Manish Butte

A Systematic Review and Meta-regression Analysis on the Impact of Increasing IgG Trough Level on Infection Rates in Primary Immunodeficiency Patients on Intravenous IgG Therapy.

J Clin Immunol. 2020 May 16;:

Authors: Lee JL, Mohamed Shah N, Makmor-Bakry M, Islahudin FH, Alias H, Noh LM, Mohd Saffian S

Abstract
PURPOSE: We conducted a systematic review and meta-regression analysis to evaluate the impact of increasing immunoglobulin G (IgG) trough levels on the clinical outcomes in patients with PID receiving intravenous immunoglobulin G (IVIG) treatment.
METHODS: Systematic search was conducted in PubMed and Cochrane. Other relevant articles were searched by reviewing the references of the reviewed article. All clinical trials with documented IgG trough levels and clinical outcome of interest in patients receiving IVIG treatment were eligible to be included in this review. Meta-regression analysis was conducted using Comprehensive Meta-analysis Software. Additional sensitivity analyses were undertaken to evaluate the robustness of the overall results.
RESULTS: Twenty-eight clinical studies with 1218 patients reported from year 2001 to 2018 were included. The mean IVIG dose used ranges from 387 to 560 mg/kg every 3 to 4 weekly, and mean IgG trough obtained ranges from 660 to 1280 mg/dL. Random-effects meta-regression slope shows that IgG trough level increases significantly by 73 mg/dL with every increase of 100 mg/kg dose of IVIG (p < 0.05). Overall infection rates reduced significantly by 13% with every increment of 100 mg/dL of IgG trough up to 960 mg/dL (p < 0.05).
CONCLUSION: This meta-analysis concludes that titrating the IgG trough levels up to 960 mg/dL progressively reduces the rate of infections, and there is less additional benefit beyond that. Further studies to validate this result are required before it can be used in clinical practice.

PMID: 32417999 [PubMed – as supplied by publisher]

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Safety of tunneled central venous catheters in pediatric hematopoietic stem cell recipients with severe primary immunodeficiency diseases.

PLoS One. 2020;15(5):e0233016

Authors: Martynov I, Klima-Frysch J, Kluwe W, Engel C, Schoenberger J

Abstract
Tunneled central venous catheters (TCVCs) provide prolonged intravenous access for pediatric patients with severe primary immunodeficiency disease (PID) undergoing hematopoietic stem cell transplantation (HSCT). However, little is known about the epidemiology and clinical significance of TCVC-related morbidity in this particular patient group. We conducted the retrospective analysis of patients with severe PID who received percutaneous landmark-guided TCVC implantation prior to HSCT. We analyzed 92 consecutive TCVC implantations in 69 patients (median [interquartile range] age 3.0 [0-11] years) with severe combined immune deficiency (n = 39, 42.4%), chronic granulomatous disease (n = 17, 18.4%), and other rare PID syndromes (n = 36, 39.2%). The median length of TCVC observation was 144.1 (85.5-194.6) days with a total of 14,040 catheter days at risk (cdr). The overall rate of adverse events during catheter insertion was 17.4% (n = 16) and 25.0% during catheter dwell period (n = 23, catheter risk [CR] per 1000 cdr = 1.64). The most common complication was TCVC-related infection with an overall prevalence of 9.8% (n = 9, CR = 0.64), followed by late dislocation (n = 6, 6.5%, CR = 0.43), early dislocation (n = 4, 4.3%) and catheter dysfunction (n = 4, 4.3%, CR = 0.28). TCVCs are safe in children with severe PID undergoing HSCT with relatively low rates of TCVC-related infection.

PMID: 32413055 [PubMed – as supplied by publisher]

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Evaluation of the frequency and diagnostic delay of primary immunodeficiency disorders among suspected patients based on the 10 warning sign criteria: A cross-sectional study in Iran.

Allergol Immunopathol (Madr). 2020 May 11;:

Authors: Bahrami A, Sayyahfar S, Soltani Z, Khodadost M, Moazzami B, Rezaei N

Abstract
INTRODUCTION: The prevalence of undiagnosed primary immunodeficiency diseases is remarkably high and contributes to increasing the rate of morbidity and mortality among this group of patients.
OBJECTIVE: To examine the 10 warning sign scoring system in patients suspected of primary immune deficiency and also estimate the diagnostic delay in patients with proven disease.
METHODS: This descriptive cross-sectional study was carried out during the years 2015-2016 in Ali Asghar (AS) Clinic and Hospital. Two hundred patients with suspected primary immune deficiency disease were eligible for inclusion in the study. Multivariable logistic regression analysis was used to determine the relation between findings.
RESULTS: In this study, the majority of suspected cases of immunodeficiency were males (57%) with a mean age of 3.33±2.89 years. Twenty-one (10.5%) patients were diagnosed with immunodeficiency disease. The mean diagnostic delay among primary immune deficient patients was 2.05±1.7 years. There was a significant relationship between having parental consanguinity (OR=2.68, 95% CI: 1.07-6.70), allergies (OR=5.03, 95% CI: 1.13-22.31), vaccine adverse effects (OR=9.31, 95% CI: 1.24-69.96) and primary immune deficiency diagnosis. No association was observed between age (OR=0.98, 95% CI: 0.84-1.14), gender (OR=0.99, 95% CI: 0.39-2.47), immune deficiency scoring (OR=0.68, 95% CI: 0.31-1.45) and primary immune deficiency diagnosis.
CONCLUSION: Ten warning sign scoring system is of less value to consider a patient suspected of having primary immune deficiency. There is a meaningful delay in diagnosis of primary immune deficiencies especially in antibody deficiency defects which seeks further upgrading of knowledge in physicians.

PMID: 32404246 [PubMed – as supplied by publisher]

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A review of kallikrein inhibitor lanadelumab in hereditary angioedema.

Immunotherapy. 2019 08;11(11):937-944

Authors: Hwang G, Johri A, Ng S, Craig T

Abstract
Hereditary angioedema with C1 esterase inhibitor deficiency is a rare disorder characterized by unpredictable swelling of the face, larynx and gastrointestinal tract. Kallikreins are serine proteases that cleave kininogens to produce bradykinin leading to inflammation. A new prophylactic drug is lanadelumab (DX-2930, SHP-643), a recombinant, fully human IgG1 monoclonal antibody kallikrein inhibitor. Pharmacokinetics show a half-life of 14 days with a dose-dependent effect. Completed trials for lanadelumab include two Phase III studies with updated efficacy in preventing angioedema in hereditary angioedema patients. Ongoing data show the safety of the targeted therapy along with less frequent administration requirements. Information on long-term safety is still needed, as well as, further studies on the correlation of subcutaneous administered dosing requirements and severity of side effects.

PMID: 31234673 [PubMed – indexed for MEDLINE]

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Systemic Redox Imbalance in Patients with Chronic Granulomatous Disease.

J Clin Med. 2020 May 09;9(5):

Authors: Heropolitanska-Pliszka E, Berk K, Maciejczyk M, Sawicka-Powierza J, Bernatowska E, Wolska-Kusnierz B, Pac M, Dabrowska-Leonik N, Piatosa B, Lewandowicz-Uszynska A, Karpinska J, Zalewska A, Mikoluc B

Abstract
The aim of our study was to evaluate redox status, enzymatic and non-enzymatic antioxidant barriers, oxidative damage of proteins, lipids and DNA, as well as concentration of coenzyme Q10 and vitamins A and E in patients with chronic granulomatous disease (CGD). The study was performed on fifteen Caucasian individuals (median age 24 years and seven months) diagnosed with CGD. The mutation in the NCF1 gene was confirmed in ten patients, and in the CYBB gene in five patients. We demonstrated high levels of total oxidant status (TOS) and oxidative stress index (OSI), lipids (↑8-isoprostanes (8-isoP), ↑4-hydroxynonenal (4-HNE)), proteins (↑advanced oxidation protein products (AOPP)) and DNA (↑8-hydroxy-2′-deoxyguanosine (8-OHdG)) oxidation products in CGD individuals as compared to sex- and age-matched healthy controls. We showed enhanced serum enzymatic activity of catalase (CAT) and superoxide dismutase-1 (SOD) and significantly decreased coenzyme Q10 concentration. Our study confirmed redox disturbances and increased oxidative damage in CGD patients, and indicated the need to compare redox imbalance depending on the type of mutation and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The question regarding effectiveness of antioxidant therapy in patients with CGD is open, and the need to establish guidelines in this area remains to be addressed.

PMID: 32397350 [PubMed]

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[Primary immunodeficiency and vaccination].

Zhonghua Er Ke Za Zhi. 2020 May 02;58(5):440-442

Authors: Wang XC

PMID: 32392968 [PubMed – in process]

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Partial T cell defects and expanded CD56bright NK cells in an SCID patient carrying hypomorphic mutation in the IL2RG gene.

J Leukoc Biol. 2020 May 11;:

Authors: Cifaldi C, Cotugno N, Di Cesare S, Giliani S, Di Matteo G, Amodio D, Piano Mortari E, Chiriaco M, Buonsenso D, Zangari P, Pagliara D, Gaspari S, Carsetti R, Palma P, Finocchi A, Locatelli F, Rossi P, Doria M, Cancrini C

Abstract
X-linked severe combined immunodeficiency (X-SCID) caused by full mutation of the IL2RG gene leads to T- B+ NK- phenotype and is usually associated with severe opportunistic infections, diarrhea, and failure to thrive. When IL2RG hypomorphic mutation occurs, diagnosis could be delayed and challenging since only moderate reduction of T and NK cells may be present. Here, we explored phenotypic insights and the impact of the p.R222C hypomorphic mutation (IL2RGR222C ) in distinct cell subsets in an 8-month-old patient with atypical X-SCID. We found reduced CD4+ T cell counts, a decreased frequency of naïve CD4+ and CD8+ T cells, and an expansion of B cells. Ex vivo STAT5 phosphorylation was impaired in CD4+ CD45RO+ T cells, yet compensated by supraphysiological doses of IL-2. Sanger sequencing on purified cell subsets showed a partial reversion of the mutation in total CD3+ cells, specifically in recent thymic emigrants (RTE), effector memory (EM), and CD45RA+ terminally differentiated EM (EMRA) CD4+ T cells. Of note, patient’s NK cells had a normal frequency compared to age-matched healthy subjects, but displayed an expansion of CD56bright cells with higher perforin content and cytotoxic potential, associated with accumulation of NK-cell stimulatory cytokines (IL-2, IL-7, IL-15). Overall, this report highlights an alteration in the NK-cell compartment that, together with the high disease-phenotype variability, should be considered in the suspicion of X-SCID with hypomorphic IL2RG mutation.

PMID: 32392633 [PubMed – as supplied by publisher]

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Education, Race/Ethnicity, and Causes of Premature Mortality Among Middle-Aged Adults in 4 US Urban Communities: Results From CARDIA, 1985-2017.

Am J Public Health. 2020 04;110(4):530-536

Authors: Roy B, Kiefe CI, Jacobs DR, Goff DC, Lloyd-Jones D, Shikany JM, Reis JP, Gordon-Larsen P, Lewis CE

Abstract
Objectives. To assess causes of premature death and whether race/ethnicity or education is more strongly and independently associated with premature mortality in a diverse sample of middle-aged adults in the United States.Methods. The Coronary Artery Risk Development in Young Adults study (CARDIA) is a longitudinal cohort study of 5114 participants recruited in 1985 to 1986 and followed for up to 29 years, with rigorous ascertainment of all deaths; recruitment was balanced regarding sex, Black and White race/ethnicity, education level (high school or less vs. greater than high school), and age group (18-24 and 25-30 years). This analysis included all 349 deaths that had been fully reviewed through month 348. Our primary outcome was years of potential life lost (YPLL).Results. The age-adjusted mortality rate per 1000 persons was 45.17 among Black men, 25.20 among White men, 17.63 among Black women, and 10.10 among White women. Homicide and AIDS were associated with the most YPLL, but cancer and cardiovascular disease were the most common causes of death. In multivariable models, each level of education achieved was associated with 1.37 fewer YPLL (P = .007); race/ethnicity was not independently associated with YPLL.Conclusions. Lower education level was an independent predictor of greater YPLL.

PMID: 32078342 [PubMed – indexed for MEDLINE]

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