Manish Butte

J Clin Immunol. 2022 Apr 29. doi: 10.1007/s10875-022-01277-7. Online ahead of print.

ABSTRACT

Common variable immunodeficiency disorders (CVID), the most common primary immune deficiency, includes heterogeneous syndromes characterized by hypogammaglobulinemia and impaired antibody responses. CVID patients frequently suffer from recurrent infections and inflammatory conditions. Currently, immunoglobulin replacement therapy (IgRT) is the first-line treatment to prevent infections and aminorate immune alterations in CVID patients. Intravenous Immunoglobulin (IVIg), a preparation of highly purified poly-specific IgG, is used for treatment of immunodeficiencies as well as for autoimmune and inflammatory disorders, as IVIg exerts immunoregulatory and anti-inflammatory actions on innate and adaptive immune cells. To determine the mechanism of action of IVIg in CVID in vivo, we determined the effect of IVIg infusion on the transcriptome of peripheral blood mononuclear cells from CVID patients, and found that peripheral blood monocytes are primary targets of IVIg in vivo, and that IVIg triggers the acquisition of an anti-inflammatory gene profile in human monocytes. Moreover, IVIg altered the relative proportions of peripheral blood monocyte subsets and enhanced the proportion of CD14⁺ cells with a transcriptional, phenotypic, and functional profile that resembles that of monocytic myeloid-derived suppressor cells (MDSC). Therefore, our results indicate that CD14 + MDSC-like cells might contribute to the immunoregulatory effects of IVIg in CVID and other inflammatory disorders.

PMID:35486340 | DOI:10.1007/s10875-022-01277-7

J Clin Immunol. 2022 Apr 29. doi: 10.1007/s10875-022-01257-x. Online ahead of print.

ABSTRACT

INTRODUCTION: Since the first description of gain of function (GOF) mutations in signal transducer and activator of transcription (STAT) 1, more than 300 patients have been described with a broad clinical phenotype including infections and severe immune dysregulation. Whilst Jak inhibitors (JAKinibs) have demonstrated benefits in several reported cases, their indications, dosing, and monitoring remain to be established.

METHODS: A retrospective, multicenter study recruiting pediatric patients with STAT1 GOF under JAKinib treatment was performed and, when applicable, compared with the available reports from the literature.

RESULTS: Ten children (median age 8.5 years (3-18), receiving JAKinibs (ruxolitinib (n = 9) and baricitinib (n = 1)) with a median follow-up of 18 months (2-42) from 6 inborn errors of immunity (IEI) reference centers were included. Clinical profile and JAKinib indications in our series were similar to the previously published 14 pediatric patients. 9/10 (our cohort) and 14/14 patients (previous reports) showed partial or complete responses. The median immune deficiency and dysregulation activity scores were 15.99 (5.2-40) pre and 7.55 (3-14.1) under therapy (p = 0.0078). Infection, considered a likely adverse event of JAKinib therapy, was observed in 1/10 patients; JAKinibs were stopped in 3/10 children, due to hepatotoxicity, pre-HSCT, and absence of response.

CONCLUSIONS: Our study supports the potentially beneficial use of JAKinibs in patients with STAT1 GOF, in line with previously published data. However, consensus regarding their indications and timing, dosing, treatment duration, and monitoring, as well as defining biomarkers to monitor clinical and immunological responses, remains to be determined, in form of international prospective multicenter studies using established IEI registries.

PMID:35486339 | DOI:10.1007/s10875-022-01257-x

Lancet. 2022 Apr 25:S0140-6736(22)00469-X. doi: 10.1016/S0140-6736(22)00469-X. Online ahead of print.

ABSTRACT

BACKGROUND: The optimal management of vulvar high-grade squamous intraepithelial lesions (vHSILs) is challenging. Surgery is the standard treatment, but recurrences are observed in half of patients. Medical treatment with imiquimod is an effective alternative, but the two modalities have not been compared in a randomised trial. The aim of this study was to compare the clinical effectiveness, histological response, human papillomavirus (HPV) clearance, acceptance, and psychosexual morbidity of primary imiquimod treatment versus surgical treatment in women with vHSIL.

METHODS: This study was a multicentre, randomised, phase 3, non-inferiority clinical trial done by the Austrian Gynaecological Oncology group at six hospitals in Austria. We recruited female patients aged 18-90 years with histologically confirmed vHSIL with visible unifocal or multifocal lesions. Main exclusion criteria were clinical suspicion of invasion, a history of vulvar cancer or severe inflammatory dermatosis of the vulva, and any active treatment for vHSIL within the previous 3 months. Women with known immunodeficiency, who were pregnant, or who were lactating were excluded. Patients were randomly assigned (1:1) by block randomisation to imiquimod or surgery, and stratified by unifocal or multifocal disease. Treatment with imiquimod was self-administered in a slowly escalating dosage scheme up to three times per week for a period of 4-6 months. Surgery consisted of excision or ablation. Patients were assessed with vulvoscopy, vulvar biopsy, HPV tests, and patient-reported outcomes at baseline and after 6 months and 12 months. The primary endpoint was complete clinical response (CCR) at 6 months after local imiquimod treatment or one surgical intervention. Primary analysis was per protocol with a non-inferiority margin of 20%. This trial is registered at ClinicalTrials.gov, NCT01861535.

FINDINGS: 110 patients with vHSIL (78% with unifocal vHSIL and 22% with multifocal vHSIL) were randomly assigned between June 7, 2013, and Jan 8, 2020. Clinical response to treatment could be assessed in 107 patients (54 in the imiquimod group and 53 in the surgery group), and 98 patients (46 in the imiquimod group and 52 in the surgery group) completed the study per protocol. 37 (80%) of 46 patients using imiquimod had CCR, compared with 41 (79%) of 52 patients after one surgical intervention, showing non-inferiority of the new treatment (difference in proportion -0·016, 95% CI -0·15 to -0·18; p=0·0056). Invasive disease was found in five patients at primary or secondary surgery, but not in patients with per-protocol imiquimod treatment. There was no significant difference in HPV clearance, adverse events, and treatment satisfaction between study groups.

INTERPRETATION: Imiquimod is a safe, effective, and well accepted alternative to surgery for women with vHSIL and can be considered as first-line treatment.

FUNDING: Austrian Science Fund and Austrian Gynaecological Oncology group.

PMID:35483400 | DOI:10.1016/S0140-6736(22)00469-X

Clin Exp Immunol. 2022 Apr 27:uxac040. doi: 10.1093/cei/uxac040. Online ahead of print.

ABSTRACT

Interleukin10 (IL10) and IL10 receptor (IL10R) deficiencies are monogenic inborn errors of immunity (IEI) causing early-onset inflammatory bowel diseases (IBD). In this report, we systematically reviewed articles that included related keywords using PubMed, Web of Science, and Scopus databases. The articles were screened for eligibility criteria before data extraction. We assessed 286 patients (44.5% female) with IL10 and/or IL10R deficiencies who were predominantly from China (40.7%), Italy (13.9%), and South Korea (8.5%). The median age of onset was 1.0 (0.3-4.0) months with a median age of genetic diagnosis at 16.0 (7.4-81.0) months. Consanguinity was reported in all evaluable patients with IL10 deficiency and in 38.2% of patients with IL10R deficiency (22.9% of patients with IL10RA, and 79.4% of patients with IL10RB deficiency). The most prevalent mutations in IL10RA were c.301C>T (p.R101W) and c.537G>A (p.T179T), those in IL10RB were c.139A>G (p.K47E) and c.611G>A (p.W204X). Auto-inflammation and enteropathy were present in all cases. The first presentation of both groups was protracted diarrhea (45.7%), bloody diarrhea (17.8%), and colitis (15.5%). Patients with IL10R deficiency had a high frequency of dermatologic manifestations (50.5%) and failure to thrive (60.5%), while IL10-deficient patients lacked those complications. In the majority of patients, the basic immunologic parameters were in normal ranges. Of the entire publications, 30.7% underwent hemopoietic stem cell transplantation, 57.5% surgery, and 86.6% immunosuppressive treatment. The ten-year survival rate was higher in patients with IL10 deficiency than in patients with IL10R deficiency. In conclusion, IL10/IL10R deficiency predominantly presents with treatment-resistant, early-onset IBD within the first months of life. We detected no clear correlation between the phenotype of patients carrying the same variant. The high prevalence of distinct clinical manifestations reported in IL10RA- and IL10RB-deficient patients might be attributable to the interactions between the target tissue and cytokines other than IL10 capable of binding to IL10RB. These results gain translational significance by contributing to earlier diagnosis, adequate therapy, and avoiding delay in the diagnosis and unfavorable outcome.

PMID:35481870 | DOI:10.1093/cei/uxac040

Pediatr Allergy Immunol. 2022 Apr;33(4):e13770. doi: 10.1111/pai.13770.

NO ABSTRACT

PMID:35470938 | DOI:10.1111/pai.13770

Pediatr Allergy Immunol. 2022 Apr;33(4):e13774. doi: 10.1111/pai.13774.

NO ABSTRACT

PMID:35470934 | DOI:10.1111/pai.13774

J Allergy Clin Immunol Pract. 2022 Apr 22:S2213-2198(22)00349-X. doi: 10.1016/j.jaip.2022.03.032. Online ahead of print.

ABSTRACT

BACKGROUND: Bacillus Calmette-Guierin (BCG) vaccination complications are common in inborn errors of immunity (IEI) due to the inability to clear live-attenuated Mycobacterium bovis. Various BCG-vaccine strains are used worldwide, and the profile of the Russian BCG-strain vaccine complications in IEI is poorly characterised.

OBJECTIVE: The present study aimed to evaluate risks of BCG-infection in a large cohort of IEI vaccinated with the Russian BCG-strain.

METHODS: We evaluated 778 IEI patients vaccinated with the Russian BCG-strain.

RESULTS: 114 (15%) developed BCG-infection, 41 (36%) with local, 19 (17%) with regional and 54 with (47%) disseminated disease. BCG-infection was seen in 58% of the patients with severe combined immunodeficiency (SCID), 82% with chronic granulomatous disease (CGD), 50% with innate immune defects (IID), 5% with combined immune defects (CID); and 2% with other IEI. BCG-infection presented at a median age of 4-5 months in SCID, CGD, CID and other IEI groups vs 12 months in IID patients (p<0,005). We found no influence of specific genetic defects, CD3+ and NK cell numbers in SCID, or dihydrorhodamine test stimulation index values in CGD on the BCG-infection risks. All SCID patients received anti-mycobacterial therapy at SCID diagnosis even in the absence of active BCG-infection. More anti-mycobacterial agents were required in disseminated relative to local or regional infection (p<0,0001). Only one of 114 patients (with SCID) died of BCG-related complications (<1%).

CONCLUSION: BCG-infection is common in IEI patients receiving BCG-vaccination. Rational early anti-mycobacterial therapy, combined with anti-cytokine agents for post-transplant inflammatory syndrome prevention, and treatment in SCID may prevent BCG-related mortality.

PMID:35470098 | DOI:10.1016/j.jaip.2022.03.032

Front Immunol. 2022 Apr 8;13:881206. doi: 10.3389/fimmu.2022.881206. eCollection 2022.

ABSTRACT

SASH3 is a lymphoid-specific adaptor protein. In a recent study, SASH3 deficiency was described as a novel X-linked combined immunodeficiency with immune dysregulation, associated with impaired TCR signaling and thymocyte survival in humans. The small number of patients reported to date showed recurrent sinopulmonary, cutaneous and mucosal infections, and autoimmune cytopenia. Here we describe an adult patient previously diagnosed with common variable immunodeficiency (CVID) due to low IgG and IgM levels and recurrent upper tract infections. Two separate, severe viral infections drew our attention and pointed to an underlying T cell defect: severe varicella zoster virus (VZV) infection at the age of 4 years and bilateral pneumonia due type A influenza infection at the age of 38. Genetic testing using an NGS-based custom-targeted gene panel revealed a novel hemizygous loss-of-function variant in the SASH3 gene (c.505C>T/p.Gln169*). The patient’s immunological phenotype included marked B cell lymphopenia with reduced pre-switch and switch memory B cells, decreased CD4⁺ and CD8⁺ naïve T cells, elevated CD4⁺ and CD8⁺ T_EMRA cells, and abnormal T cell activation and proliferation. The patient showed a suboptimal response to Streptococcus pneumoniae (polysaccharide) vaccine, and a normal response to Haemophilus influenzae type B (conjugate) vaccine and SARS-CoV-2 (RNA) vaccine. In summary, our patient has a combined immunodeficiency, although he presented with a phenotype resembling CVID. Two severe episodes of viral infection alerted us to a possible T-cell defect, and genetic testing led to SASH3 deficiency. Our patient displays a milder phenotype than has been reported previously in these patients, thus expanding the clinical spectrum of this recently identified inborn error of immunity.

PMID:35464398 | PMC:PMC9027814 | DOI:10.3389/fimmu.2022.881206

J Neuroimmunol. 2022 Apr 12;367:577866. doi: 10.1016/j.jneuroim.2022.577866. Online ahead of print.

ABSTRACT

A 49-year-old patient with a history of lymphoproliferation and autoimmune cytopenias presented with unexplained longitudinal extensive transverse myelitis. Flow cytometry on peripheral blood showed an elevated level of double negative T lymphocytes, a finding typical for autoimmune lymphoproliferative syndrome (ALPS). Inborn error of immunity (IEI) gene panel demonstrated a heterozygous variant in the FAS gene (c.857G > A, p.(Gly286Glu)), formally confirming the diagnosis. Autoimmune neurological conditions in a context of predisposition for infection and lymphoproliferation should raise suspicion of IEI. Specific testing for ALPS should be considered in patients with a history of non-malignant lymphoproliferation, multilineage cytopenias and unexplained autoimmune (neurological) manifestations.

PMID:35453041 | DOI:10.1016/j.jneuroim.2022.577866

Children (Basel). 2022 Mar 25;9(4):466. doi: 10.3390/children9040466.

ABSTRACT

BACKGROUND: Allergy is a clinical condition that reflects a deviated function of the immune system. The purpose of this study was to evaluate serum allergen-specific IgE (sIgE) along with clinical manifestations of allergy in patients with diagnosed primary immunodeficiency (PID).

METHODS: 72 patients, aged 1-17 years, diagnosed with PID and hospitalized between July 2020 and February 2021 were included in the study. Blood samples were obtained by venipuncture. sIgE (30 allergens), blood eosinophil count, as well as total IgE and IgG were measured and assessed in relation to a detailed medical examination.

RESULTS: Serum sIgE was detected in the blood of 50% of the patients in the study group, which significantly correlated (p &lt; 0.0001) with clinical symptoms of allergy. During the period of the study, 61.1% of the patients showed symptoms of allergy, with 77.27% of them having tested positive for sIgE. The total IgE level was elevated in 18.06% of the patients and correlated with clinical symptoms of allergy (p = 0.004). An elevated total IgE level was not observed in children receiving immunoglobulin replacement therapy.

CONCLUSION: The study showed that serum sIgE and total IgE together might be a plausible diagnostic tool for PID patients. However, for patients receiving immunoglobulin replacement therapy, the assessment of total IgE is not useful.

PMID:35455510 | DOI:10.3390/children9040466