Manish Butte

Front Immunol. 2022 Jan 3;12:794221. doi: 10.3389/fimmu.2021.794221. eCollection 2021.

ABSTRACT

INTRODUCTION: Severe Combined Immunodeficiency (SCID) is generally fatal if untreated; it predisposes to severe infections, including disseminated Bacille-Calmette-Guerin (BCG) disease from BCG vaccination at birth. However, delaying BCG vaccination can be detrimental to the population in tuberculosis-endemic regions. Early diagnosis of SCID through newborn screening followed by pre-emptive treatment with anti-mycobacterial therapy may be an alternative strategy to delaying routine BCG vaccination. We report the results of the first year of newborn SCID screening in Singapore while continuing routine BCG vaccination at birth.

METHOD: Newborn screening using a T-cell receptor excision circle (TREC) assay was performed in dried blood spots received between 10 October 2019 to 9 October 2020 using the Enlite Neonatal TREC kit. Patients with low TREC had lymphocyte subset analysis and full blood count performed to determine the severity of lymphopenia and likelihood of SCID to guide further management.

RESULTS: Of the 35888 newborns screened in 1 year, no SCID cases were detected, while 13 cases of non-SCID T-cell lymphopenia (TCL) were picked up. Using a threshold for normal TREC to be >18 copies/μL, the retest rate was 0.1% and referral rate to immunologist was 0.04%. Initial low TREC correlated with low absolute lymphocyte counts (ALC), and subsequent normal ALC corresponded with increases in TREC, thus patients with normal first CD3+ T cell counts were considered to have transient idiopathic TCL instead of false positive results. 7/13 (54%) had secondary TCL (from sepsis, Trisomy 21 with hydrops and stoma losses or chylothorax, extreme prematurity, or partial DiGeorge Syndrome) and 6/13 (46%) had idiopathic TCL. No cases of SCID were diagnosed clinically in Singapore during this period and for 10 months after, indicating that no cases were missed by the screening program. 8/9 (89%) of term infants with abnormal TREC results received BCG vaccination within the first 6 days of life when TREC and ALC were low. No patients developed BCG complications after a median follow-up of 17 months.

CONCLUSION: Newborn screening for SCID can be implemented while continuing routine BCG vaccination at birth. Patients with transient TCL and no underlying primary immunodeficiency are able to tolerate BCG vaccination.

PMID:35046952 | PMC:PMC8761728 | DOI:10.3389/fimmu.2021.794221

Clin Shoulder Elb. 2022 Jan 10. doi: 10.5397/cise.2021.00304. Online ahead of print.

ABSTRACT

The incidence of musculoskeletal tuberculosis (TB) is on the rise due to the current Acquired Immunodeficiency Syndrome (AIDS) pandemic. Spine is the most common osseous site, followed by other joints. TB identified in the elbow accounts for 2%-5% of skeletal TB cases, which are secondary to pulmonary TB. Primary elbow TB is rare. We report a case of primary TB of the elbow which had a negative synovial biopsy. A 46-year-old right-hand dominant female patient with chronic pain and disability of the right elbow was diagnosed with chronic non-specific arthritis based on an arthroscopic synovial biopsy. The case was diagnosed retrospectively as active TB from bone cuts post total elbow arthroplasty. Anti-tuberculosis treatment (ATT) was given postoperatively for 12 months. The patient reported good functional outcomes at 3 years of follow-up. Such atypical presentations of osteoarticular TB are challenging to diagnose. Therefore, particularly in endemic areas, clinicians should be careful before excluding such a diagnosis even after a negative biopsy. Further research should investigate whether active TB of small joints such as the elbow can be treated with ATT, and early arthroplasty should be a focus of this research.

PMID:35045599 | DOI:10.5397/cise.2021.00304

Front Pediatr. 2021 Dec 30;9:798959. doi: 10.3389/fped.2021.798959. eCollection 2021.

ABSTRACT

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder characterized by a disruption of the lymphocyte apoptosis pathway, self-tolerance, and immune system homeostasis. Defects in genes within the first apoptosis signal (FAS)-mediated pathway cause an expansion of autoreactive double-negative T cells leading to non-malignant lymphoproliferation, autoimmune disorders, and an increased risk of lymphoma. The aim of the study was to show the diagnostic dilemmas and difficulties in the process of recognizing ALPS in the light of chronic active Epstein-Barr virus (CAEBV) infection. Clinical, immunological, flow cytometric, biomarkers, and molecular genetic approaches of a pediatric patient diagnosed with FAS-ALPS and CAEBV are presented. With the ever-expanding spectrum of molecular pathways associated with autoimmune lymphoproliferative disorders, multiple genetic defects of FAS-mediated apoptosis, primary immunodeficiencies with immune dysregulation, malignant and autoimmune disorders, and infections are included in the differential diagnosis. Further studies are needed to address the issue of the inflammatory and neoplastic role of CAEBV as a triggering and disease-modifying factor in ALPS.

PMID:35036396 | PMC:PMC8757380 | DOI:10.3389/fped.2021.798959

Med J Armed Forces India. 2022 Jan;78(1):99-102. doi: 10.1016/j.mjafi.2018.11.012. Epub 2019 Apr 15.

ABSTRACT

Chronic Granulomatous Disease (CGD) is a primary immunodeficiency disorder (PID) of phagocytic cells resulting in failure to eradicate catalase positive microorganisms like Staphylococci and fungal infections; due to deficiency or malfunction of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase subunits in phagocytic leucocytes. We illustrate here one such case; a six year old girl who was admitted in our hospital with history of prolonged fever, non resolving bilateral otitis media and recurrent pneumonia. She was evaluated for an underlying PID and was found to have CGD based on Nitro blue Tetrazolium (NBT) Slide Test and flow cytometric Dihydrorhodamine (DHR) assay. The child was symptomatic despite initial treatment with first-line followed by second-line antibiotics. During the course of current systemic infection, she also developed infection-associated secondary Hemophagocytic Lympho Histiocytosis (HLH) as suggested by her clinical and laboratory parameters. Despite a thorough search, no microorganism could be isolated and so she was treated with empircal antibiotic therapy comprising of meropenem, linezolid and an antifungal. Fever resolved with gradual improvement of laboratory parameters and finally spontaneous resolution of HLH. We conclude that a high index of suspicion for PID is required in a child with recurrent infections. Identification of underlying infectious agent should be attempted to start targeted antimicrobial therapy; both to prevent as well as cure infection associated secondary HLH.

PMID:35035051 | PMC:PMC8737091 | DOI:10.1016/j.mjafi.2018.11.012

J Allergy Clin Immunol. 2022 Jan 11:S0091-6749(22)00039-2. doi: 10.1016/j.jaci.2021.12.790. Online ahead of print.

ABSTRACT

BACKGROUND: Non-infectious manifestations, i.e. allergy, autoimmunity/inflammation, lymphoproliferation and malignancies are known to be observed in many primary immunodeficiency diseases (PID) and to participate to their prognosis.

OBJECTIVE: In order to have a global view on their occurrence, we retrieved data from a retrospective cohort of 1375 patients included in the French national registry of PID (CEREDIH) for whom we had a 10-year follow-up since inclusion in the registry.

METHODS: These patients were followed for 10 years (2009-2018) by specialized centers in University Hospitals. This study shows that 20.1% of patients without prior curative therapy (n=1163) developed at least one manifestation (event) encompassing 277 events.

RESULTS: Autoimmune/inflammatory events (n=138) and malignancies (n=85) affected all age classes and virtually all PID diagnostic groups. They were associated with a risk of death that occurred in 14.2% of them (n=195), being found as causal in 43% of cases. Malignancies (OR: 5.62 [3.66 – 8.62]) and autoimmunity (OR: 1.9 [1.27 – 2.84]) were clearly identified as risk factors for lethality. Patients who underwent curative therapy (i.e. mostly allogeneic hematopoietic stem cell transplantation, a few cases of gene therapy or thymic transplantation) prior to the 10-year study period (n=212) had comparatively reduced but still detectable clinical manifestations (n=16) leading to death in 9.4% of them.

CONCLUSION: This study points to the frequency and severity of non-infectious manifestations in various PID groups across all age groups. These results warrant further prospective analysis to better assess their consequences and to adapt therapy, notably indication of curative therapy.

PMID:35031273 | DOI:10.1016/j.jaci.2021.12.790

J Clin Immunol. 2022 Jan 14. doi: 10.1007/s10875-021-01176-3. Online ahead of print.

ABSTRACT

NF-κB essential modulator (NEMO, IKK-γ) deficiency is a rare combined immunodeficiency caused by mutations in the IKBKG gene. Conventionally, patients are afflicted with life threatening recurrent microbial infections. Paradoxically, the spectrum of clinical manifestations includes severe inflammatory disorders. The mechanisms leading to autoinflammation in NEMO deficiency are currently unknown. Herein, we sought to investigate the underlying mechanisms of clinical autoinflammatory manifestations in a 12-years old male NEMO deficiency (EDA-ID, OMIM #300,291) patient by comparing the immune profile of the patient before and after hematopoietic stem cell transplantation (HSCT). Response to NF-kB activators were measured by cytokine ELISA. Neutrophil and low-density granulocyte (LDG) populations were analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMC) transcriptome before and after HSCT and transcriptome of sorted normal-density neutrophils and LDGs were determined using the NanoString nCounter gene expression panels. ISG15 expression and protein ISGylation was based on Immunoblotting. Consistent with the immune deficiency, PBMCs of the patient were unresponsive to toll-like and T cell receptor-activators. Paradoxically, LDGs comprised 35% of patient PBMCs and elevated expression of genes such as MMP9, LTF, and LCN2 in the granulocytic lineage, high levels of IP-10 in the patient’s plasma, spontaneous ISG15 expression and protein ISGylation indicative of a spontaneous type I interferon (IFN) signature were observed, all of which normalized after HSCT. Collectively, our results suggest that type I IFN signature observed in the patient, dysregulated LDGs and spontaneously activated neutrophils, potentially contribute to tissue damage in NEMO deficiency.

PMID:35028801 | DOI:10.1007/s10875-021-01176-3

IDCases. 2022 Jan 3;27:e01375. doi: 10.1016/j.idcr.2022.e01375. eCollection 2022.

ABSTRACT

Opportunistic infections are life-threatening conditions in immunocompromised patients including those with primary immunodeficiency. We describe a case of X-linked chronic granulomatous disease presenting with mesenteric abscess caused by a coinfection with Bacillus Calmette-Guérin (BCG) and Phialemonium sp. The patient received BCG vaccination at 5 months old. He developed left axillary BCG lymphadenitis at 17 months of age, and 3 months later mesenteric abscess occurred. Concomitant use of rifampicin and itraconazole at 17 months of age might have reduced serum itraconazole concentrations and led to superinfection with Phialemonium sp. in our patient, which was susceptible to itraconazole and voriconazole in vitro. The patient was successfully treated with a combination of isoniazid, rifampicin, streptomycin, ciprofloxacin, prednisolone, interferon-γ, and an increased dose of itraconazole, followed by hematopoietic stem cell transplantation. Our results suggest that clinician need to be aware of rifampicin drug interactions, and that precise detection and identification of pathogens are essential to appropriate treatment.

PMID:35028293 | PMC:PMC8739448 | DOI:10.1016/j.idcr.2022.e01375

Turk J Pediatr. 2021;63(6):1072-1077. doi: 10.24953/turkjped.2021.06.016.

ABSTRACT

BACKGROUND: Dedicator of cytokinesis 2 (DOCK2) deficiency is a rare autosomal recessive combined immunodeficiency presenting with very early onset, severe bacterial and viral infections. In DOCK2 deficiency; T, B and NK cell numbers are decreased and functions are impaired resulting in severe atrophy of secondary lymphoid tissues. The aim of this report is to provide information on clinical and laboratory features and hematopoietic stem cell transplantation (HSCT) outcomes of a DOCK2 deficient patient. The patient was diagnosed by using a targeted next generation sequencing primary immunodeficiency (PID) panel. Lymphocyte subsets were measured by flow-cytometry.

CASE: Here, we describe a patient with DOCK2 deficiency presented with severe combined immunodeficiency. He underwent HSCT without conditioning regimen before the genetic diagnosis and developed hemophagocytic lymphohistiocytosis(HLH) due to Epstein-Barr virus (EBV) infection.

CONCLUSIONS: Genetic testing is necessery for early diagnosis of DOCK2 deficiency. The curative treatment should be HSCT soon after diagnosis.

PMID:35023658 | DOI:10.24953/turkjped.2021.06.016

Clin Exp Immunol. 2022 Jan 10:uxac001. doi: 10.1093/cei/uxac001. Online ahead of print.

ABSTRACT

Understanding the T cell response to SARS-CoV-2 is key in patients who lack antibody production. We demonstrate the applicability of a functional assay to measure the T cell response in a cohort of patients with immunodeficiency.

PMID:35020892 | DOI:10.1093/cei/uxac001

Clin Exp Immunol. 2021 Dec 21:uxab034. doi: 10.1093/cei/uxab034. Online ahead of print.

ABSTRACT

Primary immunodeficiency disorders comprise a rare group of mostly monogenic disorders caused by inborn errors of immunity. The majority can be identified by either Sanger sequencing or Next Generation Sequencing. Some disorders result from large insertions or deletions leading to copy number variations (CNV). Sanger sequencing may not identify these mutations. Here we present droplet digital PCR as an alternative cost-effective diagnostic method to identify CNV in these genes. The data from patients with large deletions of NFKB1, SERPING1 and SH2D1A are presented.

PMID:35020846 | DOI:10.1093/cei/uxab034