Journal of Clinical Immunology最新文献

X-linked agammaglobulinemia (XLA) is caused by loss-of-function variants in Bruton's tyrosine kinase, leading to absence of circulating B lymphocytes and inability to produce antibodies. Despite the fear that patients with XLA would be at high risk for severe infection when the novel virus SARS-CoV-2 emerged in the society with low pre-existing immunity, most patients with XLA did not suffer from severe disease. However, some patients were critically affected. Factors associated with hospitalization in patients with XLA remain poorly described. Thus, we designed a study to determine risk factors associated with hospitalization due to Covid-19 in patients with XLA. Data was collected from 17 sites in Europe and the US, comprising n = 81 patients, with hospitalization due to SARS-CoV-2 infection in 14 patients. Nearly 17% of patients with XLA required hospitalization due to Covid-19, but only 3 patients had ventilatory support. After correcting for the effect of the date of infection during the early pandemic, univariate and multiple logistic regression analysis showed that preexisting bronchiectasis and lower IgG serum trough levels (< 8 g/L) before infection were associated with an increased risk for hospitalization, with a high rate of superinfection. The lack of vaccination seemed to contribute to this risk, and ambulatory patients had higher amounts of CD4⁺ T cells before infection compared to hospitalized patients. Thus, our data suggests a need for IgG trough levels above 8 g/L, especially in patients with bronchiectasis, to protect patients with XLA during viral infections such as Covid-19 and reduce morbidity due to superinfections.

Haploinsufficiency of cytotoxic T-lymphocyte associated protein 4 (CTLA4), a known cause of inborn errors of immunity, can lead to autoimmunity, inflammation, neoplasia and infections. A previously undescribed CTLA4 variant was identified in a patient who presented with life-threatening cutaneous infection caused by Pseudomonas aeruginosa, severe VZV infection, and Evans syndrome. Our aim was to assess the pathogenicity of the previously undescribed c.379T > G variant in the CTLA4 gene and explore its phenotypic presentation in relatives. We employed genetic and protein-based in silico analyses to evaluate the potential role of the c.379T > G variant in the CTLA4 gene. We subsequently studied CTLA4 expression ex vivo, analyzed the clinical presentation of affected carriers and compared the biological status across affected individuals, healthy carriers and noncarriers. In silico analyses revealed that the c.379T > G mutation, which is located within the ligand binding area of CTLA4, is highly pathogenic. Its clinical manifestations, which are sometimes fatal, include multiple infections, autoimmunity, inflammation of the central nervous system, lymphoproliferation and thymoma with Good's syndrome. Compared with its expression in healthy donors, the expression of CTLA4 following stimulation in memory regulatory T cells was decreased in affected individuals. Immunophenotyping revealed an increased proportion of immature and double-negative B cells in affected patients compared with their nonmutated relatives. Additionally, a reduction in naive T cells and an increase in CD4 + CD25-Foxp3 + cells were observed in carriers compared with controls. The c.379T > G variant of CTLA4, resulting in a p.Tyr127Asp substitution, is pathogenic and contributes to the development of a CTLA4 haploinsufficiency phenotype. This finding highlights the heterogeneous presentations of the disease, including oncological and neurological manifestations.

Intravenous immunoglobulin (IVIG) therapy is a well-documented and effective treatment for primary immunodeficiencies (PI). Subcutaneous immunoglobulins (SCIG) have emerged as an effective alternative for some patients that offers additional flexibility.Currently, caprylate/chromatography purified IGSC (human) 20% is approved to treat PI in North America and many countries worldwide. In this multi-center, open-label study, the pharmacokinetics (PK), efficacy, and safety of IGSC 20% were studied after biweekly (every two weeks) dosing for 16 weeks and compared to weekly IGSC 20% administration for 16 weeks in treatment-experienced PI patients. A loading/weekly maintenance SC regimen was also studied in PI patients naïve to IG treatment.In treatment-experienced patients, the least squares mean ratio of steady-state AUC_0-7 days for biweekly dosing showed non-inferiority to weekly dosing (90% confidence interval 1.0030-1.0685). Other PK parameters (C_max, T_max, steady state trough) were similar between treatments. Efficacy and safety measures were qualitatively similar to previously published results. No serious bacterial infections were reported. Annual rates for any type of infection were similar between the treatment groups. All severe treatment-related adverse events (AEs) were unrelated to treatment. Only mild to moderate suspected adverse drug reactions were observed.PK analyses showed that biweekly dosing of IGSC 20% was non-inferior to weekly dosing in treatment-experienced PI patients. Biweekly dosing had similar patterns to weekly in prevention of serious bacterial infections, rates of all infections and hospitalizations for infections. The IGSC loading/maintenance dosing regimen in naïve patients was safe and effective during the observation period.

Combined immunodeficiency due to CARMIL2 mutations is a rare autosomal recessive primary immunodeficiency characterized by impaired T-cell activation and function, leading to diverse clinical manifestations. Fewer than 50 cases have been reported worldwide. We describe the clinical and genetic features of five patients from Palestine with homozygous CARMIL2 mutations, including the first documented case of recurrent visceral leishmaniasis associated with this gene defect. This retrospective case series was conducted using whole-exome sequencing to confirm the diagnosis. All patients exhibited significant immunologic symptoms, including chronic dermatitis, cutaneous warts, recurrent respiratory infections, and mucocutaneous candidiasis. Two developed cytomegalovirus-related disease. Genetic analysis revealed two novel homozygous variants: NM_001317026.3:c.1865 C > T (p.Ala622Val) in four patients, and c.1973 C > T (p.Ala658Val) in one. Notably, one adult male developed recurrent visceral leishmaniasis, an unusual presentation not previously reported in the context of CARMIL2 deficiency. Consanguinity was identified in two families. All patients required immunomodulatory therapy, and four were evaluated for hematopoietic stem cell transplantation. This case series underscores the clinical heterogeneity of CARMIL2-associated immunodeficiency and highlights the importance of genetic testing in patients with recurrent or atypical infections, particularly in populations with a high prevalence of consanguinity. The novel link to visceral leishmaniasis expands the known phenotypic spectrum of this condition.

Background: IgA vasculitis (IgAV) is an autoimmune disorder characterized by inflammation of the small blood vessels. The pathogenesis of IgAV is believed to involve a complex interplay between immune cells, metabolites, and inflammatory cytokines (ICs).

Methods: We performed two-sample Mendelian randomization (MR) analysis to examine the causal relationship between immune cell traits, metabolites, ICs, and IgAV. Genetic variants associated with exposure, mediators and outcome were extracted from large-scale genome-wide association studies (GWAS). The inverse variance weighted (IVW) method was used as the primary approach, supported by MR Egger, weighted median, simple mode, and weighted mode methods.

Results: In this study, we identified 25 immune cells, 6 metabolites (Threonate, Carnitine C5:1, Chiro-inositol, Carnitine C18:2, 3-formylindole, Cholate to phosphate ratio) and 2 ICs (T - cell surface glycoprotein CD5, Osteoprotegerin) associated with IgAV. Meanwhile, we identified 5 immune cell-metabolites-IgAV pathways (CD28⁺CD45RA^-CD8dim AC-3-formylindole-IgAV; CD28⁺ CD45RA^- CD8dim AC-Cholate to phosphate ratio-IgAV; CD28⁺ CD45RA⁺ CD8br%T cell-3-formylindole-IgAV; CD25 on IgD⁺ CD38^- unswmem-Chiro-inositol- IgAV; HLA DR on CD14⁺ CD16^- monocyte-Chiro-inositol-IgAV; CD39⁺ secreting Treg %secreting Treg-Threonate-IgAV) and 4 immune cells-ICs-IgAV pathways (IgD^- CD38^- AC-Osteoprotegerin-IgAV; CD45 on T-Osteoprotegerin-IgAV; HLA DR on CD14⁺ CD16^- monocyte-CD5-IgAV; HLA DR on CD14⁺CD16^- monocyte-CD5-IgAV).

Conclusions: These results highlight the need for further research to investigate the underlying mechanisms and identify potential therapeutic targets for the treatment of IgAV.

Purpose: Patients with X-linked agammaglobulinemia (XLA) suffer from severe, recurrent infections potentially leading to life-threatening complications. Early diagnosis and timely treatment can prevent infections and secondary complications, emphasizing a role for newborn screening (NBS). NBS for XLA is based on quantification of kappa-deleting recombination excision circles (KRECs). KREC-based screening could result in a large number of false-positive referrals associated with high impact for parents and health care systems, indicating the need for a second tier test.

Methods: KRECs were measured in NBS cards (N = 110,491) with a multiplex TREC/KREC qPCR assay. As second tier test options, an alternative qPCR multiplex assay, epigenetic immune cell counting for relative B-cell quantification and targeted next-generation sequencing with B-cell deficiency gene panel including 73 genes were performed on NBS cards of newborns with low KRECs.

Results: In total, 136/110,491 newborns had KRECs below cut-off. With the alternative qPCR multiplex assay, 16/110 of these newborns (14.5%) had KRECs above cut-off and would not have been referred. With epigenetic immune cell counting, 16.5% (17/103) had relative B-cell counts in the range of healthy controls. Targeted NGS showed promising results as 87 out of 103 (84%) newborns with low KRECs did not show any pathogenic/likely pathogenic variants and would not have been referred for follow-up diagnostics.

Conclusion: Several second tier tests can potentially reduce the number of false-positive referrals in NBS for XLA. NGS seems to be the most effective technique in NBS for XLA and other forms of agammaglobulinemia. Our results show promising first steps towards the implementation of NBS for XLA.

Fungal infections contribute to a significant disease burden in patients with chronic granulomatous disease (CGD). While the presentation may differ depending on genotype and environmental exposure to fungus, associated mortality rates are universally high. This is a retrospective study wherein medical records of patients diagnosed with CGD from 1994 to 2022 at our center in North India were reviewed. We categorized patients into 2 groups: patients with proven invasive fungal infection and patients with probable invasive fungal infections. We analyzed demographic details, clinical details, and the overall outcome of these patients. We identified 40 patients (40.4%) with fungal infections in our cohort of 99 patients with CGD. Twenty-one patients had proven invasive fungal infection, and 19 had probable invasive fungal infection. Pneumonia was the most common presentation in our cohort (n = 35; 87.5%). Two patients had isolated osteomyelitis, 1 had brain abscess, and 2 had candidemia. Aspergillus sp. was isolated most frequently (n = 27), followed by Candida sp. (n = 5), Mucorales sp. (n = 2), Paecilomyces sp. (n = 1) and Fusarium dimerum (n = 1). Aspergillus fumigatus (n = 11) was the most identified species of Aspergillus. Eleven patients had bacterial co-infection. Twenty-one patients (52.5%) died in this cohort. Risk factors for mortality identified are X-linked CGD (p = 0.027), bacterial coinfection (p = 0.003) and infection in infancy (p = 0.045). Aspergillus sp. is the most common offending fungus, and pneumonia is the most common manifestation of fungal infection in our patients with CGD. Infants, males, and patients with bacterial coinfection should be treated more aggressively amongst patients with CGD with fungal infection.

Background: Non-Aspergillus invasive fungal infections (NAFI) are increasingly reported in patients with Chronic Granulomatous Disease (CGD), but precise clinical descriptions remain scarce.

Objective and methods: We conducted a retrospective analysis of NAFI cases among CGD patients in the French National Registry of Primary Immunodeficiencies (CEREDIH) and in a comprehensive literature review.

Results: We identified 16 proven NAFI (9 molds, 6 yeasts and 1 Pneumocystis) among 263 CGD patients from CEREDIH and included an additional 106 probable/proven NAFI from a literature review (75 molds, 29 yeasts, 1 Pneumocystis, 1 dimorphic). Mold NAFI occurred at a median age of 17 years [IQR 9-23], and were mostly located to the lungs (79%, 65/82). Mold NAFI were breakthrough in 59% of patients (35/59), and 24% were receiving immunosuppressive treatments (13/54, mostly high-dose corticosteroids, n = 11). Lung surgical biopsies yielded the highest diagnostic rate (39/39) compared to less invasive methods (BAL 8/18 and transthoracic punctures 8/12). Nine patients with mold NAFI, including 3 refractory cases, were cured after Hematopoietic Stem Cell Transplantation (HSCT). Overall mortality for mold NAFI was 25% (20/81). Yeast infections occurred at a median age of 5 years [IQR 0-13], and 36% were receiving immunosuppressive treatments (5/14, mostly anti-TNF agents, n = 4). Infections were frequently located to lymph nodes or lungs, and 64% (21/33) were disseminated. Two yeast NAFI were cured after HSCT. Mortality was 26% (7/27).

Conclusion: NAFI in CGD patients are frequently severe, often occur despite prophylaxis and under additional immunosuppression, commonly require invasive procedures for diagnosis, and may be effectively managed with HSCT.