Manish Butte

Turk Arch Pediatr. 2022 Mar;57(2):132-145. doi: 10.5152/TurkArchPediatr.2022.22033.

ABSTRACT

Inborn errors of immunity are a group of rare diseases characterized by a wide variety of manifestations, including unusually severe infections, cancer susceptibility, and exaggerated inflammation that disrupts organ function. As of 2022, over 450 gene deficiencies have been classified under ten categories, where numbers are constantly increasing. The range of inborn errors of immunity varies considerably, from mild infections to serious multisystemic disease. Whereas patients with T cell defects are liable to a broad range of pathogens, selected inborn errors of immunity may predispose hosts merely to a narrow range of microorganisms. Dysregulated immune responses often cause autoimmune manifestations that may target any organ or lead to severe allergies. Therefore, presentation to any medical discipline is possible. Historically, inborn errors of immunity have been associated with short life expectancy and poor life quality, but intensive research into the field has revolutionized this assumption. Especially with the aid of translational investigations, our clinical practice has transformed from a predominantly phenotype-driven management into one that is reinforced by an etiology-driven therapy. This review summarizes the recent advances in molecularly targeted treatment approaches in various inborn errors of immunity conditions, with many success stories corroborating the power of genomic medicine. The principles of applications learned from these rare monogenic traits, in which the functional impact of the molecular pathways is clear-cut, may be instructive for developing basic concepts toward precision therapy of the common immune-mediated disorders, including autoimmunity, infectious diseases, and allergy, which affect mass populations.

PMID:35383007 | DOI:10.5152/TurkArchPediatr.2022.22033

Allergy Asthma Clin Immunol. 2022 Apr 5;18(1):31. doi: 10.1186/s13223-022-00673-3.

ABSTRACT

BACKGROUND: Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder associated with a broad symptom presentation that is still being characterized. We report a rare case of recurrent mycoplasma skin abscesses in a patient with a history of autoimmune disorders and prolonged mycoplasma pneumonia who was diagnosed with CVID.

CASE PRESENTATION: A 34-year-old woman presented with a history of recurrent abscesses previously confirmed positive for Mycoplasma pneumoniae. Her past medical history of recurrent mycoplasma abscesses, prolonged mycoplasma pneumonia, and autoimmune disorders (mixed connective tissue disease and immune thrombocytopenia) raised suspicion of CVID. Workup included negative anti-mycoplasma antibody titers, hypogammaglobulinemia, and negative anti-pneumococcal antibody titers despite prior vaccination, solidifying the diagnosis of CVID. The patient was discharged on antibiotic and intravenous immunoglobulin therapy and now follows allergy and immunology long-term for treatment.

CONCLUSIONS: Her diagnostic history underscores the importance of considering the various criteria of CVID for diagnosis, and her unique presentation of M. pneumoniae skin abscesses highlights the broad sequelae patients with CVID can manifest.

PMID:35382862 | DOI:10.1186/s13223-022-00673-3

BMC Infect Dis. 2022 Apr 5;22(1):338. doi: 10.1186/s12879-022-07179-8.

ABSTRACT

BACKGROUND: To analyse clinical characteristics, antibiotic susceptibility, and risk factors for mortality in paediatric invasive pneumococcal disease (IPD) in Beijing.

METHODS: Paediatric IPD patients in our hospital were retrospectively collected from 2012 to 2017. Clinical manifestations, laboratory tests, antimicrobial susceptibility and serotype of isolates, and risk factors for mortality of IPD were analysed.

RESULTS: Overall, 186 IPD cases were enrolled. The major manifestations were meningitis (76), pneumonia with bacteraemia (60), bacteraemia without focus (21), and pneumonia with empyaema (22). Of 72 cases with underlying diseases, leukaemia (18.0%), congenital heart disease (15.3%), primary immunodeficiency disease (12.5%), nephrotic syndrome (12.5%), and cerebrospinal fluid leakage (12.5%) were most common. In total 96.9% of isolates would have been covered by the pneumococcal conjugate vaccine (PCV13), including 19F (32.8%), 19A (23.4%), 4 (17.2%), and 23F (9.4%). Nonsusceptibility rates of penicillin, cefotaxime, and cefepime among nonmeningitis patients increased between 2012 and 2017; The mortality rate was 21.5%. Meningitis, respiratory failure, multiple organ failure, and white blood cell count < 4000 cells/μL were independent risk factors for mortality.

CONCLUSION: Meningitis was the most common clinical manifestation of IPD, and was frequently associated with death. Strains in the PCV13 vaccine would cover most of the cases, and so wider use of PCV13 should be considered.

PMID:35382757 | DOI:10.1186/s12879-022-07179-8

J Allergy Clin Immunol Pract. 2022 Apr 2:S2213-2198(22)00328-2. doi: 10.1016/j.jaip.2022.03.017. Online ahead of print.

ABSTRACT

BACKGROUND: SARS-CoV-2 infection in patients with predominant antibody deficiency (PAD) is associated with high morbidity, yet data regarding response to SARS-CoV-2 immunization in PAD patients, including additional dose vaccine, is limited.

OBJECTIVE: We sought to characterize antibody response to SARS-CoV-2 vaccine in PAD patients and define correlates of vaccine response.

METHODS: We assessed levels and function of anti-SARS-CoV-2 antibodies in 62 PAD patients compared to matched healthy controls at baseline, at 4-6 weeks following initial series immunization – a single dose of Ad26.COV2.S (Janssen) or two doses of BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) – and at 4-6 weeks following additional dose immunization, if received.

RESULTS: Following initial series SARS-CoV-2 vaccination, PAD patients had lower mean anti-spike antibody levels compared to matched healthy controls (140.1 U/mL vs. 547.3 U/mL; p=0.02). Patients with secondary PAD (e.g., use of B-cell depletion therapy) and patients with severe primary PAD (e.g., common variable immunodeficiency with autoinflammatory complications) had the lowest mean anti-spike antibody levels. Immune correlates of a low anti-spike antibody response included low CD4+ helper T cells, low CD19+ total B cells, and low class-switched memory (CD27+IgD/M-) B cells. Additionally, a low (< 100 U/mL) anti-spike antibody response was associated with prior exposure to B-cell depletion therapy, both at any time in the past (OR 5.5; CI 1.5-20.4; p=0.01) and proximal to vaccination (OR 36.4; CI 1.7-791.9; p=0.02). Additional dose immunization with an mRNA vaccine in a subset of 31 PAD patients increased mean anti-spike antibody levels (76.3 U/mL pre- to 1065 U/mL post-additional dose; p<0.0001).

CONCLUSIONS: Patients with secondary and severe primary PAD, characterized by low helper T cells, low B cells, and/or low class-switched memory B cells, were at risk for low antibody response to SARS-CoV-2 immunization, which improved following additional dose vaccination in the majority of patients.

PMID:35381395 | DOI:10.1016/j.jaip.2022.03.017

BMC Pediatr. 2022 Apr 4;22(1):178. doi: 10.1186/s12887-022-03251-z.

ABSTRACT

BACKGROUND: Hyper IgM syndromes (HIGMS) are a group of rare primary immunodeficiency disorders. There are limited reports about HIGMS combined with severe eosinophilia.

CASE PRESENTATION: In this report, we described a 2-year-old boy with chronic cough and symptoms of hypoxia. Lung computed tomography (CT) scan showed that diffuse ground-glass changes and eosinophils in peripheral blood increased significantly. Subsequent tests revealed a notable decrease in serum IgG and IgA. The lymphocyte subgroup classification was basically normal. Pneumocystis jirovecii were detected from the bronchoalveolar lavage fluid (BALF) of the patient by metagenomic next-generation sequencing (mNGS). After treatments of caspofungin combined with sulfamethoxazole, intravenous immunoglobulin (IVIG) replacement and anti-inflammatory steroid, the clinical symptoms and pulmonary imaging noticeably improved. The absolute eosinophil count (AEC) also returned to normal range. X-linked hyper IgM syndrome was confirmed by gene test. Two months after the diagnosis, the patient underwent allogeneic stem cell transplantation (HSCT) and has recovered well.

CONCLUSIONS: Children with HIGMS are prone to opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP). Diffuse interstitial lung disease and hypoglobulinemia in a young child predict the diagnosis of a primary immunodeficiency (PID). mNGS has obvious advantages for obtaining etiological diagnosis of children with PIDs. Severe eosinophilia is rarely reported in this kind of PIDs. Considering literature review and the corresponding reaction to steroid, we proposed that eosinophilia in HIGMS might be related to infections. Steroid therapy can quickly relieve eosinophilia but is easy to rebound if the reduction is too fast. Once the diagnosis of HIGMS is confirmed, the earlier the HSCT, the better the prognosis.

PMID:35379217 | DOI:10.1186/s12887-022-03251-z

Front Genome Ed. 2022 Mar 17;4:793010. doi: 10.3389/fgeed.2022.793010. eCollection 2022.

ABSTRACT

Defects in the DOCK8 gene causes combined immunodeficiency termed DOCK8 immunodeficiency syndrome (DIDS). DIDS previously belonged to the disease category of autosomal recessive hyper IgE syndrome (AR-HIES) but is now classified as a combined immunodeficiency (CID). This genetic disorder induces early onset of susceptibility to severe recurrent viral and bacterial infections, atopic diseases and malignancy resulting in high morbidity and mortality. This pathological state arises from impairment of actin polymerization and cytoskeletal rearrangement, which induces improper immune cell migration-, survival-, and effector functions. Owing to the severity of the disease, early allogenic hematopoietic stem cell transplantation is recommended even though it is associated with risk of unintended adverse effects, the need for compatible donors, and high expenses. So far, no alternative therapies have been developed, but the monogenic recessive nature of the disease suggests that gene therapy may be applied. The advent of the CRISPR/Cas gene editing system heralds a new era of possibilities in precision gene therapy, and positive results from clinical trials have already suggested that the tool may provide definitive cures for several genetic disorders. Here, we discuss the potential application of different CRISPR/Cas-mediated genetic therapies to correct the DOCK8 gene. Our findings encourage the pursuit of CRISPR/Cas-based gene editing approaches, which may constitute more precise, affordable, and low-risk definitive treatment options for DOCK8 deficiency.

PMID:35373187 | PMC:PMC8969908 | DOI:10.3389/fgeed.2022.793010

Front Immunol. 2022 Mar 18;13:852937. doi: 10.3389/fimmu.2022.852937. eCollection 2022.

NO ABSTRACT

PMID:35371103 | PMC:PMC8971519 | DOI:10.3389/fimmu.2022.852937

J Clin Immunol. 2022 Apr 2. doi: 10.1007/s10875-022-01256-y. Online ahead of print.

ABSTRACT

PURPOSE: CD8 cytotoxic T cells (CTLs) play a critical role in the clearance of virally infected cells. SARS-CoV-2-specific CD8 T cells and functional CTLs in natural infections and following COVID-19 vaccine in primary antibody deficiency (PAD) have not been reported. In this study, we evaluated T cell response following COVID-19 or COVID-19 mRNA vaccination in patients with PADs by assessing SARS-CoV-2 tetramer-positive CD8 T cells and functional CTLs.

METHODS: SARS-CoV-2-specific CD8 and functional CTLs were examined in a patient with X-linked agammaglobulinemia (XLA) and a patient with common variable immunodeficiency (CVID) following COVID-19 infection, and in 5 patients with CVID and 5 healthy controls 1 month following 2nd dose of COVID-19 mRNA vaccine (Pfizer-BioNTech). Cells were stained with SARS-CoV-2 spike protein-specific tetramers, and for functional CTLs (CD8⁺ CD107a⁺ granzyme B⁺ perforin⁺), with monoclonal antibodies and isotype controls and analyzed by flow cytometry.

RESULTS: SARS-CoV-2-specific tetramer + CD8 T cells and functional CTLs in the patient with XLA following COVID-19 infection were higher, as compared to healthy control subject following COVID-19 infection. On the other hand, SARS-CoV2-tetramer + CD8 T cells and functional CTLs were lower in CVID patient following COVID19 infection as compared to healthy control following COVID-19 infection. SARS-CoV2-tetramer + CD8 T cells and functional CTLs were significantly lower in SARS-CoV2-naive CVID patients (n = 10) following vaccination when compared to SARS-CoV-2-naive healthy vaccinated controls (n = 10).

CONCLUSIONS: CVID is associated with reduced SARS-CoV-2-specific CD8 T cells and functional CTLs in both natural SARS-CoV-2 infection and in response to SARS-CoV-2 mRNA vaccine, whereas natural infection in XLA is associated with a robust SARS-CoV-2-specific CD8 and functional CTL responses.

PMID:35366743 | DOI:10.1007/s10875-022-01256-y

Nat Commun. 2022 Apr 1;13(1):1779. doi: 10.1038/s41467-022-29450-x.

ABSTRACT

Common variable immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, displays impaired terminal B-cell differentiation and defective antibody responses. Incomplete genetic penetrance and ample phenotypic expressivity in CVID suggest the participation of additional pathogenic mechanisms. Monozygotic (MZ) twins discordant for CVID are uniquely valuable for studying the contribution of epigenetics to the disease. Here, we generate a single-cell epigenomics and transcriptomics census of naïve-to-memory B cell differentiation in a CVID-discordant MZ twin pair. Our analysis identifies DNA methylation, chromatin accessibility and transcriptional defects in memory B-cells mirroring defective cell-cell communication upon activation. These findings are validated in a cohort of CVID patients and healthy donors. Our findings provide a comprehensive multi-omics map of alterations in naïve-to-memory B-cell transition in CVID and indicate links between the epigenome and immune cell cross-talk. Our resource, publicly available at the Human Cell Atlas, gives insight into future diagnosis and treatments of CVID patients.

PMID:35365635 | DOI:10.1038/s41467-022-29450-x

Front Immunol. 2022 Mar 11;13:857050. doi: 10.3389/fimmu.2022.857050. eCollection 2022.

ABSTRACT

Common variable immunodeficiency (CVID) is the most common symptomatic form of primary immunodeficiency. More than 50% of patients in some series suffer from autoimmune or inflammatory complications (the “CVID+” phenotype), and these are not adequately addressed by current treatments. Despite major advancements in genetics, the pathogenesis of the CVID+ phenotype has remained unexplained for most patients, necessitating the need for relevant biomarkers in both the clinic and research settings. In the clinics, reduced isotype-switched memory B cells (≤ 0.55% of B cells) and reduced T cells (CD4) can be utilized to identify those with increased complication risks. Additionally, condition-specific markers have also been suggested for lymphoma (normal or elevated IgM) and progressive interstitial lung disease (increased BAFF, normal or elevated IgM). Additional biomarkers have provided insights into disease pathogenesis, demonstrating wider systemic inflammation (increased LBP, sCD14, and sCD25; expanded ILC3), mucosal defects (increased zonulin, I-FABP), and perhaps reduced anti-inflammatory capability (reduced HDL) in CVID. Most recently, efforts have revealed elevated circulating bioactive bacterial DNA levels – marking microbial translocation and potentially linking the causation of multiple inflammatory changes previously observed in CVID. The implementation of high throughput profiling techniques may accelerate the search of relevant biomarker profiles in CVID and lead to better clinical risk stratification, revealing disease insights, and identifying potential therapeutic targets.

PMID:35359997 | PMC:PMC8962738 | DOI:10.3389/fimmu.2022.857050