Research

J Clin Med. 2023 Jul 28;12(15):4964. doi: 10.3390/jcm12154964.

ABSTRACT

BACKGROUND: Disorders of immunity are poorly recognised in some rare multisystem genetic conditions. We aim to describe syndromic features and immunological defects in children with syndromic primary immunodeficiencies (sPIDs).

METHODS: This is a retrospective descriptive study of children aged 0-18 years with sPIDs under the care of the paediatric immunology service at the Bristol Royal Hospital for Children, United Kingdom, from January 2006 to September 2021.

RESULTS: sPIDs were identified in 36 patients. Genetic diagnoses which are not commonly associated with PIDs and not included in the International Union of Immunological Societies classification were present in 7/36 (19%): Trisomy 22, Arboleda-Tham syndrome, 2p16.3 deletion syndrome, supernumerary ring chromosome 20 syndrome, Myhre syndrome, Noonan syndrome, and trichothiodystrophy/Cockayne syndrome complex. Recurrent and/or severe infections were the most common clinical features (n = 33, 92%). Approximately half had combined immunodeficiency or antibody deficiency. The most common extra-immunological manifestations include dysmorphism (72%), disorders of nervous (78%), musculoskeletal (69%), haematology/lymphatic (58%), and gastrointestinal, hepatic/pancreatic (58%) systems.

CONCLUSIONS: Patients with sPIDs often have multiorgan involvement and some are non-immunologically mediated. There should be a low threshold to clinically assess and investigate for disorders of immunity in any patients with syndromic features especially when they present with recurrent/severe/opportunistic infections, features of immune dysregulation, autoinflammation or lymphoproliferation.

PMID:37568366 | DOI:10.3390/jcm12154964

Cell Mol Biol (Noisy-le-grand). 2023 May 31;69(5):168-173. doi: 10.14715/cmb/2023.69.5.26.

ABSTRACT

Programmed death 1 (PD-1) plays an important role in the immune escape, occurrence and development of tumors by inhibiting the function of immune cells. However, its prognostic value in uterine corpus endometrial carcinoma (UCEC) and its impact on the tumor microenvironment remain to be further explored. Transcriptional datasets were retrieved from the GEPIA, TIMER and TCGA databases. “edgeR” package was used for the identification of differentially expressed genes (DEGs) between two groups of patients (PD1-high and PD1-low group). Gene set enrichment analysis (GSEA) was performed to identify underlying pathways between betweenPD1-high and PD1-low groups functioning in UCEC. Gene Correlation Analysis was used to further confirm the associations of PD1 expression with T-cell-related genes. Cytoscape software was used to identify hub genes in DEGs. Kaplan-Meier analysis was performed to validate the prognostic value of hub genes. Mutational characteristics of UCEC patients according to PD1 levels were depicted and analyzed. We found that the transcriptional expression of the PD1 gene in UCEC tumor tissues markedly increased in cohorts from the GEPIA and TCGA databases. PD1 expression was negatively correlated with gene signatures associated with the T-cell receptor signaling pathway and primary immunodeficiency. GESA confirmed that PD1 expression was negatively correlated with gene signatures associated with the T-cell receptor signaling pathway. T-cell receptor complex-related genes, ZAP70, TRAC, CD3D, CD3E, CD8A, TRBC2, TRBV28 and CD247, showed significant positive associations with PD1 expression. The results of the Kaplan-Meier OS analysis indicated that PD1, TIGIT, FASLG, ICOS and TNFRSF9 are the protective factor for patients with UCEC. The top 5 genes of mutations in the low expression group, included PTEN (56%), PIK3CA (43%), TP53 (41%), TTN (39%), and ARID1A (37%). The genes with a higher proportion of mutations in the PD1-high group are PTEN (67%), TTN (62%), PIK3CA (53%), ARID1A (52%), and MUC16 (12%). The prognosis of UCEC patients with PD1 overexpression phenotype is worse than that of the PD1 low group, which is due to the involvement of the PD1 gene in the T-cell receptor signaling pathway. This study provides a further theoretical basis and reference for targeted therapy against PD1.

PMID:37571885 | DOI:10.14715/cmb/2023.69.5.26

Blood. 2023 Aug 10:blood.2022019586. doi: 10.1182/blood.2022019586. Online ahead of print.

ABSTRACT

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by life-threatening infections and inflammatory conditions. Hematopoietic cell transplantation (HCT) is the definitive treatment for CGD, but questions remain regarding patient selection and impact of active disease on transplant outcomes. We performed a multi-institutional retrospective and prospective study of 391 patients with CGD treated either conventionally (non-HCT;n=151) enrolled from 2004-2018 or who underwent HCT (n=240) from 1996-2018. Median follow-up post-HCT was 3.7 years with a 3-year overall survival of 82% and event-free survival of 69%. In multivariate analysis, Lansky/Karnofsky score <90 and use of HLA-mismatched donors negatively impacted survival. Age, genotype, and oxidase status did not impact outcomes. Pre-HCT, patients had higher infection density, higher frequency of non-infectious lung and liver disease, and more steroid use compared to conventionally-treated patients, yet these issues did not adversely affect HCT survival. Presence of pre-HCT inflammatory conditions was associated with chronic graft versus host disease. Graft failure or receipt of second HCT occurred in 17.6% and was associated with melphalan-based conditioning and/or early mixed chimerism. By 3-5 years post-HCT, patients had improved growth and nutrition, resolved infections and inflammatory disease, and lower rates of anti-microbial prophylaxis or corticosteroid use compared to both their baseline and to conventionally-treated patients. HCT leads to durable resolution of CGD symptoms and lowers burden of disease. Patients with active infection or inflammation are candidates for transplant; HCT should be considered prior to the development of co-morbidities that could impact performance status. Clinical trial # NCT02082353.

PMID:37562003 | DOI:10.1182/blood.2022019586

J Clin Invest. 2023 Aug 10:e164918. doi: 10.1172/JCI164918. Online ahead of print.

ABSTRACT

BACKGROUND: Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) syndrome is a primary immunodeficiency disorder caused by heterozygous gain-of-function CXCR4 mutations. Myelokathexis is neutropenia from neutrophil retention in bone marrow and is associated with lymphopenia and monocytopenia. The CXCR4 antagonist plerixafor mobilizes leukocytes to the blood; however, safety and efficacy in WHIM syndrome are undefined.

METHODS: In this investigator-initiated, single-center, randomized, quadruple-masked phase 3 crossover trial, we compared the total infection severity score (TISS) as primary endpoint in an intent-to-treat manner in 19 WHIM patients for 12-months on plerixafor versus 12-months on G-CSF, the standard-of-care for severe congenital neutropenia.

RESULTS: Plerixafor was non-superior to G-CSF for TISS (p=0.65). In exploratory endpoints, plerixafor was non-inferior to G-CSF for maintaining neutrophil counts >500 cells/microliter (p=0.023) and was superior to G-CSF for maintaining lymphocyte counts >1000 cells/microliter (p<0.0001). Complete regression of a subset of large wart areas occurred on plerixafor in 5 of 7 patients with major wart burdens at baseline. Transient rash occurred on plerixafor, and bone pain was more common on G-CSF. There were no significant differences in drug preference or quality of life, or the incidence of drug failure or serious adverse events.

CONCLUSIONS: Plerixafor was not superior in WHIM patients to G-CSF for TISS, the primary endpoint. Together with wart regression and hematologic improvement, the infection severity results support continued study of plerixafor as a potential treatment for WHIM syndrome.(Funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases; clinicaltrials.gov registration number, NCT02231879).

PMID:37561579 | DOI:10.1172/JCI164918

Allergy Asthma Clin Immunol. 2023 Aug 9;19(1):69. doi: 10.1186/s13223-023-00831-1.

ABSTRACT

BACKGROUND: Inborn errors of immunity (IEIs) are considered significant challenges for children with IEIs, their families, and their medical providers. Infections are the most common complication of IEIs and children can acquire coronavirus disease 2019 (COVID-19) even when protective measures are taken.

OBJECTIVES: To estimate the incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children with IEIs and analyse the demographic parameters, clinical characteristics and treatment outcomes in children with IEIs with COVID-19 illness.

METHODS: For this systematic review, we searched ProQuest, Medline, Embase, PubMed, CINAHL, Wiley online library, Scopus and Nature through the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guideline for studies on the development of COVID-19 in children with IEIs, published from December 1, 2019 to February 28, 2023, with English language restriction.

RESULTS: Of the 1095 papers that were identified, 116 articles were included in the systematic review (73 case report, 38 cohort 4 case-series and 1 case-control studies). Studies involving 710 children with IEIs with confirmed COVID-19 were analyzed. Among all 710 IEIs pediatric cases who acquired SARS-CoV-2, some children were documented to be admitted to the intensive care unit (ICU) (n = 119, 16.8%), intubated and placed on mechanical ventilation (n = 87, 12.2%), suffered acute respiratory distress syndrome (n = 98, 13.8%) or died (n = 60, 8.4%). Overall, COVID-19 in children with different IEIs patents resulted in no or low severity of disease in more than 76% of all included cases (COVID-19 severity: asymptomatic = 105, mild = 351, or moderate = 88). The majority of children with IEIs received treatment for COVID-19 (n = 579, 81.5%). Multisystem inflammatory syndrome in children (MIS-C) due to COVID-19 in children with IEIs occurred in 103 (14.5%). Fatality in children with IEIs with COVID-19 was reported in any of the included IEIs categories for cellular and humoral immunodeficiencies (n = 19, 18.6%), immune dysregulatory diseases (n = 17, 17.9%), innate immunodeficiencies (n = 5, 10%), bone marrow failure (n = 1, 14.3%), complement deficiencies (n = 1, 9.1%), combined immunodeficiencies with associated or syndromic features (n = 7, 5.5%), phagocytic diseases (n = 3, 5.5%), autoinflammatory diseases (n = 2, 3%) and predominantly antibody deficiencies (n = 5, 2.5%). Mortality was COVID-19-related in a considerable number of children with IEIs (29/60, 48.3%). The highest ICU admission and fatality rates were observed in cases belonging to cellular and humoral immunodeficiencies (26.5% and 18.6%) and immune dysregulatory diseases (35.8% and 17.9%) groups, especially in children infected with SARS-CoV-2 who suffered severe combined immunodeficiency (28.6% and 23.8%), combined immunodeficiency (25% and 15%), familial hemophagocytic lymphohistiocytosis (40% and 20%), X-linked lymphoproliferative diseases-1 (75% and 75%) and X-linked lymphoproliferative diseases-2 (50% and 50%) compared to the other IEIs cases.

CONCLUSION: Children with IEIs infected with SARS-CoV-2 may experience higher rates of ICU admission and mortality in comparison with the immunocompetent pediatric populations. Underlying immune defects does seem to be independent risk factors for severe SARS-CoV-2 infection in children with IEIs, a number of children with SCID and CID were reported to have prolonged infections-though the number of patients is small-but especially immune dysregulation diseases (XLP1 and XLP2) and innate immunodeficiencies impairing type I interferon signalling (IFNAR1, IFNAR2 and TBK1).

PMID:37559153 | DOI:10.1186/s13223-023-00831-1

Virchows Arch. 2023 Aug 9. doi: 10.1007/s00428-023-03590-x. Online ahead of print.

ABSTRACT

Emerging entities and molecular subgroups in large B-cell lymphomas (LBCLs) were discussed during the 2022 European Association for Haematopathology/Society for Hematopathology workshop in Florence, Italy. This session focused on newly recognized diseases and their diagnostic challenges. High-grade/large B-cell lymphoma with 11q aberration (HG/LBCL-11q) is defined by chromosome 11q-gains and telomeric loss. FISH analysis is recommended for the diagnosis. HG/LBCL-11q can occur in the setting of immunodeficiency, including ataxia-telangiectasia, and predominates in children. The morphological spectrum of these cases is broader than previously thought with often Burkitt-like morphology and coarse apoptotic bodies. It has a Burkitt-like immunophenotype (CD10+, BCL6+, BCL2-) but MYC expression is weak or negative, lacks MYC rearrangement, and is in contrast to Burkitt lymphoma 50% of the cases express LMO2. LBCL with IRF4 rearrangement (LBCL-IRF4) occurs mainly in the pediatric population but also in adults. LBCL-IRF4 has an excellent prognosis, with distinguishing molecular findings. IRF4 rearrangements, although characteristic of this entity, are not specific and can be found in association with other chromosomal translocations in other large B-cell lymphomas. Other molecular subgroups discussed included primary bone diffuse large B-cell lymphoma (PB-DLBCL), which has distinctive clinical presentation and molecular findings, and B-acute lymphoblastic leukemia (B-ALL) with IGH::MYC translocation recently segregated from Burkitt lymphoma with TdT expression. This latter disorder has molecular features of precursor B-cells, often tetrasomy 1q and recurrent NRAS and KRAS mutations. In this report, novel findings, recommendations for diagnosis, open questions, and diagnostic challenges raised by the cases submitted to the workshop will be discussed.

PMID:37555980 | DOI:10.1007/s00428-023-03590-x

J Med Case Rep. 2023 Aug 4;17(1):347. doi: 10.1186/s13256-023-04050-5.

ABSTRACT

BACKGROUND: Angioimmunoblastic T-cell lymphoma is an uncommon subtype of peripheral T-cell lymphoma in children with fewer than 20 cases reported in literature.

CASE PRESENTATION: A 3-year-old Omani boy was diagnosed with ataxia-talengectasia presenting with fever and generalized lymphadenopathy. His biopsy revealed atypical lymphocytic infiltrate consistent with the diagnosis of angioimmunoblastic T-cell lymphoma. Within 3 weeks from the initial presentation and without any neoadjuvant therapy, he showed complete recovery of symptoms with absence of fever and regression of all previously affected lymph nodes. He has remained in remission ever since.

CONCLUSION: This is the first report of spontaneous improvement of angioimmunoblastic T-cell lymphoma in a patient with ataxia-telangiectasia who was 3 years old at presentation. Owing to the paucity of similar cases, this report adds valuable diagnostic, therapeutic, and monitoring data.

PMID:37537623 | PMC:PMC10401859 | DOI:10.1186/s13256-023-04050-5

Allergy Asthma Clin Immunol. 2023 Aug 7;19(1):68. doi: 10.1186/s13223-023-00827-x.

ABSTRACT

BACKGROUND: Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency caused by mutations in the WAS gene that leads to increased susceptibility to infections, thrombocytopenia, eczema, malignancies, and autoimmunity. Central nervous system (CNS) autoimmune manifestations are uncommon.

CASE PRESENTATION: We describe the case of a five-year-old boy with refractory thrombocytopenia and iron deficiency anemia who developed relapsing bilateral optic neuritis. Myelin oligodendrocyte glycoprotein antibody (MOG-IgG) via serum fluorescence-activated cell sorting assay was positive (titer 1:100), confirming a diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). At age six, molecular panel testing for genes associated with primary immunodeficiency identified a missense WAS gene variant. He was subsequently found to have decreased WAS protein expression, consistent with a diagnosis of WAS.

CONCLUSIONS: This case expands the reported spectrum of CNS autoimmunity associated with WAS and may help to inform long-term therapeutic options.

PMID:37550789 | DOI:10.1186/s13223-023-00827-x

Front Immunol. 2023 Jul 20;14:1199727. doi: 10.3389/fimmu.2023.1199727. eCollection 2023.

ABSTRACT

The relationship between metabolic and inflammatory pathways play a pathogenic role in various cardiometabolic disorders and is potentially also involved in the pathogenesis of other disorders such as cancer, autoimmunity and infectious diseases. Common variable immunodeficiency (CVID) is the most common primary immunodeficiency in adults, characterized by increased frequency of airway infections with capsulated bacteria. In addition, a large proportion of CVID patients have autoimmune and inflammatory complications associated with systemic inflammation. We summarize the evidence that support a role of a bidirectional pathogenic interaction between inflammation and metabolic disturbances in CVID. This include low levels and function of high-density lipoprotein (HDL), high levels of triglycerides (TG) and its major lipoprotein very low-density lipoprotein (VLDL), and an unfavorable fatty acid (FA) profile. The dysregulation of TG, VLDL and FA were linked to disturbed gut microbiota profile, and TG and VLDL levels were strongly associated with lipopolysaccharides (LPS), a marker of gut leakage in blood. Of note, the disturbed lipid profile in CVID did not include total cholesterol levels or high low-density lipoprotein levels. Furthermore, increased VLDL and TG levels in blood were not associated with diet, high body mass index and liver steatosis, suggesting a different phenotype than in patients with traditional cardiovascular risk such as metabolic syndrome. We hypothesize that these metabolic disturbances are linked to inflammation in a bidirectional manner with disturbed gut microbiota as a potential contributing factor.

PMID:37545531 | PMC:PMC10398391 | DOI:10.3389/fimmu.2023.1199727

J Allergy Clin Immunol Pract. 2023 Aug 4:S2213-2198(23)00815-2. doi: 10.1016/j.jaip.2023.07.042. Online ahead of print.

ABSTRACT

BACKGROUND: Debates on the allocation of medical resources during the COVID-19 pandemic revealed the need for a better understanding of immunologic risk. Studies highlighted variable clinical outcomes of SARS-CoV-2 infections in individuals with defects in both adaptive and innate immunity, suggesting additional contributions from other factors. Notably, none of these studies controlled for variables linked with social determinants of health.

OBJECTIVE: To determine the contributions of determinants of health to risk of hospitalization for SARS-CoV-2 infection among individuals with inborn errors of immunodeficiencies.

METHODS: This is a retrospective, single-center cohort study of 166 individuals with inborn errors of immunity, aged two months through 69 years, who developed SARS-CoV-2 infections from March 1, 2020 through March 31, 2022. Risks of hospitalization was assessed using a multivariable logistic regression analysis.

RESULTS: The risk of SARS-CoV-2-related hospitalization was associated with underrepresented racial and ethnic populations (odds ratio [OR] 4.50; confidence interval [CI], 1.57 – 13.4), a diagnosis of any genetically-defined immunodeficiency (OR 3.32; CI, 1.24 – 9.43), obesity (OR 4.24; CI, 1.38 – 13.3), and neurologic disease (OR 4.47; CI, 1.44 – 14.3. COVID-19 vaccination was associated with reduced hospitalization risk (OR 0.52; CI, 0.31 – 0.81). Defects in T cell and innate immune function, immune-mediated organ dysfunction, and social vulnerability were not associated with increased risk of hospitalization after controlling for covariates.

CONCLUSIONS: The associations between race, ethnicity, and obesity with increased risk of hospitalization for SARS-CoV-2 infection indicate the importance of variables linked with social determinants of health as immunologic risk factors for individuals with inborn errors of immunity.

PMID:37544429 | DOI:10.1016/j.jaip.2023.07.042