Manish Butte

Health-Related Quality of Life and Multidimensional Fatigue Scale in Children with Primary Immunodeficiencies.

J Clin Immunol. 2020 Apr 15;:

Authors: Ridao-Manonellas S, Fábregas-Bofill A, Núñez-Rueda G, González-Amores M, García-Prat M, López-Seguer L, Rivière JG, Martín-Nalda A, Mendoza-Palomar N, Melendo-Pérez S, Soler-Palacín P

Abstract
PURPOSE: Patients with primary immunodeficiency disease (PID) have an increased risk of experiencing physical activity limitations, social difficulties, and psychological problems due to their chronic condition. Evaluation of their health-related quality of life (HRQOL) and fatigue is crucial in these patients to help understand their complex disease and provide adequate medical care.
METHODS: In this study, we evaluated HRQOL and fatigue in pediatric and young adult patients with PID attending our center. Participants completed the Pediatric Quality of Life Inventory (PedsQL), version 4.0, and the PedsQL multidimensional fatigue module, standard version.
RESULTS: Fifty-three PID patients were recruited (age range: 2-23 years). The mean HRQOL score obtained was 66.61 (SD: 18.73) out of 100, and the emotional and work/school dimensions were the ones most highly affected. There were no significant differences in reported quality of life between patients and their caregivers. The mean patient-reported fatigue value was 68.81 (SD: 17.80) out of 100, and the rest-related dimension was the one most highly affected. In the caregivers’ assessment, general fatigue was the most highly affected dimension.
CONCLUSIONS: The results of this study show that quality of life is poor and fatigue measures are considerably increased in our young adult and pediatric patients with PIDs. These findings can indicate areas requiring more intensive interventions, and they will serve as a basis for comparison of future results.

PMID: 32291562 [PubMed – as supplied by publisher]

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Clinical, immunological and genetic characteristic of patients with clinical phenotype associated to LRBA-deficiency in Colombia.

Colomb Med (Cali). 2019 Sep 30;50(3):176-191

Authors: Martínez-Jaramillo C, Gutierrez-Hincapie S, Arango JCO, Vásquez-Duque GM, Erazo-Garnica RM, Franco JL, Trujillo-Vargas CM

Abstract
Background: LPS-responsive beige -like anchor protein (LRBA) deficiency is a primary immunodeficiency disease caused by loss of LRBA protein expression, due to biallelic mutations in LRBA gene. LRBA deficiency patients exhibit a clinically heterogeneous syndrome. The main clinical complication of LRBA deficiency is immune dysregulation. Furthermore, hypogammaglobulinemia is found in more than half of patients with LRBA-deficiency. To date, no patients with this condition have been reported in Colombia.
Objective: To evaluate the expression of the LRBA protein in patients from Colombia with clinical phenotype associated to LRBA-deficiency.
Methods: In the present study the LRBA-expression in patients from Colombia with clinical phenotype associated to LRBA-deficiency was evaluated. After then, the clinical, the immunological characteristics and the possible genetic variants in LRBA or other genes associated with the immune system in patients that exhibit decrease protein expression was evaluated.
Results: In total, 112 patients with different clinical manifestations associated to the clinical LRBA phenotype were evaluated. The LRBA expression varies greatly between different healthy donors and patients. Despite the great variability in the LRBA expression, six patients with a decrease in LRBA protein expression were observed. However, no pathogenic or possible pathogenic biallelic variants in LRBA, or in genes related with the immune system were found.
Conclusion: LRBA expression varies greatly between different healthy donors and patients. Reduction LRBA-expression in 6 patients without homozygous mutations in LRBA or in associated genes with the immune system was observed. These results suggest the other genetic, epigenetic or environmental mechanisms, that might be regulated the LRBA-expression.

PMID: 32284663 [PubMed – in process]

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A novel variant in the neutrophil cytosolic factor 2 (NCF2) gene results in severe disseminated BCG infectious disease: A clinical report and literature review.

Mol Genet Genomic Med. 2020 Apr 12;:e1237

Authors: AlKhater SA, Deswarte C, Casanova JL, Bustamante J

Abstract
BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder (PID) affecting NADPH oxidase activity. The rarest form of the disease is considered to be caused by NCF2 gene bi-allelic variant. Here, we report the clinical and molecular characterization of a patient presenting with early-onset severe disease due to bi-allelic NCF2 variant.
METHODS: Gene mutational analysis was performed by whole-exome and Sanger sequencing.
RESULTS: The patient presented with a history of fever and rash since the age of 1 month, followed by destructive osteomyelitis and necrotizing lymphadenopathy. The patient received the Bacillus Calmette-Guérin (BCG) vaccine at birth; she was subsequently diagnosed with disseminated BCG infection. Whole-exome sequencing identified a private (unreported) homozygous variant in NCF2 (c.290C > A) that results in a nonconservative change, p.Ala97Asp, in the p67phox protein. The variant is located in the third helix of the TRP domain, which is crucial for the binding of GTPase RAC2 to the NADPH oxidase complex.
CONCLUSION: We identified a novel NCF2 variant located in the region interacting with RAC2 that is linked to a severe and early CGD phenotype in the setting of disseminated BCG infection. Our findings support postponing BCG vaccination until 6-12 months of age and after PID assessment.

PMID: 32281309 [PubMed – as supplied by publisher]

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β2 Integrin Gene (ITGB2) mutation spectra in Pakistani families with leukocyte adhesion deficiency type 1 (LAD1).

Immunobiology. 2020 Apr 02;:151938

Authors: Nawaz Tipu H, Raza R, Jaffar S, Khan A, Anwar MZ, Ahmad W, Raza SI

Abstract
Leukocyte adhesion deficiency I (LADI) is an autosomal recessive type of primary immunodeficiency characterized by occurrence of repeated bacterial infections, impaired pus formation and wound healing. Genetic variations in the β-2 integrin subunit encoding gene ITGB2 have been implicated in causing the disorder. In the present study, we have investigated twelve patients presenting LAD1 features. After collecting clinical and family history, flow cytometry was used to determine levels of CD18 in the patients. Clinical history revealed that umbilical cord separation occurred mostly after 19 days in the patients. Recurrent skin infections were found in seven patients. Eight patients had at least one elder sibling who died due to repeated infections. All patients had marked neutrophilia with only 0.77% of neutrophils expressing CD18. Total 12 patients suffering from LAD1 were Sanger sequenced for ITGB2 gene. Five variants, including a novel p.(Cys286Phe) and four previously reported [p.(Gly273Arg), p.(Asp128Tyr), p.(Cys62*), IVS7 + 1G > A] were identified in 8 cases, while no pathogenic variant was observed in remaining four cases. This study represents the first comprehensive clinical and genetic characterization of LAD1 in Pakistani population. This will facilitate diagnosis and genetic counselling of patients with immunodeficiency disorders in Pakistani population.

PMID: 32279896 [PubMed – as supplied by publisher]

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[Hereditary angioedema due to C1-esterase inhibitor deficiency : novel approaches].

Rev Med Suisse. 2020 Apr 08;16(689):675-678

Authors: Stehlin F, Ribi C

Abstract
Hereditary angioedema type 1 and 2 are due to a deficiency in C1–esterase inhibitor. This molecule inhibits the generation of bradykinin, a potent inflammatory mediator that increases vascular permeability. Upon accumulation of bradykinin, patients affected develop painful subcutaneous or submucosal edemas that last for several days. In case the upper airways are affected, there is risk of suffocation. This type of angioedema does not respond to antihistamines, cortico-steroids or epinephrine. Management of angioedema attacks consists in injecting C1-esterase inhibitor concentrate or icatibant, a bradykinin receptor B2 antagonist. Preventive measures aim at reducing the frequency and the severity of angioedema attacks. Inhibition of -plasma kallikrein by lanadelumab, a monoclonal antibody adminis-tered subcutaneously, is effective and well tolerated.

PMID: 32270933 [PubMed – indexed for MEDLINE]

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Health-Related-Quality of Life in Common Variable Immunodeficiency Italian patients switched to remote assistance during the COVID-19 pandemic.

J Allergy Clin Immunol Pract. 2020 Apr 09;:

Authors: Pulvirenti F, Cinetto F, Milito C, Bonanni L, Pesce AM, Leodori G, Garzi G, Miglionico M, Tabolli S, Quinti I

Abstract
BACKGROUND: A rapidly expanding epidemic of the new coronavirus has become the focus of global scientific attention. Data are lacking on impact of SARS-CoV-2 pandemic on Health-Related Quality of Life among patients affected by Primary Antibody Deficiencies.
AIM OF THE STUDY: to identify factors impacting the Health-Related-Quality of Life among Italian patients affected by Primary Antibody Deficiencies switched to remote assistance at the time of the COVID-19 pandemic.
METHODS: Survey on quality of life in 158 Primary Antibody Deficiency patients measured by the CVID_QoL, a disease-specific tool, and by the GHQ-12, a generic tool to assess the risk of anxiety/depression. Since the beginning of COVID-19 epidemic, we shifted all PAD patients to home therapy, and activated remote visits. Questionnaires were sent by email four weeks later. CVID_QoL and GHQ-12 data scores were compared with the same set of data from a survey done in 2017.
RESULTS: Of 210 patients, 158 (75%) agreed to participate. The quality of life worse in the group of patients who become at risk of anxiety/depression at the study time. Health-Related-Quality of Life was similar in patients forced to shift from hospital-based to home-based immunoglobulin treatment and in patients who continued their usual home-based replacement. The risk of anxiety/depression is associated to SARS-CoV-2 pandemia and to patients’ fragility, and not to related clinical conditions associated with Common Variable Immune Deficiencies. The anxiety to run out of medications is a major new issue.
CONCLUSIONS: COVID-19 epidemic impacted HRQoL and the risk of anxiety/depression of PAD patients. The remote assistance program was a useful possibility to limit personal contacts without influencing the HRQoL.

PMID: 32278865 [PubMed – as supplied by publisher]

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Characterization of the clinical and immunological phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations.

J Allergy Clin Immunol. 2020 Apr 09;:

Authors: Lorenzini T, Fliegauf M, Klammer N, Frede N, Proietti M, Bulashevska A, Camacho-Ordonez N, Varjosalo M, Kinnunen M, de Vries E, van der Meer JWM, Ameratunga R, Roifman CM, Schejter YD, Kobbe R, Hautala T, Atschekzei F, Schmidt RE, Schröder C, Stepensky P, Shadur B, Pedroza LA, van der Flier M, Martínez-Gallo M, Gonzalez-Granado LI, Allende LM, Shcherbina A, Kuzmenko N, Zakharova V, Neves JF, Svec P, Fischer U, Ip W, Bartsch O, Barış S, Klein C, Geha R, Chou J, Alosaimi M, Weintraub L, Boztug K, Hirschmugl T, Dos Santos Vilela MM, Holzinger D, Seidl M, Lougaris V, Plebani A, Alsina L, Piquer-Gibert M, Deyà-Martínez A, Slade CA, Aghamohammadi A, Abolhassani H, Hammarström L, Kuismin O, Helminen M, Allen HL, Thaventhiran JE, Freeman AF, Cook M, Bakhtiar S, Christiansen M, Cunningham-Rundles C, Patel NC, Rae W, Niehues T, Brauer N, Syrjänen J, Seppänen MRJ, Burns SO, Tuijnenburg P, Kuijpers TW, NIHR-BioResource – Rare Diseases Consortium, Warnatz K, Grimbacher B

Abstract
BACKGROUND: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunological phenotypes.
OBJECTIVE: We set out to characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations.
METHODS: In a world-wide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; additionally, 32 variants were assessed by functional in vitro testing of NF-κB signaling.
RESULTS: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88·9%), reduced switched memory B cells (60·3%), and respiratory (83%) and gastrointestinal (28·6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57·4%), lymphoproliferation (52·4%), non-infectious enteropathy (23·1%), opportunistic infections (15·7%), autoinflammation (29·6%), and malignancy (16·8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents.
CONCLUSION: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Due to its multi-system involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.

PMID: 32278790 [PubMed – as supplied by publisher]

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