Research

J Clin Immunol. 2023 Jan 20. doi: 10.1007/s10875-022-01422-2. Online ahead of print.

ABSTRACT

PURPOSE: Summarize the characteristics of a large cohort of BCG disease and compare differences in clinical characteristics and outcomes among different genotypes and between primary immunodeficiency disease (PID) and patients without identified genetic etiology.

METHODS: We collected information on patients with BCG disease in our center from January 2015 to December 2020 and divided them into four groups: chronic granulomatous disease (CGD), Mendelian susceptibility to mycobacterial disease (MSMD), severe combined immunodeficiency disease (SCID), and gene negative group.

RESULTS: A total of 134 patients were reviewed, and most of them had PID. A total of 111 (82.8%) patients had 18 different types of pathogenic gene mutations, most of whom (91.0%) were classified with CGD, MSMD, and SCID. CYBB was the most common gene mutation (52/111). BCG disease behaves differently in individuals with different PIDs. Significant differences in sex (P < 0.001), age at diagnosis (P = 0.013), frequency of recurrent fever (P = 0.007), and vaccination-homolateral axillary lymph node enlargement (P = 0.039) and infection severity (P = 0.006) were noted among the four groups. The CGD group had the highest rate of males and the oldest age at diagnosis. The MSMD group had the highest probability of disseminated infection (48.3%). The course of anti-tuberculosis treatment and the survival time between patients with PID and without identified genetic etiology were similar.

CONCLUSION: Greater than 80% of BCG patients have PID; accordingly, gene sequencing should be performed in patients with BCG disease for early diagnosis. BCG disease behaves differently in patients with different types of PID. Patients without identified genetic etiology had similar outcomes to PID patients, which hints that they may have pathogenic gene mutations that need to be discovered.

PMID:36662455 | DOI:10.1007/s10875-022-01422-2

J Clin Immunol. 2023 Jan 20. doi: 10.1007/s10875-023-01434-6. Online ahead of print.

ABSTRACT

PURPOSE: Patients with inborn errors of immunity (IEI) manifest various initial symptoms; however, those that are critical for the early diagnosis of IEI have not been identified. Also, the significance of the ten warning signs of primary immunodeficiency (PID) among infants has not been established. This study aimed to conduct a nationwide survey of IEI in Japan and investigated the initial manifestations based on onset age.

METHODS: Among 1298 patients, data regarding the initial manifestation were available from 505 patients. Patients with autoinflammatory diseases, complement deficiency, and phenocopies of IEI were excluded.

RESULTS: The ten warning signs were positive in 67.3% of the cases. The positivity rate was low (20.5%) in patients with immune dysregulation. Although the positivity rate was low (36.6%) in patients aged less than 3 months, they were highly positive for family history of IEI (26.8%). Infectious symptoms were the most commonly observed in all age groups and in all disease categories. Symptoms of “immune dysregulation” were present in approximately 15% of the patients. Regarding the anatomical category, almost all initial symptoms were “systemic” infections in patients with X-linked severe combined immunodeficiency. Moreover, “respiratory” symptoms were the most common in patients with IEI aged ≥ 1 year and accounted for more than 50% in all age groups in patients with common variable immunodeficiency.

CONCLUSION: These results highlight the significance of the 10 warning signs and may serve as clinical indicators for early diagnosis, considering the initial presentation of IEI.

PMID:36662456 | DOI:10.1007/s10875-023-01434-6

CMAJ. 2023 Jan 17;195(2):E91-E96. doi: 10.1503/cmaj.220604-f.

NO ABSTRACT

PMID:36649959 | DOI:10.1503/cmaj.220604-f

J Immunol. 2023 Feb 1;210(3):219-220. doi: 10.4049/jimmunol.2200840.

NO ABSTRACT

PMID:36649581 | DOI:10.4049/jimmunol.2200840

Ther Adv Hematol. 2023 Jan 12;14:20406207221149245. doi: 10.1177/20406207221149245. eCollection 2023.

ABSTRACT

Hodgkin lymphoma is a special type of lymphoma in which tumor cells frequently undergo multiple genetic lesions that are associated with accompanying pathway abnormalities. These pathway abnormalities are dominated by active signaling pathways, such as the JAK-STAT (Janus kinase-signal transducer and activator of transcription) pathway and the NFκB (nuclear factor kappa-B) pathway, which usually result in hyperactive survival signaling. Targeted therapies often play an important role in hematologic malignancies, such as CAR-T therapy (chimeric antigen receptor T-cell immunotherapy) targeting CD19 and CD22 in diffuse large B-cell lymphoma, while in Hodgkin lymphoma, the main targets of targeted therapies are CD30 molecules and PD1 molecules. Drugs targeting other molecules are also under investigation. This review summarizes the actionable genetic lesions, current treatment options, clinical trials for Hodgkin lymphoma and the potential value of those genetic lesions in clinical applications.

PMID:36654739 | PMC:PMC9841868 | DOI:10.1177/20406207221149245

J Clin Immunol. 2023 Jan 17. doi: 10.1007/s10875-022-01420-4. Online ahead of print.

ABSTRACT

Leukocyte adhesion deficiency-III (LAD-III) is an extremely rare autosomal recessive syndrome caused by mutations in FERMT3, the gene encoding kindlin-3. The genetic alterations in this gene lead to abnormal expression or activity of kindlin-3 in leukocytes and platelets. Kindlin-3 acts as an important regulator of integrin activation. LAD-III has features of the bleeding syndrome of Glanzmann and also of leukocyte adhesion deficiency. In this study, we report on two families, one of Turkish and one of Syrian origin, with clinical features of LAD-III, loss of kindlin-3 protein expression, and a functional leukocyte defect. A novel, homozygous deletion in FERMT3 (c.921delC, p.Ser307Argfs*21) was found in the Turkish patient. The parents were carriers of the mutation, consistent with an autosomal recessive inheritance. A common c.1525C > T (p.Arg509*) mutation was found in the Syrian patient. In conclusion, beside the variant c.1525C > T in the FERMT3 gene, which was previously found in more than 15 patients in Anatolia, our study is the first to identify the novel homozygous variant c.921delC in the FERMT3 gene.

PMID:36648575 | DOI:10.1007/s10875-022-01420-4

Cureus. 2022 Dec 13;14(12):e32470. doi: 10.7759/cureus.32470. eCollection 2022 Dec.

ABSTRACT

X-linked agammaglobulinemia (XLA) is a rare primary immunodeficiency disorder. It occurs in around one in 200,000 live births and is caused by mutations in the Bruton Tyrosine Kinase (BTK) gene leading to B lymphocyte deficiency and increased susceptibility to infection. Infection is the most common initial clinical presentation, followed by family history and neutropenia. Even in patients with a positive family history, only 34% of patients were diagnosed before clinical symptoms arose. Over half of patients are diagnosed by two years of age. Treatment is aimed at replacing immunoglobulin using intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) and prophylactic antibiotics to prevent infections. Despite these therapies, patients still suffer from repetitive infections. Another significant source of morbidity in patients with XLA is a chronic lung disease. By the time of diagnosis, 62% of patients had at least one case of pneumonia. We describe the case of a patient who has developed an accelerated course of chronic obstructive pulmonary disease (COPD) secondary to pre-existing X-linked agammaglobulinemia and recurrent respiratory infections.

PMID:36644069 | PMC:PMC9835111 | DOI:10.7759/cureus.32470

Front Immunol. 2022 Dec 27;13:1070068. doi: 10.3389/fimmu.2022.1070068. eCollection 2022.

ABSTRACT

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) haploinsufficiency is a T-cell hyperactivation disorder that can manifest with both immunodeficiency and immune dysregulation. Approximately one-third of patients may present mild symptoms and remain stable under supportive care. The remaining patients may develop severe multiorgan autoimmunity requiring lifelong immunosuppressive treatment. Hematopoietic stem cell transplantation (HSCT) is potentially curable for patients with treatment-resistant immune dysregulation. Nevertheless, little experience is reported regarding the management of complications post-HSCT. We present case 1 (CTLA-4 haploinsufficiency) and case 2 (CTLA-4 insufficiency-like phenotype) manifesting with severe autoimmunity including cytopenia and involvement of the central nervous system (CNS), lung, and gut and variable impairment of humoral responses. Both patients underwent HSCT for which the main complications were persistent mixed chimerism, infections, and immune-mediated complications [graft-versus-host disease (GVHD) and nodular lung disease]. Detailed management and outcomes of therapeutic interventions post-HSCT are discussed. Concretely, post-HSCT abatacept and human leukocyte antigen (HLA)-matched sibling donor lymphocyte infusions may be used to increase T-cell donor chimerism with the aim of correcting the immune phenotype of CTLA-4 haploinsufficiency.

PMID:36636328 | PMC:PMC9831655 | DOI:10.3389/fimmu.2022.1070068

Lancet Gastroenterol Hepatol. 2023 Jan 9:S2468-1253(22)00337-5. doi: 10.1016/S2468-1253(22)00337-5. Online ahead of print.

ABSTRACT

Genomic medicine enables the identification of patients with rare or ultra-rare monogenic forms of inflammatory bowel disease (IBD) and supports clinical decision making. Patients with monogenic IBD frequently experience extremely early onset of treatment-refractory disease, with complex extraintestinal disease typical of immunodeficiency. Since more than 100 monogenic disorders can present with IBD, new genetic disorders and variants are being discovered every year, and as phenotypic expression of the gene defects is variable, adaptive genomic technologies are required. Monogenic IBD has become a key area to establish the concept of precision medicine. Clear guidance and standardised, affordable applications of genomic technologies are needed to implement exome or genome sequencing in clinical practice. This joint British Society of Gastroenterology and British Society of Paediatric Gastroenterology, Hepatology and Nutrition guideline aims to ensure that testing resources are appropriately applied to maximise the benefit to patients on a national scale, minimise health-care disparities in accessing genomic technologies, and optimise resource use. We set out the structural requirements for genomic medicine as part of a multidisciplinary team approach. Initiation of genomic diagnostics should be guided by diagnostic criteria for the individual patient, in particular the age of IBD onset and the patient’s history, and potential implications for future therapies. We outline the diagnostic care pathway for paediatric and adult patients. This guideline considers how to handle clinically actionable findings in research studies and the impact of consumer-based genomics for monogenic IBD. This document was developed by multiple stakeholders, including UK paediatric and adult gastroenterology physicians, immunologists, transplant specialists, clinical geneticists, scientists, and research leads of UK genetic programmes, in partnership with patient representatives of several IBD and rare disease charities.

PMID:36634696 | DOI:10.1016/S2468-1253(22)00337-5

BMC Cancer. 2023 Jan 9;23(1):33. doi: 10.1186/s12885-022-10497-4.

ABSTRACT

BACKGROUND: Diminished immune defense plays an important role in cancer development. Cancer risk in immunocompromised patients may differ. Identifying individuals with elevated cancer risk can inform strategies for routine cancer screening. This study aimed to understand and compare cancer incidence and risk in three patient groups: recipients of solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT); diagnosis of primary or secondary immunodeficiency disorder (PID/SID); and recipients of tumor necrosis factor inhibitor (TNF-i) therapy.

METHODS: This retrospective cohort study used the University of Utah Health System database and Huntsman Cancer Institute tumor registry. Patients aged ≥18 years with SOT/HSCT, PID/SID or ≥ 3 months of TNF-i therapy were included. The date of transplant, diagnosis of PID/SID, or 1st TNF-i medication order date was defined as the index date. We calculated cumulative cancer incidence by Kaplan-Meier method. A Cox-proportional hazard regression model with a stepwise variable selection process was used to identify independent risk factors associated with the time to onset of a new primary cancer.

RESULTS: In total, 13,887 patients were included which comprised of 2982 (21%) SOT/HSCT, 7542 (54%) PID/SID and 3363 (24%) patients receiving TNF-i. The mean (SD) age ranged from 46.8 (15) years – 50.4 (18.2) years. The proportion of white patients ranged from 72.3-84.8%. The estimated cumulative cancer incidence was 11.5% in the SOT/HSCT cohort, 14.3% in the PID/SID cohort, and 8.8% in the TNF-i cohort. The multivariable model adjusted for age, benign in-situ disease, Charlson Comorbidity Index, hypertension/cardiovascular disease/end stage renal disease, gender, race/ethnicity, and renal cyst as significant risk factors. The adjusted hazard ratios for cancer development in SOT/HSCT and PID/SID cohorts compared to the TNF-i cohort over the full follow-up period were 1.57 (95% CI: 1.16-2.13) and 2.14 (95% CI: 1.65-2.77), respectively.

CONCLUSION: A significantly increased risk of cancer was observed in PID/SID patients and SOT/HSCT patients compared to TNF-i patients. Age ≥ 50 years, male gender, and clinical comorbidities were additional factors impacting cancer risk. PID/SID and SOT/HSCT patients may benefit from more intensive cancer screening.

PMID:36624408 | DOI:10.1186/s12885-022-10497-4