Manish Butte

APMIS. 2023 Sep 20. doi: 10.1111/apm.13351. Online ahead of print.

ABSTRACT

Good’s syndrome, an infrequent adult-onset immunodeficiency is characterized by the triad of thymoma, hypogammaglobulinemia, and increased susceptibility to recurrent infections. The clinical presentation is highly variable, with a spectrum ranging from recurrent bacterial and opportunistic infections to concomitant autoimmune diseases and, sometimes malignant pathologies. Due to heterogeneous clinical phenotypes and the lack of adequate diagnostic criteria, its recognition is often challenging, even delaying it by years. It is one of the most unusual, less studied form of the immune deficiency syndromes with a still unknown pathophysiology. It was initially considered a thymoma-associated variant of primary antibody deficiencies with a reduced or absent number of mature B cells, but it later emerged that significant defects of T cell-mediated immune functions are the underlying cause of opportunistic infections. On the basis of current evidence, Good’s syndrome is evaluated as a distinct acquired form of combined immunodeficiency states and classified as a phenocopy of primary immunodeficiency diseases. Epigenetic and acquired genetic factors can play an ultimate role in its evolution.

PMID:37729389 | DOI:10.1111/apm.13351

Pediatr Allergy Immunol. 2023 Sep;34(9):e14015. doi: 10.1111/pai.14015.

ABSTRACT

BACKGROUND: A few studies assessed the clinical and immunological features of selective IgM deficiency (SIgMD), especially in the pediatric age. We aimed to characterize the clinical and immunological phenotypes of a cohort of pediatric patients with SIgMD according to the different diagnostic criteria available.

METHODS: In this multicenter study, we evaluated pediatric SIgMD patients diagnosed at the Pediatric Clinic in Pavia, Italy, or through the Italian Primary Immunodeficiency NETwork (IPINET) and monitored changes in their diagnosis over a time frame that ranges from several months to several years.

RESULTS: Forty-eight patients with SIgMD were included (mean serum IgM: 33 mg/dL). The most common clinical manifestations were recurrent infections (67%) and allergies (48%). Subgroup analysis according to SIgMD definition criteria of the European Society for Immunodeficiencies (ESID) showed no significant difference in clinical manifestations, also considering the group with additional immunological abnormalities. Sixteen patients had long-term follow-up, during which 87% preserved their SIgMD diagnosis, while two patients showed a reduction in IgA in addition to low IgM.

CONCLUSIONS: Our data suggest that the identification of a reduction in serum IgM in children should lead to a complete immunological work-up to obtain a comprehensive clinical and immunological characterization of the patient. The follow-up of these patients is fundamental to define the disease evolution and appropriate management.

PMID:37728524 | DOI:10.1111/pai.14015

Front Allergy. 2023 Sep 1;4:1237852. doi: 10.3389/falgy.2023.1237852. eCollection 2023.

ABSTRACT

Transcription factors (TFs) are critical components involved in regulating immune system development, maintenance, and function. Monogenic defects in certain TFs can therefore give rise to inborn errors of immunity (IEIs) with profound clinical implications ranging from infections, malignancy, and in some cases severe allergic inflammation. This review examines TF defects underlying IEIs with severe atopy as a defining clinical phenotype, including STAT3 loss-of-function, STAT6 gain-of-function, FOXP3 deficiency, and T-bet deficiency. These disorders offer valuable insights into the pathophysiology of allergic inflammation, expanding our understanding of both rare monogenic and common polygenic allergic diseases. Advances in genetic testing will likely uncover new IEIs associated with atopy, enriching our understanding of molecular pathways involved in allergic inflammation. Identification of monogenic disorders profoundly influences patient prognosis, treatment planning, and genetic counseling. Hence, the consideration of IEIs is essential for patients with severe, early-onset atopy. This review highlights the need for continued investigation into TF defects to enhance our understanding and management of allergic diseases.

PMID:37727514 | PMC:PMC10505736 | DOI:10.3389/falgy.2023.1237852

Immunol Res. 2023 Sep 19. doi: 10.1007/s12026-023-09420-1. Online ahead of print.

ABSTRACT

Immunoglobulin A Deficiency (IgAD) is the most common primary immunodeficiency and is significantly associated with Celiac Disease (CD), which recognizes a specific background of human leukocyte antigens (HLA) predisposition (including HLA-DQB1*02:01 allele). A number of studies investigated the role of HLA in IgAD etiopathogenesis: HLA-DQB1*02 alleles are included in the main haplotypes linked to this primary immunodeficiency. In this preliminary study, we investigated the potential impact of HLA-DQB1*02:01 allelic status on total serum IgA levels: 108 serum samples from the bone marrow donors’ registry were analyzed for total IgA concentration with respect to the HLA-DQB1*02:01 status. Although total serum IgA levels between HLA-DQB1*02:01 carriers and HLA-DQB1*02:01 negative donors were not different, we observed a statistically significant difference (p=0.0118) in total serum IgA levels among donors with low IgA concentration (<80mg/dL) in the sub-analysis between HLA-DQB1*02:01 positive group (including both homozygous and heterozygous carriers) compared to HLA-DQB1*02:01 negative donors. Our results might suggest a role of HLA-DQB1*02:01 allelic variant in the determination of total serum IgA levels, at least in patients affected with IgA deficiency and/or otherwise predisposed to it; however, larger and more standardized studies are needed to confirm this speculation.

PMID:37725324 | DOI:10.1007/s12026-023-09420-1

Cureus. 2023 Aug 16;15(8):e43578. doi: 10.7759/cureus.43578. eCollection 2023 Aug.

ABSTRACT

Background Cytomegalovirus (CMV) reactivation may occur as the shedding of the virus from various body sites or could represent an active disease that might be fatal if untreated. Distinguishing between the two states may prove very difficult. The role of the CMV disease in patients with hematological malignancies or transplant patients is more defined than that in other immunocompromised patients where neither anti-CMV prophylaxis is used nor plasma CMV levels are monitored. Here, we try to examine cases with CMV viremia in the latter group of patients in an attempt to make a distinction between CMV infection and disease to determine which patients would benefit from treatment. Methods Elderly patients, patients with rheumatological disorders, and patients with inflammatory bowel disease (IBD) and with clinical suspicion of CMV disease who were referred to the infectious diseases service at Sultan Qaboos University Hospital were examined from 1 January 2018 to 31 January 2023. We added a patient we found in our referral log book from 2012. Clinical, epidemiological, and laboratory data were retrieved from the hospital information system. Plasma CMV levels and CMV body fluid levels including pulmonary samples obtained from bronchoalveolar lavage (BAL) in suspected cases of CMV pneumonitis and gastrointestinal (GI) CMV levels obtained from stool and gastrointestinal tissue biopsies in suspected cases of gastrointestinal CMV disease were collected. COBAS^® AmpliPrep/COBAS^® TaqMan^®assay (Roche Molecular Systems, Inc., Branchburg, NJ) was used to measure CMV copies per milliliter. Results A total of 28 patients were considered to have CMV disease, 12 of whom were elderly (≥60 years) and the rest were young and middle aged (Y/M). The most common comorbidities of the elderly included chronic kidney disease (CKD), hypertension (HTN), and diabetes mellitus (DM). In the Y/M group, seven patients had systemic lupus erythematosus (SLE), one had antineutrophil cytoplasmic antibody (ANCA) associated vasculitis, four patients had IBD, two had IBD plus primary immunodeficiencies (one patient had agammaglobulinemia and one had combined deficiencies), and one patient had combined immunodeficiency. CKD was a common finding in the SLE patients. Diarrhea was the most common CMV presentation occurring in 19 patients (67.9%), being bloody in 10 patients. Four patients had pulmonary presentations, and four had hematological presentations in the form of anemia or pancytopenia. Nineteen patients were given CMV antiviral treatment, and one patient received it during the first episode but not in the second episode. Twenty-eight-day mortality in the treated group was 20% versus 55.5% in the untreated group. The majority of the deaths occurred in the SLE and elderly patients. Thrombocytopenia occurred in 60.7%, 70.6% of whom died signaling a potential predictive role for thrombocytopenia in early empirical CMV antiviral treatment and in prognosis. Conclusion The difficulty in distinguishing CMV infection from CMV disease remains a concern in the elderly and SLE patients. In our small study, there was a survival benefit in early screening for CMV and initiating preemptive CMV antiviral therapy in these two groups even before CMV disease is proven. This urgency was not observed for patients with IBD or primary immunodeficiencies. A major common factor for CMV disease was CKD, whereas thrombocytopenia was an indicator of disease and prognosis.

PMID:37719566 | PMC:PMC10503534 | DOI:10.7759/cureus.43578

Medicine (Baltimore). 2023 Sep 15;102(37):e35120. doi: 10.1097/MD.0000000000035120.

ABSTRACT

In recent years, there has been growing evidence linking mitochondrial dysfunction to the development and progression of cancer. However, the role of mitochondrial metabolism-related genes (MMRGs) in testicular germ cell tumor (TGCT) remains unclear. We downloaded clinical pathology, transcriptome, and somatic mutation data for TGCT from public databases and conducted univariate Cox regression analysis to investigate prognostic correlations. We also used consensus clustering to identify molecular subtypes, comparing differential expression genes, biological processes, Kyoto Encyclopedia of Genes and Genomes pathways, mutations, prognosis, immune infiltration, drug sensitivity, and immune therapeutic response between these subtypes. We constructed multi-gene risk features and nomograms for TGCT prognosis. Fifteen MMRGs were significantly correlated with progression-free survival in TGCT patients. Based on these genes, we identified 2 molecular subtypes which showed significant differences in somatic mutations, prognosis, and immune cell infiltration. These subtypes could also indicate drug sensitivity and immune therapeutic response; the subtype with poor prognosis showed a higher potential benefit from some drugs and immunotherapy. Abnormalities in immune-related biological processes and extracellular matrix as well as Kyoto Encyclopedia of Genes and Genomes pathways such as PI3K-AKT signaling pathway, pat5hways in cancer, primary immunodeficiency, and neutrophil extracellular trap formation were associated with significant differences in phenotypes among subtypes. Finally, we constructed an 8-gene TGCT risk feature based on differential expression genes between subtypes which performed well in TGCT patient prognostic evaluation. Our study elucidated the prognostic correlation between MMRGs and TGCT and established MMRG-derived molecular subtypes and risk features for personalized treatment of TGCT which have potential clinical application value.

PMID:37713839 | DOI:10.1097/MD.0000000000035120

Medicine (Baltimore). 2023 Sep 15;102(37):e35229. doi: 10.1097/MD.0000000000035229.

ABSTRACT

RATIONALE: In 2022, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron spread widely around the world. In the context of most literature reporting weakened virulence of the virus, immunocompromised patients who have not been vaccinated should be vigilant for the development of encephalitis following SARS-CoV-2 infection.

PATIENT CONCERNS: A 58-year-old male patient with immunodeficiency presented with respiratory and psychiatric symptoms after contracting SARS-CoV-2 Omicron variant.

DIAGNOSES: The patient was diagnosed with coronavirus disease 2019 infection and associated acute primary encephalitis.

INTERVENTIONS: The patient was received comprehensive treatment including Azvudine antiviral therapy, immunoglobulin infusion, and methylprednisolone anti-inflammatory therapy.

OUTCOMES: The patient’s condition improved and he was discharged smoothly. One month after discharge, the patient returned for follow-up, and the occipital lobe still had a few slow waves on electroencephalogram, but the patient reported no seizure events since discharge.

LESSONS: During the prevalence of the SARS-CoV-2 Omicron variant, we believe that it is still necessary to be vigilant about immunocompromised patients developing encephalitis. Early use of cranial magnetic resonance imaging as a diagnostic assistance is conducive to early diagnosis and treatment of patients.

PMID:37713824 | DOI:10.1097/MD.0000000000035229

Acta Derm Venereol. 2023 Sep 13;103:adv6497. doi: 10.2340/actadv.v103.6497.

ABSTRACT

The aim of this study was to analyse sick leave in generalized pustular psoriasis, the most severe form of pustular psoriasis. Prolonged sick leave of >14 days was analysed for 502 patients with generalized pustular psoriasis compared with controls with psoriasis vulgaris and matched controls from the general population. Using data from the Swedish National Patient Register, and the Longitudinal integrated database for health insurance and labour market studies, the study estimated the mean number of sick leave days in the year of first diagnosis of generalized pustular psoriasis (index year) and for 2 years before and after the index year. Patients with generalized pustular psoriasis were on sick leave to a larger extent than both control populations for all study years. The number of sick leave days peaked in the index year and then reduced. Compared with the control populations, sick leave in generalized pustular psoriasis was already higher prior to diagnosis, indicating delayed diagnosis and/or a comorbidity burden.

PMID:37707292 | DOI:10.2340/actadv.v103.6497

Front Immunol. 2023 Aug 30;14:1209570. doi: 10.3389/fimmu.2023.1209570. eCollection 2023.

ABSTRACT

Common Variable Immunodeficiency (CVID), a complex primary immunodeficiency syndrome defined by defective B cell responses to infection and vaccination, has heterogeneous clinical manifestations. Gastrointestinal (GI) complications in CVID, both infectious and non-infectious, can cause significant impairment leading to malabsorption and frank malnutrition. In order to better characterize the spectrum of GI disease associated with CVID, we describe 114 patients with GI disease (15.6%) from our 728 patient single center CVID cohort. Norovirus, Giardia and Cytomegalovirus were the most frequently isolated infectious pathogens. CVID enteropathy was the most encountered GI diagnosis based on endoscopy, with only a minority of patients having Crohn’s disease (6.1%) or ulcerative colitis/proctitis (4.5%). Concurrent autoimmunity (30.7%), lung disease (18.4%) and malignancy (8.7%) were also present in significant proportion of subjects. Lastly, 16 of 47 (34%) who underwent whole exome sequencing demonstrated a culprit gene defect associated with CVID.

PMID:37711607 | PMC:PMC10498782 | DOI:10.3389/fimmu.2023.1209570

Ther Adv Allergy Rhinol. 2023 Sep 11;14:27534030231199675. doi: 10.1177/27534030231199675. eCollection 2023 Jan-Dec.

ABSTRACT

BACKGROUND: Selective anti-polysaccharide antibody deficiency (SPAD) with CD5 B-cell predominance and autoimmune phenomena was identified in a male cohort first reported by Antall et al in 1999. The phenotypically likewise and genotypically identical X-linked immunodeficiency with magnesium defect, Epstein-Barr Virus infection, and neoplasia (XMEN) disease was defined as a novel primary immunodeficiency (PID) in 2011. Recent studies of the magnesium transporter 1 (MAGT1) gene mutation reveal glycosylation defects contributing to more phenotypic variance than the “XMEN” title pathologies. The updated title, “X-linked MAGT1 deficiency with increased susceptibility to EBV-infection and N-linked glycosylation defect,” was proposed in 2020.

OBJECTIVES: To reflect the patient population more accurately, a prospective classification update may consider MAGT1 glycobiological errors contributing to phenotypic variance but also pre-genetic testing era reports with CD5 B-cell predominance.

METHODS: Patient 1 from Antall et al presented at 28 years of age for further immunological evaluation of his CD5/CD19 B-cell predominance diagnosed at 5 years old.

DESIGN: Immune re-evaluation done through flow cytometry and next-generation sequencing.

RESULTS: Flow cytometry B-cell phenotyping revealed persistent CD5+CD19+ (93%). Flow cytometric histogram quantified reduced activator CD16+CD56+ natural killer and CD8+ T-cell receptor, Group 2, Member D (NKG2D) glycoprotein expression. A c.923-1_934 deletion loss of function mutation was identified in the MAGT1 gene.

CONCLUSION: We suggest the novel PID XMEN, based on its CD5 B-cell predominance, had been discovered and reported over a decade earlier as CD5+ PID based on the MAGT1 mutation found in the same. We encourage consideration of combining these labels and recent findings to offer the most accurate classification of this disease.

PMID:37706151 | PMC:PMC10496486 | DOI:10.1177/27534030231199675