Manish Butte

Hum Immunol. 2022 Jan 21:S0198-8859(22)00005-2. doi: 10.1016/j.humimm.2022.01.003. Online ahead of print.

ABSTRACT

X-linked agammaglobulinemia (XLA) is an X-linked recessive primary immunodeficiency disorder caused due to a pathogenic variant in the Bruton tyrosine (BTK) gene with an incidence of 1:379,000 live births and 1:190,000 male births. Patients affected with XLA present with recurrent infections of the gastrointestinal and respiratory tracts. Here we report the first case series of 17 XLA patients of 10 South Indian families with a wide spectrum of clinical and genetic features. In our cohort, patients presented mainly with recurrent pneumonia, gastrointestinal infection, otitis media, pyoderma, abscesses, empyema, arthritis, and osteomyelitis. Using next-generation and Sanger sequencing we have identified 10 unique pathogenic and likely pathogenic variants in 17 patients. This encompasses three nonsynonymous, two stop-gain, two frameshifts, two structural, and one splicing variant, out of which two of them are novel. Based on the type of variant, patients had variable clinical features and treatment responses. We have also evaluated Btk protein expression for six patients in comparison to the healthy individuals and determined mosaic Btk expression patterns in four mothers. We have also performed family screening in 6 families using Sanger sequencing and identified 19 carriers for the variant. The diagnosis for the patients led to the proper treatment i.e. 15 patients were on intravenous immunoglobulin (IVIG) and the other two had successful hematopoietic stem cell transplantation (HSCT). Unfortunately, two of our patients died due to sepsis, while on IVIG. We envision the present study could help in better understanding of patients with XLA and help in family screening and prenatal diagnosis. To the best of our knowledge, this is the largest case series of patients affected with XLA from South India.

PMID:35074268 | DOI:10.1016/j.humimm.2022.01.003

Front Cell Infect Microbiol. 2022 Jan 7;11:790488. doi: 10.3389/fcimb.2021.790488. eCollection 2021.

ABSTRACT

Disseminated coccidioidomycosis (DCM), often a severe and refractory disease leading to poor outcomes, is a risk for people with certain primary immunodeficiencies (PID). Several DCM-associated PID (STAT4, STAT3, IFNγ, and Dectin-1) are modeled in mice. To determine if vaccination could provide these mice protection, mice with mutations in Stat4, Stat3, Ifngr1, Clec7a (Dectin-1), and Rag-1 (T- and B-cell deficient) knockout (KO) mice were vaccinated with the live, avirulent, Δcps1 vaccine strain and subsequently challenged intranasally with pathogenic Coccidioides posadasii Silveira strain. Two weeks post-infection, vaccinated mice of all strains except Rag-1 KO had significantly reduced lung and spleen fungal burdens (p<0.05) compared to unvaccinated control mice. Splenic dissemination was prevented in most vaccinated immunodeficient mice while all unvaccinated B6 mice and the Rag-1 KO mice displayed disseminated disease. The mitigation of DCM by Δcps1 vaccination in these mice suggests that it could also benefit humans with immunogenetic risks of severe disease.

PMID:35071044 | PMC:PMC8777018 | DOI:10.3389/fcimb.2021.790488

Gland Surg. 2021 Dec;10(12):3334-3341. doi: 10.21037/gs-21-745.

ABSTRACT

BACKGROUND: Breast cancer (BC) is the most common form of cancer in women. BC brain metastasis (BM) is associated with poor prognosis, especially for Triple negative breast cancer (TNBC). However, the driver genes of this clinical characteristic are poorly understood.

METHODS: This study conducted a transcriptome-wide analysis of gene expression levels in BCBM samples from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets. Clinical data and gene expression matrix of TNBC samples were collected. Differential analysis and functional enrichment of metastasis vs. non metastasis data samples were conducted. Genes associated with overall survival and BM event was scanned.

RESULTS: Up-regulation in 120 genes and down-regulation in 56 genes were found in TNBC metastasis data. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) clustering using expression alternated genes showed unique immune-gene enrichment in BM samples. Immune response category GO:000695 was found as the most significant term associated with metastasis event. KEGG pathways including cytokine pathways and Primary immunodeficiency were significantly changed in metastasis samples. ESR1 and FYB2 genes expression changes were found to be linked to survival or BM events.

CONCLUSIONS: Our results suggest that data-mining on the immune microenvironment of BM might be useful in future study.

PMID:35070893 | PMC:PMC8749083 | DOI:10.21037/gs-21-745

Front Immunol. 2022 Jan 6;12:726406. doi: 10.3389/fimmu.2021.726406. eCollection 2021.

ABSTRACT

X-linked moesin associated immunodeficiency (X-MAID) is a primary immunodeficiency disease in which patients suffer from profound lymphopenia leading to recurrent infections. The disease is caused by a single point mutation leading to a R171W amino acid change in the protein moesin (moesin^R171W). Moesin is a member of the ERM family of proteins, which reversibly link the cortical actin cytoskeleton to the plasma membrane. Here, we describe a novel mouse model with global expression of moesin^R171W that recapitulates multiple facets of patient disease, including severe lymphopenia. Further analysis reveals that these mice have diminished numbers of thymocytes and bone marrow precursors. X-MAID mice also exhibit systemic inflammation that is ameliorated by elimination of mature lymphocytes through breeding to a Rag1-deficient background. The few T cells in the periphery of X-MAID mice are highly activated and have mostly lost moesin^R171W expression. In contrast, single-positive (SP) thymocytes do not appear activated and retain high expression levels of moesin^R171W. Analysis of ex vivo CD4 SP thymocytes reveals defects in chemotactic responses and reduced migration on integrin ligands. While chemokine signaling appears intact, CD4 SP thymocytes from X-MAID mice are unable to polarize and rearrange cytoskeletal elements. This mouse model will be a valuable tool for teasing apart the complexity of the immunodeficiency caused by moesin^R171W, and will provide new insights into how the actin cortex regulates lymphocyte function.

PMID:35069520 | PMC:PMC8770857 | DOI:10.3389/fimmu.2021.726406

Clin Immunol. 2022 Jan 19:108932. doi: 10.1016/j.clim.2022.108932. Online ahead of print.

ABSTRACT

A patient presented severe combined immunodeficiency (SCID)-like symptoms. The presence of a substantial number of CD4⁺ T-cells in the peripheral blood was not explained by maternal engraftment. Genetic analysis revealed a novel RFXANK mutation, c.232C > T, resulting in a stop codon, with consequently defective transcription of MHC class II resulting in bare lymphocyte syndrome (BLS) type II. The initial unawareness of complete absence of MHC class II expression and normal T-cell receptor excision circles (TREC)-levels delayed the final diagnosis. After identification of the genetic defect the patient was scheduled for hematopoietic stem cell transplantation (HSCT). Here, we present and discuss the diagnostic and therapeutic approach of a novel case of BLS type II in relation to T-cell development.

PMID:35065305 | DOI:10.1016/j.clim.2022.108932

Clin Immunol. 2022 Jan 18:108931. doi: 10.1016/j.clim.2022.108931. Online ahead of print.

ABSTRACT

Accurate and timely diagnosis of primary immunodeficiencies (PID) is an ongoing effort. Individuals with PID can be severely impacted by their disease and many experience chronic complications, treatment burden, and reduced quality of life (QoL). This review focuses on the impact of delayed diagnosis and treatment burden on patient QoL and outcomes. Adults tend to experience longer delays in diagnosis than pediatric populations. The median diagnostic delay has reduced over recent decades, but remains high for some antibody deficiency variants, such as common variable immunodeficiency. The largest burden impacting QoL tends to be poorly controlled disease and persistent chronic conditions rather than treatment burden. Hospitalization, physician/emergency room visits, and bronchiectasis were the most expensive PID complications prior to diagnosis and cost analyses estimate cost reductions once appropriate treatment is initiated. A combination of poor awareness, lack of infrastructure, and resources supporting national registries play a major role in delayed diagnosis.

PMID:35063670 | DOI:10.1016/j.clim.2022.108931

Med Oncol. 2022 Jan 20;39(3):33. doi: 10.1007/s12032-021-01623-6.

ABSTRACT

Keynote-826 study demonstrated that the addition of pembrolizumab to standard systemic therapy contributes to progression-free and overall survival in patients with persistent, recurrent, or metastatic cervical cancer receiving chemotherapy with or without bevacizumab. However, we do have some comments about the study. The lack of additional survival benefit of pembrolizumab in patients with de novo metastatic disease or in elderly patients or in patients with combined positive score (CPS) < 1 may be due to the absence of abscopal immune effects of radiotherapy or primary resistance (immunodeficiency or immune escape or immunosenescence) to adaptive immunotherapy. We believe that new studies are needed to add pembrolizumab particularly in the treatment of the patients with de novo metastatic disease, PD-L1 CPS of < 1%, and advanced cervical cancer in geriatric population.

PMID:35059847 | DOI:10.1007/s12032-021-01623-6

BMC Infect Dis. 2022 Jan 20;22(1):69. doi: 10.1186/s12879-021-06968-x.

ABSTRACT

BACKGROUND: Chronic granulomatous disease (CGD) is a rare inherited primary immunodeficiency syndrome, manifested as recurrent infections and inflammatory complications. Although prophylactic treatment with antibiotics and antifungals improved the outcome of CGD patients, infections remain the major cause of mortality.

CASE PRESENTATION: A boy aged 3 years and 8 months was admitted to hospital complaining of lip swelling with fever for half a month and neck abscess for 11 days. After a thorough examination, severe pneumonia, respiratory failure, oral and maxillofacial space infection, and perianal abscess were confirmed. However, his condition didn’t improve after initial comprehensive therapy. Subsequently, overlapping infections of Nocardia farcinica and Aspergillus fumigatus were identified by metagenomic next-generation sequencing. He was treated with imipenem, linezolid, and voriconazole intravenously, plus taking oral compound sulfamethoxazole. Later, his condition improved. Through whole-exome sequencing, the child was ultimately diagnosed as X-linked chronic granulomatous disease (X-CGD) caused by CYBB gene mutation. Allogeneic hematopoietic stem cell transplantation was the potential sanative approach but there were no available human leukocyte antigen compatible donors for the child. The family requested to transfer to a superior hospital for further treatment. Two months later, we followed up the child’s family. Unfortunately, the child had expired due to severe infection.

CONCLUSION: To our knowledge, this is the first case of overlapping infection of Nocardia farcinica and Aspergillus fumigatus identified by metagenomic next-generation sequencing in a child with X-CGD from China. For infectious pathogens that are hard to diagnosis by traditional detection methods, metagenomic next-generation sequencing is recommended as an adminicle or indispensable approach for microbial identification. Patients with X-CGD have poor prognosis, early diagnosis and intervention of X-CGD may reduce the mortality.

PMID:35057749 | DOI:10.1186/s12879-021-06968-x

Intern Med J. 2022 Jan 20. doi: 10.1111/imj.15694. Online ahead of print.

ABSTRACT

BACKGROUND: Immunoglobulin is an expensive and scarce resource and usage is increasing worldwide. Immunoglobulin is used to treat a variety of clinical conditions, particularly primary and acquired immunodeficiencies and immune mediated neurological disorders. As immunoglobulin usage continues to increase, plasma collection must increase accordingly in order to sustain immunoglobulin production. The New Zealand Blood Service (NZBS) is the provider of immunoglobulin in New Zealand (NZ). Information regarding national immunoglobulin usage warrants analysis given the rise in usage.

AIMS: We set out to review immunoglobulin usage in NZ with a focus on the trend in the amount used, number of patients, clinical indications and compliance with international guidelines. A comparison with international immunoglobulin usage was performed. The impact on national plasma collection was reviewed.

METHODS: Data on immunoglobulin usage, number of patients, and plasma collection over the past decade was obtained from the NZBS Tableau database. Data from international literature was reviewed.

RESULTS: Immunoglobulin usage in NZ has been increasing over the past decade, with an annual growth rate of 6.4%. The three main indications for immunoglobulin are primary immunodeficiency disorders, chronic inflammatory demyelinating polyneuropathy (CIDP), and acquired hypogammaglobulinaemia secondary to haematological malignancies. Prominent growth in usage is evident for CIDP and acquired hypogammaglobulinaemia. Immunoglobulin usage in NZ is low compared other countries such as Australia and the United States. There has been a marked increase in plasma donations in order to keep up with immunoglobulin demand.

CONCLUSIONS: Immunoglobulin is a strategic resource and appropriate usage is critical to regulate demand. This article is protected by copyright. All rights reserved.

PMID:35049107 | DOI:10.1111/imj.15694

Int J Rheum Dis. 2022 Jan 20. doi: 10.1111/1756-185X.14289. Online ahead of print.

ABSTRACT

Polyautoimmunity or multiple autoimmune syndrome (MAIS) is increasingly being recognized in pediatric clinical practice, often in conjunction with systemic lupus erythematosus (SLE). Besides multi-organ autoimmunity, children with SLE are often at a higher risk of developing infections including tuberculosis. The tendency to develop infections and multiple autoimmune diseases in childhood SLE often occurs in the absence of monogenic primary immunodeficiency disease. Conversely, children with inborn errors of immunity, of which selective IgA deficiency (sIgAD) is the most common, may develop recurrent infections and autoimmune disorders including SLE. Herein, we report a child with MAIS (including SLE) and sIgAD who developed drug-resistant tuberculosis, which was managed successfully with second-line anti-tubercular drug therapy. To the best of our knowledge, this combination of rare findings has not been reported previously in the pediatric literature. Although a majority of patients with sIgAD are either asymptomatic or have mild infections/autoimmunity, the index child had a myriad of infectious illnesses and multi-organ autoimmunity. Our case highlights the prudence of thoroughly evaluating children with SLE for other autoimmune diseases and vice versa. Given the higher probability of inherited disorders, including early complement deficiencies and monogenic interferonopathies, in childhood SLE compared with adult SLE, it may be prudent to perform a basic immunological workup (for example, immunoglobulin levels, 50% hemolytic complement) in such patients. A more extensive immunological and genetic evaluation (including next-generation sequencing) may also be required in the presence of unusual clinical or laboratory features, a positive family history, or a complicated clinical course.

PMID:35048520 | DOI:10.1111/1756-185X.14289