LE DEFICIT IMMUNITAIRE COMMUN VARIABLE (A PROPOS DE 6 CAS)

Common variable immunodeficiency (CVID) is a constitutional deficit in the antibody. It can be of transmission recessive, dominating or related to X. The CVID is the only being able to appear at the adulthood. The fundamental cause of this disorder remains unknown. The disease is characterized by the heterogeneity of the clinical picture and the immunological characteristic Our study’s goal is to present un discuss 6 cases of CVID hospitalized at the clinical Immunology Unit, of the Pediatry I department in the child hospital of Casablanca, between March 1998 and March 2004. The mean age at the first clinical symptoms is 11 years. Our six patients, suffered from recurrent pneumonias, the recurrent sinusitis, the chronic diarrhea with failure to thrive and granulomatous disease. They all had a hypogammaglobulinemia, the taking in charge consisted in an infections episode treatment as well as a nutrition rehabilitation with intravenous immunoglobulin antibiotic prophylaxis and a respiratory kinesitherapy. Our set was characterized by the severity of the clinical phenotype, especially by the therapeutic means insufficiency, and the delay of the diagnostic. A considerable effort should be achieved in order to make doctors more sensitive, tools of diagnosis and the hold in charge.Le déficit immunitaire commun variable (DICV) est un déficit primitif en anticorps, de transmission récessive, dominante ou liée à l’X, et qui peut se révéler à l’âge adulte. Son mécanisme moléculaire est encore inconnu. Le diagnostic est caractérisé par une hétérogénéité du tableau clinique et immunologique. L’objectif de notre travail est de présenter et discuter 6 cas de DICV, hospitalisés à l’unité d’immunologie clinique de la Pédiatrie I à l’hôpital d’Enfants de Casablanca, sur 6 ans (1998 – 2004). L’âge moyen de début des symptômes est de 11 ans. Nos 6 malades avaient présenté des broncho-pneumopathies à répétitions, des infections ORL, des diarrhées chroniques avec retentissement staturo-pondéral, et un cas de sarcoïdose. Ils avaient présenté tous une hypogammaglobulinémie globale. La prise en charge a consisté en un traitement des épisodes infectieux, une perfusion des immunoglobulines, une antibioprophylaxie et une kinésithérapie respiratoire. Le tableau clinique de nos malades reste sévère du fait du retard du diagnostic et de l’insuffisance des moyens thérapeutiques ; c’est pourquoi un effort doit être réalisé, afin de sensibiliser les médecins, pour établir un diagnostic précoce et une prise en charge adéquate

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men

Déficits immunitaires primitifs: approche diagnostique pour les pays émergents

International audiencePrimary immunodeficiencies (PIDs) correspond to various genetic diseases characterized by a heterogeneous clinical expression in children and a frequent revelation in adults Faced to clinical suspicion of an immune deficiency, the existence of syndrome features may evoke defined PID entities that need specific immunological analysis Otherwise, the diagnostic approach of PID requires four steps the first one is to rule out an acquired immune deficiency mainly HIV infection The second step is based on elementary biological investigations cell blood count, measure of G, A, and M immunoglobulins combined or not to protein electrophoresis, and an assessment of total hemolytic complement This line of analysis permit to discriminate cellular, humoral, phagocytic or complement deficiencies which can be further illustrated using specialized immunological investigations such as lymphocyte subpopulations phenotyping, quantification of immunoglobulin subclasses, detection of specific antibodies, T lymphocytes proliferation assay, nitroblue tetrazolium reduction (NBT) test, CD18 phenotyping, measure of C3 and C4 complement components The last step needs collaboration with genetic research laboratories in order to establish the genotype of the immunodeficiency (C) 2010 Elsevier Masson SAS All rights reservedLes déficits immunitaires primitifs (DIP) correspondent à environ 300 maladies génétiques actuellement connues, d’expression clinique hétérogène se révélant parfois tardivement chez l’adulte. Devant la suspicion d’un déficit immunitaire, la présence de signes syndromiques permet d’emblée d’évoquer des entités de DIP bien définies nécessitant un bilan étiologique spécifique. Sinon, dans l’optique d’optimiser les moyens exploratoires, la mise en évidence d’un DIP impose une démarche diagnostique en étapes. La première étape vise surtout à éliminer un déficit immunitaire acquis notamment, une infection à VIH ; la deuxième étape repose sur un bilan biologique de base (numération formule sanguine-plaquette, dosage des immunoglo-bulines [IgG, IgA, IgM] et/ou électrophorèse des protides, étude du complément hémolytique CH50). Confronté à la clinique, ce bilan initial permettra de distinguer quatre catégories de déficits : cellulaire, humoral, phagocytaire ou du complément pour lesquels la troisième étape grâceà des explorations immunologiques spécialisées (étude des sous-populations lymphocytaires, dosage des sous-classes d’Ig, recherche d’anticorps spécifiques, tests de prolifération lymphoctaire, test au NBT, étude phénotypique de CD18, dosage des fractions du complément... ) permettra de confirmer le DIP et de préciser sa nature. Enfin, la quatrième étape sera menée en collaboration avec des laboratoires de recherche spécialisés pour déterminer le type moléculaire du déficit

Mycobacterial disease in patients with chronic granulomatous disease: A retrospective analysis of 71 cases

PubMed ID: 26936803Background Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex. From the first year of life onward, most affected patients display multiple, severe, and recurrent infections caused by bacteria and fungi. Mycobacterial infections have also been reported in some patients. Objective Our objective was to assess the effect of mycobacterial disease in patients with CGD. Methods We analyzed retrospectively the clinical features of mycobacterial disease in 71 patients with CGD. Tuberculosis and BCG disease were diagnosed on the basis of microbiological, pathological, and/or clinical criteria. Results Thirty-one (44%) patients had tuberculosis, and 53 (75%) presented with adverse effects of BCG vaccination; 13 (18%) had both tuberculosis and BCG infections. None of these patients displayed clinical disease caused by environmental mycobacteria, Mycobacterium leprae, or Mycobacterium ulcerans. Most patients (76%) also had other pyogenic and fungal infections, but 24% presented solely with mycobacterial disease. Most patients presented a single localized episode of mycobacterial disease (37%), but recurrence (18%), disseminated disease (27%), and even death (18%) were also observed. One common feature in these patients was an early age at presentation for BCG disease. Mycobacterial disease was the first clinical manifestation of CGD in 60% of these patients. Conclusion Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD. © 2016 American Academy of Allergy, Asthma & Immunolog

Outcomes and Treatment Strategies for Autoimmunity and Hyperinflammation in Patients with RAG Deficiency

Background: Although autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series. Objective: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency. Methods: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology. Results: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients. Conclusions: Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management. © 2019 The Author

The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged <70 y and in >4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death

Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/ml; in plasma diluted 1:10) of IFN-α and/or IFN-ω are found in about 10% of patients with critical COVID-19 (coronavirus disease 2019) pneumonia but not in individuals with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or IFN-ω (100 pg/ml; in 1:10 dilutions of plasma) in 13.6% of 3595 patients with critical COVID-19, including 21% of 374 patients >80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1124 deceased patients (aged 20 days to 99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected individuals from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or IFN-ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of individuals carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals <70 years, 2.3% between 70 and 80 years, and 6.3% >80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over 80s and total fatal COVID-19 cases. © 2021 The Authors, some rights reserved