAP). Molecular modeling and functional analysis showed that this variant had decreased protein stability, similar to other pathogenic missense variants in SH2D1A. The family described in this report highlights the broadly heterogeneous clinical presentations of XLP and the accompanying diagnostic challenges in individuals presenting in adulthood. In addition, this report raises the possibility of a biphasic distribution of XLP cases, some of which may be mistaken for age-related malignancies and autoimmune conditions.

PMID: 30990878 [PubMed – in process]

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Long-lasting low NK cell activity after hemophagocytic lymphohistiocytosis in an infant with spontaneous recovery.

Pediatr Int. 2019 Apr 16;:

Authors: Fujiki T, Nishimura R, Yachie A

PMID: 30989722 [PubMed – as supplied by publisher]

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Progressive Immunodeficiency with Gradual Depletion of B and CD4⁺ T Cells in Immunodeficiency, Centromeric Instability and Facial Anomalies Syndrome 2 (ICF2).

Diseases. 2019 Apr 04;7(2):

Authors: Sogkas G, Dubrowinskaja N, Bergmann AK, Lentes J, Ripperger T, Fedchenko M, Ernst D, Jablonka A, Geffers R, Baumann U, Schmidt RE, Atschekzei F

Abstract
Immunodeficiency, centromeric instability and facial anomalies syndrome 2 (ICF2) is a rare autosomal recessive primary immunodeficiency disorder. So far, 27 patients have been reported. Here, we present three siblings with ICF2 due to a homozygous ZBTB24 gene mutation (c.1222 T>G, p. (Cys408Gly)). Immune deficiency in these patients ranged from late-onset combined immunodeficiency (CID) with severe respiratory tract infections and recurrent shingles to asymptomatic selective antibody deficiency. Evident clinical heterogeneity manifested despite a common genetic background, suggesting the pathogenic relevance of epigenetic modification. Immunological follow-up reveals a previously unidentified gradual depletion of B and CD4⁺ T cells in all three presented patients with transition of a common variable immunodeficiency (CVID)-like disease to late-onset-CID in one of them. Considering all previously published cases with ICF2, we identify inadequate antibody responses to vaccines and reduction in CD27⁺ memory B cells as prevalent immunological traits. High mortality among ICF2 patients (20%) together with the progressive course of immunodeficiency suggest that hematopoietic stem cell transplantation (HSCT) should be considered as a treatment option in due time.

PMID: 30987377 [PubMed]

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