Manish Butte

Acetaminophen inhibits the neutrophil oxidative burst: implications for diagnostic testing.

J Allergy Clin Immunol Pract. 2020 Jul 21;:

Authors: Almutairi A, Zaman F, Day-Lewis M, Tsitsikov E, Reiter A, Xue K, Geha RS, Chou J, Yee CSK

Abstract
BACKGROUND: Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by recurrent bacterial and fungal infections, granuloma formation, and inflammatory disease. Impaired neutrophil oxidative function is an essential diagnostic criterion. In vitro exposure of neutrophils to acetaminophen, a commonly used over the counter medication, has been associated with reduced neutrophil oxidative function. The clinical implications of acetaminophen intake for DHR testing remain unknown.
OBJECTIVE: To evaluate the effect of in vivo administration of therapeutic doses of acetaminophen upon DHR diagnostic testing.
METHODS: We performed DHR testing in 15 healthy adults before and after administering a single dose of acetaminophen. We retrospectively reviewed 195 DHR test results from hospitalized patients who had received acetaminophen, NSAID, or corticosteroid before testing.
RESULTS: DHR testing was abnormal in 100% (n=15) of healthy adults two hours after acetaminophen intake. We identified 195 instances of DHR testing ≤72 hours after acetaminophen ingestion in hospitalized patients who did not have CGD. DHR results were abnormal in 43/195 cases (22.1%). Frequency of false positive testing was increased in patients who received acetaminophen within 24 hours of testing, and in patients who received >1 dose of acetaminophen. NSAID and corticosteroid intake were not associated with abnormal DHR.
CONCLUSION: Patients treated with acetaminophen have decreased neutrophil oxidative burst as measured by DHR testing. To avoid falsely abnormal testing for CGD, patients should be advised to avoid acetaminophen for at least 24 hours prior to DHR testing.

PMID: 32707237 [PubMed – as supplied by publisher]

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Presence of Genetic Variants Among Young Men With Severe COVID-19.

JAMA. 2020 Jul 24;:

Authors: van der Made CI, Simons A, Schuurs-Hoeijmakers J, van den Heuvel G, Mantere T, Kersten S, van Deuren RC, Steehouwer M, van Reijmersdal SV, Jaeger M, Hofste T, Astuti G, Corominas Galbany J, van der Schoot V, van der Hoeven H, Hagmolen Of Ten Have W, Klijn E, van den Meer C, Fiddelaers J, de Mast Q, Bleeker-Rovers CP, Joosten LAB, Yntema HG, Gilissen C, Nelen M, van der Meer JWM, Brunner HG, Netea MG, van de Veerdonk FL, Hoischen A

Abstract
Importance: Severe coronavirus disease 2019 (COVID-19) can occur in younger, predominantly male, patients without preexisting medical conditions. Some individuals may have primary immunodeficiencies that predispose to severe infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Objective: To explore the presence of genetic variants associated with primary immunodeficiencies among young patients with COVID-19.
Design, Setting, and Participants: Case series of pairs of brothers without medical history meeting the selection criteria of young (age <35 years) brother pairs admitted to the intensive care unit (ICU) due to severe COVID-19. Four men from 2 unrelated families were admitted to the ICUs of 4 hospitals in the Netherlands between March 23 and April 12, 2020. The final date of follow-up was May 16, 2020. Available family members were included for genetic variant segregation analysis and as controls for functional experiments.
Exposure: Severe COVID-19.
Main Outcome and Measures: Results of rapid clinical whole-exome sequencing, performed to identify a potential monogenic cause. Subsequently, basic genetic and immunological tests were performed in primary immune cells isolated from the patients and family members to characterize any immune defects.
Results: The 4 male patients had a mean age of 26 years (range, 21-32), with no history of major chronic disease. They were previously well before developing respiratory insufficiency due to severe COVID-19, requiring mechanical ventilation in the ICU. The mean duration of ventilatory support was 10 days (range, 9-11); the mean duration of ICU stay was 13 days (range, 10-16). One patient died. Rapid clinical whole-exome sequencing of the patients and segregation in available family members identified loss-of-function variants of the X-chromosomal TLR7. In members of family 1, a maternally inherited 4-nucleotide deletion was identified (c.2129_2132del; p.[Gln710Argfs*18]); the affected members of family 2 carried a missense variant (c.2383G>T; p.[Val795Phe]). In primary peripheral blood mononuclear cells from the patients, downstream type I interferon (IFN) signaling was transcriptionally downregulated, as measured by significantly decreased mRNA expression of IRF7, IFNB1, and ISG15 on stimulation with the TLR7 agonist imiquimod as compared with family members and controls. The production of IFN-γ, a type II IFN, was decreased in patients in response to stimulation with imiquimod.
Conclusions and Relevance: In this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants of X-chromosomal TLR7 were identified that were associated with impaired type I and II IFN responses. These preliminary findings provide insights into the pathogenesis of COVID-19.

PMID: 32706371 [PubMed – as supplied by publisher]

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Progressive bronchiectasis and CMC in a patient with STAT1 GOF – a rare case of primary immunodeficiency.

Adv Respir Med. 2020;88(3):271-277

Authors: Dmeńska H, Pac M, Skomska-Pawliszak M, Pietrucha B, Wolska-Kuśnierz B, Piątosa B, Komarnicka J, Heropolitańska-Pliszka E

Abstract
Bronchiestasis is a common complication developing in patients with primary immunodeficiency disorders. AD GOF STAT1 defi-ciency is characterized by CMC, repeated infections, and autoimmunity. It is the most frequently diagnosed entity in a group of PIDs with CMC. Here, we present the first Polish case of a female patient with early-onset bronchiestasis accompanied by CMC and a severe course of infections who was genetically diagnosed with AD GOF1 STAT1 mutation at the age of 15.

PMID: 32706110 [PubMed – in process]

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Adverse reactions and influencing factors in children with primary immunodeficiencies receiving intravenous immunglobulin replacement.

Allergol Immunopathol (Madr). 2020 Jul 20;:

Authors: Ibis IBP, Erdur B, Erdem SB, Karaman S, Gulez N, Genel F

Abstract
OBJECTIVES: We aimed to determine adverse reactions and influencing factors, within the scope of the number of patients and total infusions, in patients with primary immunodeficiencies receiving intravenous immunoglobulin (IVIG) replacement.
MATERIALS AND METHODS: Children with primary immunodeficiencies receiving IVIG replacement in Izmir Dr Behcet Uz Children’s Hospital, between June 2014 and June 2016, were included in our study.
RESULTS: The total number of the patients receiving IVIG replacement was 145 (37 female, 108 male). The number of total IVIG infusions was 1214. Adverse reactions were observed in 44.8% of the patients and 14.2% of the infusions. Common variable immunodeficiency was the most common diagnosis of the patients and adverse reactions most commonly developed in this group (24.2%). In all infusions the most frequent adverse reaction was headache (7.8%); fever was the most frequent immediate side effect (3.9%), whereas headache was the most common delayed adverse effect (5.1%). By logistic regression analyses, history of adverse reaction to IVIG in previous infusions, existence of concomitant infectious disease, past or family history of atopic disease, to receive IVIG infusion at the first time, or being under 10 years old were found associated with adverse reactions. There was no correlation between the concentration of IVIG preparations and the rate of side-effect development.
CONCLUSIONS: In our study no severe adverse reaction to IVIG was observed, but many mild or moderate side effects occurred. Therefore, IVIG indications must be well identified. Patients, family of the patients and health care workers must be informed for adverse reactions.

PMID: 32703652 [PubMed – as supplied by publisher]

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A New Conditioning Regimen Can Significantly Promote Post-Transplant Immune Reconstitution and Improve the Outcome of Umbilical Cord Blood Transplantation for Patients.

Stem Cells Dev. 2019 10 15;28(20):1376-1383

Authors: Yu ZP, Ding JH, Sun AN, Chen BA, Ge Z, Wu DP

Abstract
This study included data from 81 consecutively enrolled patients with hematological diseases who had been treated with unrelated umbilical cord blood transplantation (UCBT) between September 2014 and April 2019. All patients received intense conditioning regimens with combined fludarabine and high-dose cyclophosphamide (FC) before undergoing UCBT. Sixty-seven patients received a single UCBT, and 14 patients received a double UCBT. Fifty patients were pretreated with the fludarabine, busulfan, and cyclophosphamide (FBC) protocol, while 31 patients were treated with FC before transplantation. Graft-versus-host disease (GVHD) was prevented with cyclosporine A and mycophenolate mofetil administration. According to low-resolution, human leukocyte antigen (HLA) donor-recipient matching at six sites, 53 patients had 5-6 matches, while 28 patients had 4 matches. Seventy-eight patients (96.3%) achieved complete engraftment in this study. Thirty-six patients developed acute GVHD (aGVHD). The cumulative incidence of grade I-II aGVHD at day 100 posthematopoietic stem cell transplantation was 29.6%, and the cumulative incidence of grade III-IV aGVHD was 14.8%. At the end of the follow-up, 12 patients died due to treatment-related complications, and 4 died of disease relapse after transplantation. The transplant-related deaths were due to transplant-related infection (8 of 81), GVHD (2 of 81), and organ toxicity (2 of 81). The probability of overall survival (OS) was 80.2%. A higher dose of cyclophosphamide combined with fludarabine conditioning in UCBT was an effective curative method for treatment of hematologic disorders and could enhance the engraftment of umbilical cord blood stem cells, promote post-transplant immune reconstitution, and improve OS.

PMID: 31464164 [PubMed – indexed for MEDLINE]

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Deciphering the Role of Host Genetics in Susceptibility to Severe COVID-19.

Front Immunol. 2020;11:1606

Authors: Carter-Timofte ME, Jørgensen SE, Freytag MR, Thomsen MM, Brinck Andersen NS, Al-Mousawi A, Hait AS, Mogensen TH

Abstract
Coronavirus disease-19 (COVID-19) describes a set of symptoms that develop following infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Whilst COVID-19 disease is most serious in patients with significant co-morbidities, the reason for healthy individuals succumbing to fulminant infection is largely unexplained. In this review, we discuss the most recent findings in terms of clinical features and the host immune response, and suggest candidate immune pathways that may be compromised in otherwise healthy individuals with fulminating COVID-19. On the basis of this early knowledge we reason a potential genetic effect on host immune response pathways leading to increased susceptibility to SARS-CoV-2 infection. Understanding these pathways may help not only in unraveling disease pathogenesis, but also in suggesting targets for therapy and prophylaxis. Importantly such insight should instruct efforts to identify those at increased risk in order to institute preventative measures, such as prophylactic medication and/or vaccination, when such opportunities arise in the later phases of the current pandemic or during future similar pandemics.

PMID: 32695122 [PubMed – in process]

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Symptomatic hypoglycemia in a child with common variable immunodeficiency: Deficient anterior pituitary with variable immune deficiency (DAVID) syndrome.

Clin Pediatr Endocrinol. 2020;29(3):111-113

Authors: Nogueira M, Pinheiro M, Maia R, Silva RS, Costa C, Campos T, Leão M, Vitor AB, Castro-Correia C, Fontoura M

Abstract
Deficient anterior pituitary with variable immune deficiency (DAVID) syndrome is a rare condition characterized by symptomatic ACTH deficiency and primary hypogammaglobulinemia, caused by pathogenic variants of the nuclear factor kappa-B subunit 2 (NF-κB2) gene. We report the case of a 9-yr-old boy diagnosed with common variable immunodeficiency at the age of 3, who is under monthly intravenous immunoglobulin. The patient was admitted twice to the pediatric emergency service at the age of 9 due to symptomatic hypoglycemic events. During the hypoglycemic crisis, serum cortisol was low (< 0.1 μg/dL), ACTH level was inappropriately low (4.4 ng/L) and the ACTH stimulation test failed to raise the blood cortisol level. Pituitary magnetic resonance imaging showed a hypoplastic pituitary. Other pituitary deficiencies, primary hyperinsulinism and other metabolic diseases were excluded. He started hydrocortisone replacement treatment while maintaining immunoglobulin substitution and he remains asymptomatic. Molecular analysis revealed the heterozygous nonsense pathogenic variant, c.2557C>T (Arg853Ter) in the NF-κB2 gene. Thus, symptomatic hypoglycemia in a child with primary immunodeficiency should raise the suspicion of DAVID syndrome, prompting NF-κB2 molecular analysis, to allow timely and appropriated therapy and genetic counseling.

PMID: 32694887 [PubMed]

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