Manish Butte

Pediatr Pulmonol. 2021 Sep 2. doi: 10.1002/ppul.25636. Online ahead of print.

NO ABSTRACT

PMID:34473915 | DOI:10.1002/ppul.25636

J Exp Med. 2021 Nov 1;218(11):e20210566. doi: 10.1084/jem.20210566. Epub 2021 Sep 2.

ABSTRACT

Autosomal dominant (AD) NFKB1 deficiency is thought to be the most common genetic etiology of common variable immunodeficiency (CVID). However, the causal link between NFKB1 variants and CVID has not been demonstrated experimentally and genetically, and there has been insufficient biochemical characterization and enrichment analysis. We show that the cotransfection of NFKB1-deficient HEK293T cells (lacking both p105 and its cleaved form p50) with a κB reporter, NFKB1/p105, and a homodimerization-defective RELA/p65 mutant results in p50:p65 heterodimer-dependent and p65:p65 homodimer-independent transcriptional activation. We found that 59 of the 90 variants in patients with CVID or related conditions were loss of function or hypomorphic. By contrast, 258 of 260 variants in the general population or patients with unrelated conditions were neutral. None of the deleterious variants displayed negative dominance. The enrichment in deleterious NFKB1 variants of patients with CVID was selective and highly significant (P = 2.78 × 10-15). NFKB1 variants disrupting NFKB1/p50 transcriptional activity thus underlie AD CVID by haploinsufficiency, whereas neutral variants in this assay should not be considered causal.

PMID:34473196 | DOI:10.1084/jem.20210566

Res Pract Thromb Haemost. 2021 Aug 24;5(6):e12587. doi: 10.1002/rth2.12587. eCollection 2021 Aug.

ABSTRACT

BACKGROUND: Rituximab is a monoclonal anti-CD20 antibody used as a second-line treatment for immune thrombocytopenia (ITP). As additional treatments for ITP emerge, identifying the most appropriate patients and optimal timing for rituximab are important but challenging without established predictors of response to therapy.

OBJECTIVES: The purpose of this study was to describe demographic, clinical, and laboratory characteristics of pediatric and adult patients with ITP to identify differences in evaluation before rituximab administration and correlates of platelet response.

METHODS: This is a retrospective cohort study describing the characteristics of patients with ITP treated with rituximab from 2010 to 2020 at two academic tertiary care centers.

RESULTS: A total of 64 patients met criteria for inclusion. Complete rituximab response (56%) was not significantly different between children (58%, n = 24) and adults (55%, n = 40). Response rate was similar in those with primary versus secondary ITP (53% vs 62%). Among patients treated with rituximab, Evans Syndrome was more common in children than adults (42% vs 18%). Immunologic labs assessed before rituximab varied by age and were more commonly evaluated in children (lymphocyte subsets 88% vs 22%). Immunologic markers, including antinuclear antibody, direct antiglobulin testing, immunoglobulin levels, and lymphocyte subsets, did not predict response to rituximab in pediatric or adult patients with ITP.

CONCLUSIONS: Pre-rituximab immunologic evaluation varied significantly between adults and children, which could represent institution-specific practice patterns or a more general practice difference. If the latter, underlying immunodeficiency in adults with ITP may be underrecognized. Standardized guidance for pre-rituximab immunologic evaluation is needed.

PMID:34466770 | PMC:PMC8385184 | DOI:10.1002/rth2.12587

BMC Infect Dis. 2021 Aug 30;21(1):890. doi: 10.1186/s12879-021-06594-7.

ABSTRACT

BACKGROUND: Hepatitis A is one of the most common infectious causes of acute hepatitis, and currently, a neglected global public health problem necessitating an urgent response in Somalia. Hepatitis A infection and its rare complication of acute liver failure in children are largely based on very limited data. The aim of the study was therefore to investigate the Hepatitis A infection and its rare complication of acute liver failure in children in Somalia.

METHODS: This retrospective study was conducted on children aged 0-18 years who were admitted to the pediatric departments of the Somalia Mogadishu-Turkey Training and Research Hospital, Somali, from June 2019 and December 2019. Patients who were tested for hepatitis A infection during the study period and had complete data were included. Children with chronic disease, primary or secondary immunodeficiency, blood transfusion history, and missing data were excluded. Abstracted data including patients’ demographics, clinical presentation, laboratory results, ultrasonographic findings, length of hospital stay, clinical course and outcome were retrieved from the hospital database system.

RESULTS: Of the 13,047 children, 219 were analyzed. Of the 219 Hepatitis A cases, 25 (11%) were diagnosed with pediatric acute liver failure (PALF). The mean age of children with Hepatitis A was 6.7 years. The majority of cases were reported in the 5-9 (39.7%) year age range. Hepatic encephalopathy, length of hospital stay, levels of albumin, and values of PT, aPPT, and INR were significantly higher in children with acute live failure. The presence of cholecystitis and cholecystitis with ascites in the sonographic evaluation were poor prognostic markers for acute liver failure.

CONCLUSIONS: This study revealed hepatitis A virus infection and its related acute liver failure among hospitalized children in Somalia of which 11% had PALF. Hence, the introduction of Hepatitis A vaccination, which is the main public health tool, into the national immunization program, the improvement of hygiene conditions, raising awareness of the disease, and increasing health literacy are necessary to prevent the consequence of the Hepatitis A virus in children.

PMID:34461848 | DOI:10.1186/s12879-021-06594-7

Mol Ther Nucleic Acids. 2021 May 29;25:237-250. doi: 10.1016/j.omtn.2021.05.015. eCollection 2021 Sep 3.

ABSTRACT

Gene editing via homology-directed repair (HDR) currently comprises the best strategy to obtain perfect corrections for pathogenic mutations of monogenic diseases, such as the severe recessive dystrophic form of the blistering skin disease epidermolysis bullosa (RDEB). Limitations of this strategy, in particular low efficiencies and off-target effects, hinder progress toward clinical applications. However, the severity of RDEB necessitates the development of efficient and safe gene-editing therapies based on perfect repair. To this end, we sought to assess the corrective efficiencies following optimal Cas9 nuclease and nickase-based COL7A1-targeting strategies in combination with single- or double-stranded donor templates for HDR at the COL7A1 mutation site. We achieved HDR-mediated correction efficiencies of up to 21% and 10% in primary RDEB keratinocytes and fibroblasts, respectively, as analyzed by next-generation sequencing, leading to full-length type VII collagen restoration and accurate deposition within engineered three-dimensional (3D) skin equivalents (SEs). Extensive on- and off-target analyses confirmed that the combined treatment of paired nicking and single-stranded oligonucleotides constituted a highly efficient COL7A1-editing strategy, associated with a significantly improved safety profile. Our findings, therefore, represent a further advancement in the field of traceless genome editing for genodermatoses.

PMID:34458008 | PMC:PMC8368800 | DOI:10.1016/j.omtn.2021.05.015

Front Immunol. 2021 Aug 12;12:698721. doi: 10.3389/fimmu.2021.698721. eCollection 2021.

ABSTRACT

The gastrointestinal (GI) tract is frequently affected by inborn errors of immunity (IEI), and GI manifestations can be present in IEI patients before a diagnosis is confirmed. We aimed to investigate clinical features, endoscopic and histopathologic findings in IEI patients. This was a retrospective cohort study conducted from 1995 to 2020. Eligible patients were diagnosed with IEI and had GI manifestations that were enough to require endoscopies. IEI was classified according to the International Union of Immunological Societies classification. Of 165 patients with IEI, 55 (33.3%) had GI manifestations, and 19 (11.5%) underwent endoscopy. Among those 19 patients, nine (47.4%) initially presented with GI manifestations. Thirteen patients (68.4%) were male, and the mean age of patients 11.5 ± 7.9 years (range, 0.6 – 26.6) when they were consulted and evaluated with endoscopy. The most common type of IEI with severe GI symptoms was “Disease of immune dysregulation” (31.6%) followed by “Phagocyte defects” (26.3%), according to the International Union of Immunological Societies classification criteria. Patients had variable GI symptoms such as chronic diarrhea (68.4%), hematochezia (36.8%), abdominal pain (31.6%), perianal disease (10.5%), and recurrent oral ulcers (10.5%). During the follow-up period, three patients developed GI tract neoplasms (early gastric carcinoma, mucosa associated lymphoid tissue lymphoma of colon, and colonic tubular adenoma, 15.8%), and 12 patients (63.2%) were diagnosed with inflammatory bowel disease (IBD)-like colitis. Investigating immunodeficiency in patients with atypical GI symptoms can provide an opportunity for correct diagnosis and appropriate disease-specific therapy. Gastroenterologists and immunologists should consider endoscopy when atypical GI manifestations appear in IEI patients to determine if IBD-like colitis or neoplasms including premalignant and malignant lesions have developed. Also, if physicians in various fields are better educated about IEI-specific complications, early diagnosis and disease-specific treatment for IEI will be made possible.

PMID:34456911 | PMC:PMC8397536 | DOI:10.3389/fimmu.2021.698721

Allergol Int. 2021 Aug 26:S1323-8930(21)00096-4. doi: 10.1016/j.alit.2021.08.008. Online ahead of print.

ABSTRACT

Monogenic diseases of the immune system, also known as inborn errors of immunity (IEIs), are caused by single-gene mutations and result in immune deficiency and dysregulation. More than 400 monogenic diseases have been described to date, and this number is rapidly expanding. The increasing availability of next-generation sequencing is now facilitating the diagnosis of IEIs. It is known that IEIs can predispose a person to not only infectious diseases but also cancer and immune disorders, such as inflammatory, autoimmune, and atopic diseases. IEIs with eosinophilia and atopic diseases can occur in several disorders. IEIs with eosinophilia have provided insights into human immunity and the pathogenesis of allergic diseases. Eosinophilia is not a rare finding in clinical practice, and it often poses problems in terms of etiologic research and differential diagnoses. Secondary eosinophilia is the most common form. The main underlying conditions are infectious diseases such as parasitic infections, allergic disorders, drug reactions, and of course IEIs. In clinical settings, the recognition of IEIs in the context of an allergic phenotype with eosinophilia is critical for prompt diagnosis and appropriate treatment aimed at modulating pathophysiological mechanisms and improving clinical symptoms.

PMID:34456137 | DOI:10.1016/j.alit.2021.08.008

Pediatr Rep. 2021 Aug 7;13(3):483-489. doi: 10.3390/pediatric13030055.

ABSTRACT

Common variable immunodeficiency (CVID) is a primary immune deficit (PID) mainly characterized by hypogammaglobulinemia. In addition to increased susceptibility to infections and several immune-mediated manifestations, patients with CVID frequently develop bronchiectasis because of recurrent respiratory infections. This occurrence could be more likely if the diagnosis of CVID is delayed, as it often happens in less resourced clinical settings. A 15-year-old female patient was admitted to a tertiary hospital in Kazakhstan for consultation regarding a previous and established diagnosis of bronchiectasis. The clinical history was characterized by recurrent respiratory infections for several years, in addition to the development of a mixed restrictive-obstructive respiratory syndrome. Therefore, she underwent chest computerized tomography, which confirmed the presence of multiple and bilateral bronchiectasis. The clinical discussion on this patient highlighted that serum immunoglobulins were never measured previously and, thus, their assessment was strongly recommended. Based on that, a diagnosis of CVID was finally achieved, and the patient started the appropriate immunoglobulin replacement therapy. To our knowledge, this report is the first English-language publication on CVID and bronchiectasis from Central Asia. Bronchiectasis is currently an important medical problem in developing countries and populations with low socioeconomic status, where the diagnosis of the underlying cystic fibrosis and non-cystic fibrosis comorbidities can be delayed and more difficult than in countries with more accessible health care systems and facilities. This case report emphasized this important clinical issue in Central Asia and should raise the medical attention and awareness of this health problem, in order to improve the diagnostic timing and rate.

PMID:34449684 | DOI:10.3390/pediatric13030055

World J Clin Cases. 2021 Aug 16;9(23):6872-6878. doi: 10.12998/wjcc.v9.i23.6872.

ABSTRACT

BACKGROUND: Trismus is a common problem with various causes. Any abnormal conditions of relevant anatomic structures that disturb the free movement of the jaw might provoke trismus. Trismus has a detrimental effect on the quality of life. The outcome of this abnormality is critically dependent on timely diagnosis and treatment, and it is difficult to identify the true origin in some cases. We present a rare case of trismus due to fungal myositis in the pterygoid muscle, excluding any other possible pathogenesis.

CASE SUMMARY: The patient presented with a 2-mo history of restricted mouth opening. Computed tomography showed obvious enlargement of the left pterygoid muscles. Furthermore, the patient had trismus without obvious predisposing causes. The primary diagnosis was pterygoid myosarcoma. Consequently, lesionectomy of the left pterygoid muscle was performed. Intraoperative frozen biopsy implied the possibility of an uncommon infection. Postoperative pathologic examination confirmed myositis and necrosis in the pterygoid muscle. Fungi were detected in both muscle tissue and surrounding necrotic tissue. The patient recovered well with antifungal therapy and mouth opening exercises. The rarity of fungal myositis may be responsible for the misdiagnosis. Although the origin of pathogenic fungi is still unknown, we believe that both hematogenous spread and local invasion could be the most likely sources. To the best of our knowledge, this is the first case in the literature that reported fungal myositis in pterygoid muscles as the only reason that results in trismus.

CONCLUSION: Surgeons should remain vigilant to the possibility of trismus originating from fungal myositis.

PMID:34447837 | PMC:PMC8362531 | DOI:10.12998/wjcc.v9.i23.6872

Front Immunol. 2021 Aug 10;12:671755. doi: 10.3389/fimmu.2021.671755. eCollection 2021.

ABSTRACT

Primary immune regulatory disorders (PIRD) are associated with autoimmunity, autoinflammation and/or dysregulation of lymphocyte homeostasis. Autoimmune lymphoproliferative syndrome (ALPS) is a PIRD due to an apoptotic defect in Fas-FasL pathway and characterized by benign and chronic lymphoproliferation, autoimmunity and increased risk of lymphoma. Clinical manifestations and typical laboratory biomarkers of ALPS have also been found in patients with a gene defect out of the Fas-FasL pathway (ALPS-like disorders). Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), we identified more than 600 patients suffering from 24 distinct genetic defects described in the literature with an autoimmune lymphoproliferative phenotype (ALPS-like syndromes) corresponding to phenocopies of primary immunodeficiency (PID) (NRAS, KRAS), susceptibility to EBV (MAGT1, PRKCD, XIAP, SH2D1A, RASGRP1, TNFRSF9), antibody deficiency (PIK3CD gain of function (GOF), PIK3R1 loss of function (LOF), CARD11 GOF), regulatory T-cells defects (CTLA4, LRBA, STAT3 GOF, IL2RA, IL2RB, DEF6), combined immunodeficiencies (ITK, STK4), defects in intrinsic and innate immunity and predisposition to infection (STAT1 GOF, IL12RB1) and autoimmunity/autoinflammation (ADA2, TNFAIP3,TPP2, TET2). CTLA4 and LRBA patients correspond around to 50% of total ALPS-like cases. However, only 100% of CTLA4, PRKCD, TET2 and NRAS/KRAS reported patients had an ALPS-like presentation, while the autoimmunity and lymphoproliferation combination resulted rare in other genetic defects. Recurrent infections, skin lesions, enteropathy and malignancy are the most common clinical manifestations. Some approaches available for the immunological study and identification of ALPS-like patients through flow cytometry and ALPS biomarkers are provided in this work. Protein expression assays for NKG2D, XIAP, SAP, CTLA4 and LRBA deficiencies and functional studies of AKT, STAT1 and STAT3 phosphorylation, are showed as useful tests. Patients suspected to suffer from one of these disorders require rapid and correct diagnosis allowing initiation of tailored specific therapeutic strategies and monitoring thereby improving the prognosis and their quality of life.

PMID:34447369 | PMC:PMC8382720 | DOI:10.3389/fimmu.2021.671755