Research

Rev Chilena Infectol. 2021 Aug;38(4):574-579. doi: 10.4067/S0716-10182021000400574.

ABSTRACT

Chronic granulomatous disease (CGD) is a rare primary immuno-deficiency. It is characterized by an alteration in the function of phagocytes causing recurrent bacterial and fungal infections. This is a case report of a child with multifocal osteomyelitis by Serratia marcescens, an infrequent as a cause of bone infections, although associated with CGD. The study of infections with clinical presentation and unusual agents should lead to suspicion of CGD. The diagnosis early in life, as well as timely antimicrobial treatment and the subsequent antimicrobial prophylaxis will avoid infectious recurrences and sequelae.

PMID:34652406 | DOI:10.4067/S0716-10182021000400574

J Clin Immunol. 2021 Oct 14. doi: 10.1007/s10875-021-01148-7. Online ahead of print.

ABSTRACT

BACKGROUND: Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder of phagocytes due to defects in any of the five subunits of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. An initial diagnosis of CGD is made by flow cytometry-based dihydrorhodamine assay or nitro blue tetrazolium test, which is further confirmed by molecular assays. Expression of five subunits of NADPH oxidase components by either flow cytometric or western blot analysis provides clues toward the potential gene targets which are subsequently confirmed by various genetic assays. Immunohistochemistry (IHC) and immunofluorescence (IF) have never been earlier used to determine the expression of different subunits of NADPH oxidase system. We evaluated the utility of IHC and IF in determining the underlying pathogenic variants of CGD.

MATERIALS AND METHODS: Twelve genetically confirmed cases of CGD, comprising of biopsy specimens (n = 6), tissue blocks from autopsy cases (n = 3), and cellblocks of cell pellet prepared from peripheral blood (n = 4) were included. IHC for p67phox and p47phox subunits and IF for cytochrome b558 were performed.

RESULTS: All 4 cases with pathogenic variation of NCF2 gene showed loss of expression for p67phox subunit. Two cases with pathogenic variation of NCF1 gene showed loss of expression for p47phox subunit. Five cases, except a single case with CYBB gene pathogenic variation, showed loss of expression for cytochrome b558 on IF. Thus, loss of expression consistently matched with the underlying genetic defects assessed by sequencing.

CONCLUSIONS: Our results confirm our hypothesis that IHC and IF are two rapid, economical, pathologist-friendly techniques providing pertinent information regarding the underlying pathogenic variants and such immuno-analysis can be easily performed on the tissue.

PMID:34651207 | DOI:10.1007/s10875-021-01148-7

Neurooncol Adv. 2021 Sep 20;3(1):vdab140. doi: 10.1093/noajnl/vdab140. eCollection 2021 Jan-Dec.

ABSTRACT

BACKGROUND: Pharmaceutical intervention in the CNS is hampered by the shielding function of the blood-brain barrier (BBB). To induce clinical anesthesia, general anesthetics such as isoflurane readily penetrate the BBB. Here, we investigated whether isoflurane can be utilized for therapeutic drug delivery.

METHODS: Barrier function in primary endothelial cells was evaluated by transepithelial/transendothelial electrical resistance, and nanoscale STED and SRRF microscopy. In mice, BBB permeability was quantified by extravasation of several fluorescent tracers. Mouse models including the GL261 glioma model were evaluated by MRI, immunohistochemistry, electron microscopy, western blot, and expression analysis.

RESULTS: Isoflurane enhances BBB permeability in a time- and concentration-dependent manner. We demonstrate that, mechanistically, isoflurane disturbs the organization of membrane lipid nanodomains and triggers caveolar transport in brain endothelial cells. BBB tightness re-establishes directly after termination of anesthesia, providing a defined window for drug delivery. In a therapeutic glioblastoma trial in mice, simultaneous exposure to isoflurane and cytotoxic agent improves efficacy of chemotherapy.

CONCLUSIONS: Combination therapy, involving isoflurane-mediated BBB permeation with drug administration has far-reaching therapeutic implications for CNS malignancies.

PMID:34647026 | PMC:PMC8500692 | DOI:10.1093/noajnl/vdab140

Oral Surg Oral Med Oral Pathol Oral Radiol. 2021 Sep 13:S2212-4403(21)00611-8. doi: 10.1016/j.oooo.2021.09.004. Online ahead of print.

ABSTRACT

Lymphoproliferative disorders (LPDs) are a group of conditions characterized by excessive production of lymphocytes manifested in various patterns including lymphadenopathy, tumor-like lesions, and lymphomas. LPD may be stimulated by Epstein-Barr virus (EBV) infection that most commonly appears in the setting of immunocompromised status such as long-term use of immunosuppressive medications and in individuals with primary immunodeficiency disorders. EBV mucocutaneous ulcer is a benign LPD reaction that mostly regresses spontaneously but sometimes requires medical or surgical intervention. This article presents a case of oral EBV mucocutaneous ulceration that affected an individual with a history of complex primary immunodeficiency disorders consisted of common variable immunodeficiency disease associated with T-cell dysfunction. This case is unique because the oral lesions led to the diagnosis of concurrent widespread EBV-negative follicular lymphomas, seemingly unrelated to her EBV-positive LPD oral disease. Yet, both occurred in the setting of severe immunosuppression from the primary immunodeficiency disorders.

PMID:34645592 | DOI:10.1016/j.oooo.2021.09.004

Allergy Asthma Clin Immunol. 2021 Oct 11;17(1):107. doi: 10.1186/s13223-021-00605-7.

ABSTRACT

BACKGROUND: Severe combined immunodeficiency (SCID) is a group of relatively rare primary immunodeficiency disorders (PIDs), characterized by disturbed development of T cells and B cells, caused by several genetic mutations that bring on different clinical presentations. SCID may be inherited as an autosomal recessive or an X-linked genetic trait.

CASE PRESENTATION: A 6-year-old male presented with a history of food allergy, productive coughs, and recurrent purulent rhinitis, poor weight gain and hypothyroidism. The total count of CD4+ T lymphocytes, along with their naïve and central memory subpopulations, as well as central memory CD8+ T cells were decreased in flow cytometry. A nucleotide substitution in exon one of interleukin 2 receptor gamma chain (IL-2RG) gene (c.115 G>A, p.D39N, ChrX: 70,331,275) was reported, based on which the diagnosis of X-liked SCID was confirmed. Antiviral and antibiotic prophylaxis, along with monthly IVIG (intravenous immunoglobulin) was started and the patient was subsequently referred for hematopoietic stem cell transplantation.

CONCLUSION: PIDs should be considered as the differential diagnosis in any patient with unexplained and bizarre symptoms associated with recurrent infections, allergic and autoimmune manifestations. Clinicians should also bear X-SCID in mind in case of approach to any patient with poor weight gain, unusual allergic or endocrine manifestations, even in the case of a normal or increased level of serum immunoglobulins or T and B cells numbers.

PMID:34635152 | DOI:10.1186/s13223-021-00605-7

Front Immunol. 2021 Sep 24;12:695993. doi: 10.3389/fimmu.2021.695993. eCollection 2021.

ABSTRACT

DNA ligase IV (LIG4) deficiency is an extremely rare autosomal recessive primary immunodeficiency disease caused by mutations in LIG4. Patients suffer from a broad spectrum of clinical problems, including microcephaly, growth retardation, developmental delay, dysmorphic facial features, combined immunodeficiency, and a predisposition to autoimmune diseases and malignancy. In this study, the clinical, molecular, and immunological characteristics of 15 Chinese patients with LIG4 deficiency are summarized in detail. p.R278L (c.833G>T) is a unique mutation site present in the majority of Chinese cases. We conducted pedigree and haplotype analyses to examine the founder effect of this mutation site in China. This suggests that implementation of protocols for genetic diagnosis and for genetic counseling of affected pedigrees is essential. Also, the search might help determine the migration pathways of populations with Asian ancestry.

PMID:34630384 | PMC:PMC8498043 | DOI:10.3389/fimmu.2021.695993

J Clin Immunol. 2021 Oct 10. doi: 10.1007/s10875-021-01147-8. Online ahead of print.

ABSTRACT

BACKGROUND: Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder caused by mutations in the ataxia telangiectasia mutated (ATM) gene. A-T patients manifest considerable variability in clinical and immunological features, suggesting the presence of genetic modifying factors. A striking heterogeneity has been observed in class switching recombination (CSR) in A-T patients which cannot be explained by the severity of ATM mutations.

METHODS: To investigate the cause of variable CSR in A-T patients, we applied whole-exome sequencing (WES) in 20 A-T patients consisting of 10 cases with CSR defect (CSR-D) and 10 controls with normal CSR (CSR-N). Comparative analyses on modifier variants found in the exomes of these two groups of patients were performed.

RESULTS: For the first time, we identified some variants in the exomes of the CSR-D group that were significantly associated with antigen processing and presentation pathway. Moreover, in this group of patients, the variants in four genes involved in DNA double-strand breaks (DSB) repair signaling, in particular, XRCC3 were observed, suggesting an association with CSR defect.

CONCLUSION: Additional impact of certain variants, along with ATM mutations, may explain the heterogeneity in CSR defect phenotype among A-T patients. It can be concluded that genetic modulators play an important role in the course of A-T disease and its clinical severity.

PMID:34628594 | DOI:10.1007/s10875-021-01147-8

Ann Allergy Asthma Immunol. 2021 Oct 7:S1081-1206(21)01131-5. doi: 10.1016/j.anai.2021.10.001. Online ahead of print.

ABSTRACT

OBJECTIVE: Inborn errors of immunity (IEI) are rare genetic conditions affecting the immune system. The rate of IEI’s, their presentation, course and treatment, are all affected by a multitude of social determinants, eventually affecting prognosis. This review summarizes the current knowledge of the social determinants affecting infectious susceptibility, genetic predisposition, diagnosis and treatment of IEI.

DATA SOURCES: Pubmed.

STUDY SELECTIONS: search terms included “consanguinity” “social determinants” and “founder effect”. Further studies were selected based on relevant citations.

RESULTS: Changes in climate and human behavior have modulated the spread of disease vectors and infectious organisms. Consanguinity increases the rate of autosomal recessive conditions, changes the distribution and affects the severity of IEI. Access to sophisticated genetic and immunologic diagnostic modalities affects genetic counseling and timely diagnosis. Effective genetic counselling should address to the patient’s genetic background and ethical code. Access to appropriate and timely treatment of immunodeficiencies is scarce in some regions of the world.

CONCLUSION: High consanguinity rate and reduced access to prophylactic measures increase the burden of immunodeficiencies in many low- and medium-income countries. Poor access to diagnostic and treatment modalities in these regions further adversely affect patients’ prognosis. Increased awareness among healthcare professionals and the public, and increased collaboration with Western countries aid in diagnosis of these conditions. Further advancements require improved public funding to the prevention, diagnosis and treatment of IEI.

PMID:34628007 | DOI:10.1016/j.anai.2021.10.001

Infect Dis Ther. 2021 Oct 8. doi: 10.1007/s40121-021-00528-1. Online ahead of print.

ABSTRACT

INTRODUCTION: Histopathological characteristics of cytomegalovirus (CMV) lymphadenitis have been well described. Rare studies have reported the immune status and clinical features. Clinically, experts believed that CMV lymphadenitis develops in immunocompromised and immunocompetent patients. Infectious mononucleosis (IM)-like syndrome is the most well-known clinical presentation.

METHODS: We reviewed archived CMV immunohistochemical stains on lymphoid tissues. The clinicopathological features of CMV-positive cases were studied.

RESULTS: For lymph nodes, we detected CMV in 29% (5/17) allogeneic peripheral blood hematopoietic stem cell transplantation (PBSCT) recipients, 29% (4/14) post-autologous PBSCT patients, 13% (6/47) patients treated with intravenous chemotherapy, and 9% (9/96) immunocompetent patients. We detected CMV in 7% (2/24) of tonsils but not in the nasopharynx, tongue base, or spleen specimens. The patients with iatrogenic immunodeficiency ranged from 37 to 76 years old. CMV infections developed a few years after lymphoma treatment (median duration after allogeneic PBSCT, 932 days; after autologous PBSCT, 370 days; and after chemotherapy, 626 days). The most common clinical presentation was neck mass (13/25, 42%), followed by asymptomatic image finding (10/25, 40%). Positron emission tomography/computed tomography (PET/CT) scan showed increased uptake compared to the liver in all patients (11/11, 100%). Of 10 lymphoma patients, 8 (80%) had a Deauville score of 4-5; they accounted for 30% (8/27) of lymphoma patients with false-positive PET/CT scan results. All cases were self-limiting. 96% (23/25) cases had Epstein-Barr virus coinfection, and EBER-positive cells were predominantly in a few germinal centers.

CONCLUSIONS: Cytomegalovirus (CMV) lymphadenitis and tonsillitis were subclinical infections, not primary CMV infection with IM-like syndrome. The lymphadenopathy typically developed a few years after lymphoma treatments in the middle-aged and the elderly. The lesions mimicked lymphoma relapse in PET scans. Therefore, recognizing CMV infection in lymphoid tissues is of clinical importance.

PMID:34623624 | DOI:10.1007/s40121-021-00528-1

Sci Immunol. 2021 Oct 15;6(64):eabh0891. doi: 10.1126/sciimmunol.abh0891. Epub 2021 Oct 8.

ABSTRACT

[Figure: see text].

PMID:34623902 | DOI:10.1126/sciimmunol.abh0891