Manish Butte

Expert Rev Clin Immunol. 2022 Oct 5. doi: 10.1080/1744666X.2022.2132938. Online ahead of print.

ABSTRACT

INTRODUCTION: Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency. Due to the wide spectrum of the CVID manifestations, the differential diagnosis becomes complicated, ends in a diagnostic delay and increased morbidity and mortality rates. Autoimmunity is one of the important complications associated with CVID. While immunoglobulin replacement therapy has considerably decreased the mortality rate in CVID patients, mainly infection-related mortality, other complications such as autoimmunity appeared prevalent and, in some cases, life threatening.

AREAS COVERED: In this article, genetics, responsible immune defects, autoimmune manifestations in different organs, and the diagnosis and treatment processes in CVID patients are reviewed, after searching the literature about these topics.

EXPERT OPINION: Considering the many phenotypes of CVID and the fact that it remained undiagnosed until older ages, it is important to include various manifestations of CVID in the differential diagnosis. Due to the different manifestations of CVID, including autoimmune diseases, interdisciplinary collaboration of physicians from different fields is highly recommended, as discussed in the manuscript. Meanwhile, it is important to determine which patients could benefit from genetic diagnostic studies since such studies are not necessary for establishing the diagnosis of CVID.

PMID:36197300 | DOI:10.1080/1744666X.2022.2132938

J Allergy Clin Immunol. 2022 Oct 1:S0091-6749(22)01326-4. doi: 10.1016/j.jaci.2022.09.022. Online ahead of print.

ABSTRACT

Human natural killer (NK) cells are innate lymphoid cells that mediate important effector functions in the control of viral infection and malignancy. Their ability to distinguish ‘self’ from ‘non-self’ and lyse virally infected and tumorigenic cells through germline-encoded receptors makes them important players in maintaining human health and a powerful tool for immunotherapeutic applications and fighting disease. Here, I introduce our current understanding of NK cell biology, including key facets of NK cell differentiation and the acquisition and execution of NK cell effector function. Further, the clinical relevance of NK cells in both primary immunodeficiency and immunotherapy is addressed. Together, this review is intended to provide an up-to-date and comprehensive overview of this important and interesting innate immune effector cell subset.

PMID:36195172 | DOI:10.1016/j.jaci.2022.09.022

Case Rep Pediatr. 2022 Sep 19;2022:7089907. doi: 10.1155/2022/7089907. eCollection 2022.

ABSTRACT

Invasive fungal infection is a major threat to chronic granulomatous disease (CGD) patients. We present a rare case of invasive mycosis in a CGD boy. An 11-year-old preadolescent boy presented with fever, hypoxia, and dyspnea. Physical examination revealed left neck enlarged lymph nodes with healed scars. The chest revealed bilateral diminished air entry with bilateral coarse crackles. Peripheral blood leukocyte count was 28.260/μL with 84% neutrophil, 11% lymphocyte, and 4.4% monocyte. The patient’s condition deteriorated regardless of the empirical antibacterial against MRSA and suspected tuberculosis. A sputum sample was submitted for mycological investigation, and budding yeasts with pseudohyphae were detected in the direct smear and were isolated in pure culture using Sabouraud agar. Candida tropicalis was identified from cultural and microscopic features and confirmed by the Vitek 2 automated system. This result confirmed the invasive mycosis, obviously due to the underlying primary immunodeficiency, chronic granulomatous disease (CGD). Amphotericin was added, and he also received IV methylprednisolone for seven days. The patient improved and was weaned off oxygen with no fever. However, the patient was referred to a higher center for further workup, which confirmed CGD’s diagnosis. He is on the list for HLA-identical bone marrow transplantation (BMT).

PMID:36193209 | PMC:PMC9526550 | DOI:10.1155/2022/7089907

Front Cell Infect Microbiol. 2022 Sep 16;12:947486. doi: 10.3389/fcimb.2022.947486. eCollection 2022.

ABSTRACT

Whipple’s disease is a rare chronic systemic disease that affects almost any organ system of the body caused by the intracellular bacterium Tropheryma whipplei, which is found ubiquitously in the environment. Sequencing of the T. whipplei genome has revealed that it has a reduced genome (0.93 Mbp), a characteristic shared with other intracellular bacteria. Until our research started, 19 T. whipplei strains had been sequenced from cultures originated in France, Canada, and Germany. The genome of T. whipplei bacterium has not been studied in Asia yet. Here, two metagenome-assembled genomes (MAGs) of T. whipplei from China were reconstructed through metagenomic next-generation sequencing (mNGS) and genome binning. We also provided genomic insights into the geographical role and genomic features by analyzing the whole genome. The whole-genome phylogenetic tree was constructed based on single-nucleotide polymorphism (SNP) distance calculations and then grouped by distance similarity. The phylogenetic tree shows inconsistencies with geographic origins, thus suggesting that the variations in geographical origins cannot explain the phylogenetic relationships among the 21 T. whipplei strains. The two Chinese strains were closely related to each other, and also found to be related to strains from Germany (T. whipplei TW08/27) and France (T. whipplei Bcu26 and T. whipplei Neuro1). Furthermore, the Average Nucleotide Identity (ANI) matrix also showed no association between geographic origins and genomic similarities. The pan-genome analysis revealed that T. whipplei has a closed pan-genome composed of big core-genomes and small accessory genomes, like other intracellular bacteria. By examining the genotypes of the sequenced strains, all 21 T. whipplei strains were found to be resistant to fluoroquinolones, due to the genetic mutations in genes gyrA, gyrB, parC, and parE. The 21 T. Whipplei strains shared the same virulence factors, except for the alpC gene, which existed in 7 out of the 21 T. whipplei strains. When comparing 21 entire T. whipplei pan-genomes from various nations, it was discovered that the bacterium also possessed a closed genome, which was a trait shared by intracellular pathogens.

PMID:36189364 | PMC:PMC9523146 | DOI:10.3389/fcimb.2022.947486

World J Clin Pediatr. 2022 Sep 9;11(5):429-436. doi: 10.5409/wjcp.v11.i5.429. eCollection 2022 Sep 9.

ABSTRACT

BACKGROUND: A leukocyte adhesion defect (LAD) is a rare primary immunodeficiency disorder. LAD type 1 (LAD-1) is the most common, which is caused by ITGB2 mutation resulting in dysfunction of β2 integrin, which impairs leukocyte adherence to the endothelium.

CASE SUMMARY: The first two cases of LAD-1 in Thailand presented with recurrent omphalitis, soft tissue infection, marked leukocytosis, and neutrophilia. One patient experienced delayed umbilical cord separation. Mutation analysis was performed by direct DNA sequencing of the ITGB2 gene. The results revealed two novel homozygous missense mutations, c.920C>T (p.Leu307Pro) in exon 8 and c.758G>A (p.Arg253His) in exon 7, and one novel homozygous nonsense mutation, c.262C>T (p.Gln88Ter) in exon 4, in the genomic DNA of the first and second patients, respectively. Heterozygous mutations were identified in the parents of both patients, suggesting a carrier status. The patients were administered intravenous antibiotics for infections with good clinical responses. Hematopoietic stem cell transplantation could not be performed due to the unavailability of matched donors. However, a significant decline in infections was observed after antibiotic prophylaxis. Several follow-up visits were conducted for both patients. They are currently 6 years old.

CONCLUSION: Molecular analysis is essential for definitive diagnosis, early treatment implementation, and prevention of LAD-1 in future pregnancy.

PMID:36185095 | PMC:PMC9516493 | DOI:10.5409/wjcp.v11.i5.429

Clin Immunol. 2022 Sep 29:109135. doi: 10.1016/j.clim.2022.109135. Online ahead of print.

NO ABSTRACT

PMID:36184050 | DOI:10.1016/j.clim.2022.109135

Allergy Asthma Clin Immunol. 2022 Sep 30;18(1):87. doi: 10.1186/s13223-022-00726-7.

ABSTRACT

Immunoglobulin replacement therapy is the standard-of-care treatment for patients with primary immunodeficiency diseases who have impaired antibody production and function. Clinicians and patients may consider intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) options, and each route may offer different benefits for the individual. IVIG requires fewer infusion sites and less frequent infusions than some formulations of SCIG. However, SCIG does not require venous access, is associated with fewer systemic adverse infusion reactions than IVIG, and can independently be self-administered at home. Importantly, tailoring treatment experiences to the needs of the individual may improve treatment adherence and quality of life for patients with primary immunodeficiency diseases who often rely on long-term or lifelong treatment. This review aims to educate United States (US) healthcare providers on the administration process of SCIG, with a focus on more concentrated formulations of SCIG and facilitated SCIG. It provides practical guidance on initiating, optimizing, and monitoring SCIG therapy. The advantages and disadvantages of the different treatment options are also presented for discussion between the patient and clinician.

PMID:36180928 | DOI:10.1186/s13223-022-00726-7

Clin Immunol. 2022 Sep 27:109131. doi: 10.1016/j.clim.2022.109131. Online ahead of print.

ABSTRACT

Monogenic immune dysregulation diseases (MIDD) are caused by defective immunotolerance. This study was designed to increase knowledge on the prevalence and spectrum of MIDDs, genetic patterns, and outcomes in Middle East and North Africa (MENA). MIDD patients from 11 MENA countries (Iran, Turkey, Kuwait, Oman, Algeria, Egypt, United Arab Emirates, Tunisia, Jordan, Qatar, and Azerbaijan) were retrospectively evaluated. 343 MIDD patients (58% males and 42% female) at a median (IQR) age of 101 (42-192) months were enrolled. The most common defective genes were LRBA (23.9%), LYST (8.2%), and RAB27A (7.9%). The most prevalent initial and overall manifestations were infections (32.2% and 75.1%), autoimmunity (18.6% and 41%), and organomegaly (13.3% and 53.8%), respectively. Treatments included immunoglobulin replacement therapy (53%), hematopoietic stem cell transplantation (HSCT) (14.3%), immunosuppressives (36.7%), and surgery (3.5%). Twenty-nine (59.2%) patients survived HSCT. Along with infectious complications, autoimmunity and organomegaly may be the initial or predominant manifestations of MIDD.

PMID:36179983 | DOI:10.1016/j.clim.2022.109131

Front Immunol. 2022 Sep 13;13:930031. doi: 10.3389/fimmu.2022.930031. eCollection 2022.

ABSTRACT

Most non-polio enterovirus infections in immunocompetent individuals are acute and self-limiting in nature; however, infection can be severe, chronic and have devastating outcomes in immunocompromised hosts. Therapeutic strategies have predominantly involved supportive care, with the lack of approved antiviral treatments proving challenging for management. We report a case of an 8-month-old child who presented with severe enterovirus encephalitis following gene therapy for X-linked severe combined immunodeficiency (X-SCID) and who demonstrated clinical and microbiological improvement after a novel regimen of favipiravir, fluoxetine, and high-dose intravenous immunoglobulin (IVIg). The patient presented 6 weeks post-gene therapy with rapid neurological deterioration in the context of incomplete immune reconstitution, with microbiological and radiological evidence confirming enterovirus encephalitis. His neurologic examination stabilised 8 weeks after treatment, and he subsequently demonstrated excellent immune recovery. This is the first case report of combined therapy with favipiravir, fluoxetine, and high-dose IVIg in the context of severe enterovirus encephalitis in an immunocompromised host. This case highlights the importance of considering enterovirus encephalitis in immunocompromised patients presenting with both acute and chronic neurological signs, as well as developmental regression. The demonstrated treatment success and the associated low risk of toxicity warrant further investigation of this therapeutic regimen.

PMID:36177038 | PMC:PMC9513597 | DOI:10.3389/fimmu.2022.930031

Front Immunol. 2022 Sep 13;13:937738. doi: 10.3389/fimmu.2022.937738. eCollection 2022.

ABSTRACT

INTRODUCTION: Multiparameter flow cytometry (FCM) immunophenotyping is an important tool in the diagnostic screening and classification of primary immunodeficiencies (PIDs). The EuroFlow Consortium recently developed the PID Orientation Tube (PIDOT) as a universal screening tool to identify lymphoid-PID in suspicious patients. Although PIDOT can identify different lymphoid-PIDs with high sensitivity, clinical validation in a broad spectrum of patients with suspicion of PID is missing. In this study, we investigated the diagnostic performance of PIDOT, as part of the EuroFlow diagnostic screening algorithm for lymphoid-PID, in a daily practice at a tertiary reference center for PID.

METHODS: PIDOT was tested in 887 consecutive patients suspicious of PID at the Ghent University Hospital, Belgium. Patients were classified into distinct subgroups of lymphoid-PID vs. non-PID disease controls (non-PID DCs), according to the IUIS and ESID criteria. For the clinical validation of PIDOT, comprehensive characterization of the lymphoid defects was performed, together with the identification of the most discriminative cell subsets to distinguish lymphoid-PID from non-PID DCs. Next, a decision-tree algorithm was designed to guide subsequent FCM analyses.

RESULTS: The mean number of lymphoid defects detected by PIDOT in blood was 2.87 times higher in lymphoid-PID patients vs. non-PID DCs (p < 0.001), resulting in an overall sensitivity and specificity of 87% and 62% to detect severe combined immunodeficiency (SCID), combined immunodeficiency with associated or syndromic features (CID), immune dysregulation disorder (ID), and common variable immunodeficiency (CVID). The most discriminative populations were total memory and switched memory B cells, total T cells, TCD4+cells, and naive TCD4+cells, together with serum immunoglobulin levels. Based on these findings, a decision-tree algorithm was designed to guide further FCM analyses, which resulted in an overall sensitivity and specificity for all lymphoid-PIDs of 86% and 82%, respectively.

CONCLUSION: Altogether, our findings confirm that PIDOT is a powerful tool for the diagnostic screening of lymphoid-PID, particularly to discriminate (S)CID, ID, and CVID patients from other patients suspicious of PID. The combination of PIDOT and serum immunoglobulin levels provides an efficient guide for further immunophenotypic FCM analyses, complementary to functional and genetic assays, for accurate PID diagnostics.

PMID:36177024 | PMC:PMC9513319 | DOI:10.3389/fimmu.2022.937738