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COVID-19 , Control de Enfermedades Transmisibles , Participación de la Comunidad , Gobierno , Hospitales Especializados , Comités Consultivos , COVID-19/diagnóstico , COVID-19/epidemiología , COVID-19/prevención & control , COVID-19/transmisión , Prueba de COVID-19 , Vacunas contra la COVID-19 , Desarrollo de Medicamentos , Gobierno Federal , Humanos , India/epidemiología , Laboratorios , Política Pública , Asociación entre el Sector Público-Privado , Derivación y Consulta , SARS-CoV-2 , Gobierno EstatalRESUMEN
Living organisms are exposed to exogenous and endogenous agents that affect genomic integrity by creating DNA double strand breaks (DSBs). These breaks are repaired by DNA repair proteins to maintain homeostasis. Defects in DNA repair pathways also affect lymphocyte development and maturation, as DSB sites are critical intermediates for rearrangements required for V(D)J recombination. Recent classifications for inborn errors of immunity (IEIs) have listed DNA repair defect genes in a separate group, which suggests the importance of these genes for adaptive and innate immunity. We report an interesting case of a young female (index P1) with mutations in two different genes, DCLRE1C and FANCA, involved in DNA repair pathways. She presented with clinical manifestations attributed to both defects. With the advent of NGS, more than one defect is increasingly identified in patients with IEIs. Familial segregation studies and appropriate functional assays help ascertain the pathogenicity of these mutations and provide appropriate management and genetic counseling.
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Bioensayo , Anemia de Fanconi , Humanos , Femenino , Genómica , Homeostasis , Inmunidad InnataRESUMEN
DOCK8 deficiency affects various cell subsets belonging to both the innate and adaptive immune systems. Clinical diagnosis is challenging, as many cases present with severe atopic dermatitis as the only initial manifestation. Though flow cytometry helps in the presumptive diagnosis of DOCK8-deficient patients by evaluating their DOCK8 protein expression, it requires subsequent confirmation by molecular genetic analysis. Currently, haematopoietic stem cell transplantation (HSCT) is the only curative treatment option available for these patients. There is a paucity of data from India on the clinical diversity and molecular spectrum of DOCK8 deficiency. In the present study, we report the clinical, immunological and molecular findings of 17 DOCK8-deficient patients from India diagnosed over the last 5 years.
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Síndrome de Job , Humanos , India , Factores de Intercambio de Guanina Nucleótido/genéticaRESUMEN
Background & objectives: Accurate diagnosis of immunodeficiencies requires a critical comparison of values with age-matched controls. In India, the existing reference values for rare lymphocyte subsets are currently not available and we rely on the data originating from other countries for the interpretation of the results. Furthermore, there is limited information on normal variation for these rare-subset parameters in Indian children. So, this study aimed to establish normative values for clinically important lymphocyte subsets in Indian children at different age groups. Methods: 148 children aged ≥16 yr were enrolled in this study. The study population included 61 per cent males and 39 per cent females and was divided into the following groups: cord blood (n=18), 0-6 months (n=9), 6-12 months (n=13), 1-2 yr (n=19), 2-5 yr (n=27), 5-10 yr (n=25) and 10-16 yr (n=37). The absolute and relative percentage of lymphocytes, T, B, natural killer cell, along with activated, naïve and memory subsets, was determined by flow cytometry. Results: Median values and the 10th and 90th percentiles were obtained for 34 lymphocyte sub-populations. The T and B naïve compartments showed a decreasing trend, whereas memory cells showed an increase with age. The activated T cell subset shows an increasing pattern up to one year and then declines gradually. Double negative T cells are relatively stable. TCRgd+T cell percentage increases with age. Interpretation & conclusions: This single-centre pilot study provides preliminary data that justifies the need for future large-scale multi centric studies to generate a reference range for interpreting extended immunophenotyping profiles in the paediatric age group, making it possible for clinicians to assess the immunological status in inborn errors of immunity, infectious and autoimmune diseases.
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Subgrupos Linfocitarios , Subgrupos de Linfocitos T , Masculino , Femenino , Niño , Humanos , Proyectos Piloto , Recuento de Linfocitos , Inmunofenotipificación , Citometría de Flujo , India/epidemiología , Valores de ReferenciaRESUMEN
The energy metabolism of myeloid cells depends primarily on glycolysis. 1,5-Anhydroglucitol (1,5AG), a natural monosaccharide, is erroneously phosphorylated by glucose-phosphorylating enzymes to produce 1,5-anhydroglucitol-6-phosphate (1,5AG6P), a powerful inhibitor of hexokinases. The endoplasmic reticulum transporter (SLC37A4/G6PT) and the phosphatase G6PC3 cooperate to dephosphorylate 1,5AG6P. Failure to eliminate 1,5AG6P is the mechanism of neutrophil dysfunction and death in G6PC3-deficient mice. Sodium glucose cotransporter 2 (SLGT2) inhibitor reduces 1,5AG level in the blood and restores the neutrophil count in G6PC3-deficient mice. In the investigator-initiated study, a 30-year-old G6PC3-deficient woman with recurrent infections, distressing gastrointestinal symptoms, and multi-lineage cytopenia was treated with an SLGT2-inhibitor. A significant increase in all the hematopoietic cell lineages and substantial improvement in the quality of life was observed.
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Enfermedad del Almacenamiento de Glucógeno Tipo I , Mielopoyesis , Neutropenia , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Humanos , Ratones , Antiportadores , Glucosa-6-Fosfatasa/genética , Glucosa-6-Fosfatasa/metabolismo , Proteínas de Transporte de Monosacáridos/genética , Monoéster Fosfórico Hidrolasas/metabolismo , Calidad de Vida , Enfermedad del Almacenamiento de Glucógeno Tipo I/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Femenino , AdultoRESUMEN
PURPOSE: Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome mainly caused by uncontrolled activation of antigen presenting cells and CD8 T cells. CD8 T cell exhaustion is a known phenomenon in chronic viral infections and cancer. However, the role of T cell exhaustion is not yet identified in HLH in the background of persistent inflammation. So, currently, we have characterized the CD8 T cells using flow cytometry to understand the phenomenon of exhaustion in these cells in HLH. METHODS: We have comprehensively evaluated lymphocyte subsets and characterized CD8 T cells using immunophenotypic markers like PD1, TIM3, LAG3, Ki67, Granzyme B, etc. in a cohort of 21 HLH patients. Effector cytokine secretion and degranulation by CD8 T cells are also studied. RESULTS: Our findings indicate skewed lymphocyte subsets and aberrantly activated CD8 T cells in HLH. CD8 T cells exhibit significantly increased expression of PD1, TIM3, and LAG3 prominently in primary HLH as compared to controls. PD1 + CD8 T cells express elevated levels of Granzyme B and Ki67. Moreover, CD8 T cells are hypofunctional as evidenced by significantly reduced cytokine secretion and compromised CD107a degranulation. CONCLUSION: The study has revealed that CD8 + cytotoxic T lymphocytes from HLH patients exhibited high expression of exhaustion markers with overall impaired function. To the best of our understanding, this is the first report suggesting functional exhaustion of CD8 T cells in both primary and secondary HLH. Future studies to understand the association of exhaustion with disease outcome are needed for its probable therapeutic implementation.
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Linfocitos T CD8-positivos/inmunología , Linfohistiocitosis Hemofagocítica/inmunología , Adolescente , Adulto , Anciano , Antígenos CD/inmunología , Niño , Preescolar , Citocinas/inmunología , Femenino , Granzimas/inmunología , Receptor 2 Celular del Virus de la Hepatitis A/inmunología , Humanos , Lactante , Antígeno Ki-67/inmunología , Masculino , Persona de Mediana Edad , Fenotipo , Receptor de Muerte Celular Programada 1/inmunología , Adulto Joven , Proteína del Gen 3 de Activación de LinfocitosRESUMEN
World Health Organisation recommends the practice of BCG vaccination at birth in countries which have a high incidence of tuberculosis and/or high leprosy burden. The BCG vaccination is considered safe for a competent immune system. However, in children with weakened immune systems cause of which can be primary or secondary, the vaccine may lead to side effects which can be localized or disseminated. In this study, we report a spectrum of inborn errors of immunity (IEI) commonly referred to as primary immunodeficiency disorders (PIDs) diagnosed in a large cohort of patients presenting with complications to BCG vaccination from India. Retrospective data analysis of patients referred to ICMR- National Institute of Immunohematology (ICMR-NIIH) for IEI workup between 2007 and 2019 was done. IEI was identified in n = 52/90 (57.7%) patients presenting with BCG complications. Of these, n = 13(14.4%) patients were diagnosed with severe combined immune deficiency, n = 15(16.7%) with chronic granulomatous disease, n = 19(21.1%) with Inborn errors of IFN-γ immunity, n = 4(4.4%) with Combined immunodeficiency and n = 1(1.1%) with Leucocyte Adhesion Deficiency type1. Majority of cases with BCGosis (88%) had an underlying IEI. This study strongly highlights the need for evaluation of patients with BCG complications for underlying IEI. While disseminated BCGosis strongly predicts underlying IEI, even localized persistent adenitis may be a warning sign of underlying IEI. It is also strongly recommended to record a family history of previous sibling death prior to administration of this live vaccine and deferring live vaccine till the diagnosis of IEI is ruled out in cases with a positive family history.
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Vacuna BCG/efectos adversos , Enfermedad Granulomatosa Crónica/patología , Inmunodeficiencia Combinada Grave/patología , Tuberculosis Pulmonar/prevención & control , Vacunación/efectos adversos , Vacuna BCG/inmunología , Femenino , Enfermedad Granulomatosa Crónica/diagnóstico , Enfermedad Granulomatosa Crónica/inmunología , Humanos , India , Lactante , Masculino , Mycobacterium tuberculosis/inmunología , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/inmunología , Resultado del TratamientoAsunto(s)
Enfermedades Autoinmunes , Síndrome Linfoproliferativo Autoinmune , Humanos , Síndrome Linfoproliferativo Autoinmune/genética , Enfermedades Autoinmunes/genética , Fenotipo , Mutación , Receptor fas/genética , Apoptosis/genética , Proteína de Dominio de Muerte Asociada a Fas/genética , Proteína de Dominio de Muerte Asociada a Fas/metabolismoAsunto(s)
Autoinmunidad/genética , Complejo CD3/deficiencia , Síndromes de Inmunodeficiencia/genética , Anticuerpos/inmunología , Linfocitos B/inmunología , Complejo CD3/genética , Complejo CD3/inmunología , Preescolar , Resultado Fatal , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Síndromes de Inmunodeficiencia/inmunología , Lactante , Células Asesinas Naturales/inmunología , Mutación Missense , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/inmunologíaAsunto(s)
Antígenos HLA-DR/genética , Inmunidad Celular/inmunología , Inmunidad Humoral/inmunología , Inmunodeficiencia Combinada Grave/inmunología , Inmunodeficiencia Combinada Grave/terapia , Agammaglobulinemia/genética , Agammaglobulinemia/inmunología , Recuento de Linfocito CD4 , Relación CD4-CD8 , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Preescolar , Proteínas de Unión al ADN/genética , Antígenos HLA-DR/inmunología , Humanos , Masculino , Proteínas Nucleares/genética , Factores de Transcripción del Factor Regulador X/genética , Inmunodeficiencia Combinada Grave/genética , Transactivadores/genética , Factores de Transcripción/genéticaRESUMEN
The diagnosis and treatment of patients with mendelian susceptibility to mycobacterial disease (MSMD) pose consistent challenges due to the diverse infection spectrum observed in this population. Common clinical manifestations include Bacillus Calmette-Guérin vaccine (BCG) complications in countries where routine BCG vaccination is practiced, while in non-BCG-vaccinating countries, Non-Tuberculous Mycobacteria (NTM) is prevalent. In tuberculosis-endemic regions, Mycobacterium tuberculosis (MTB) has a high prevalence, along with other intracellular organisms. Isolating these organisms presents a significant challenge, and treatment is often initiated without confirming the specific species. This review primarily focuses on the methods and challenges associated with diagnosing and treating MSMD patients.
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Enfermedad Granulomatosa Crónica/complicaciones , Enfermedad Granulomatosa Crónica/genética , Síndrome Mucocutáneo Linfonodular/complicaciones , Mutación , NADPH Oxidasas/genética , Alelos , Biomarcadores , Niño , Análisis Mutacional de ADN , Femenino , Genotipo , Enfermedad Granulomatosa Crónica/diagnóstico , Humanos , Inmunofenotipificación , Síndrome Mucocutáneo Linfonodular/diagnóstico , LinajeRESUMEN
Major Histocompatibility Complex (MHC) Class II deficiency is a rare autosomal recessive primary immunodeficiency caused by mutations in regulatory genes of MHC Class II proteins. Clinical manifestations include respiratory/gastrointestinal infections, failure-to-thrive, septicemia and early death. A 9-mo-old-girl presented with repeated episodes of pneumonia requiring hospitalization and ventilator support since the last 5 mo. Examination revealed absent tonsils, sparse scalp-hair, seborrhea and firm hepato-splenomegaly. Radiograph showed absence of thymic shadow with diffuse pulmonary infiltrates. CT scan showed multiple bilateral ground glass pulmonary opacities with patchy consolidation. Primary immunodeficiency disorder was suspected in view of repeated pulmonary infections, failure to thrive and suggestive family history. Lymphocyte subset assay revealed lymphocytopenia and HLA typing showed absence of HLA-DR expression on B cells suggestive of MHC Class II deficiency. Targeted gene panel detected a homozygous mutation in the RFX-5 gene (RFX5: c.848_849del:p.R283Tfs*6;Homozygous). Though this patient succumbed, parents have been counseled regarding need for prenatal diagnosis.
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The emergence of vaccine-derived polioviruses (VDPVs) in patients with Primary Immunodeficiency (PID) is a threat to the polio-eradication program. In a first of its kind pilot study for successful screening and identification of VDPV excretion among patients with PID in India, enteroviruses were assessed in stool specimens of 154 PID patients across India in a period of two years. A total of 21.42% of patients were tested positive for enteroviruses, 2.59% tested positive for polioviruses (PV), whereas 18.83% of patients were positive for non-polio enteroviruses (NPEV). A male child of 3 years and 6 months of age diagnosed with Hyper IgM syndrome was detected positive for type1 VDPV (iVDPV1) with 1.6% nucleotide divergence from the parent Sabin strain. E21 (19.4%), E14 (9%), E11 (9%), E16 (7.5%), and CVA2 (7.5%) were the five most frequently observed NPEV types in PID patients. Patients with combined immunodeficiency were at a higher risk for enterovirus infection as compared to antibody deficiency. The high susceptibility of PID patients to enterovirus infection emphasizes the need for enhanced surveillance of these patients until the use of OPV is stopped. The expansion of PID surveillance and integration with a national program will facilitate early detection and follow-up of iVDPV excretion to mitigate the risk for iVDPV spread.
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OBJECTIVES: LPS-responsive beige-like anchor protein (LRBA) deficiency abolishes LRBA protein expression due to biallelic mutations in the LRBA gene that lead to autoimmune manifestations, inflammatory bowel disease, hypogammaglobulinemia in early stages, and variable clinical manifestations. MATERIALS AND METHODS: Mutational analysis of the LRBA gene was performed in Indian patients using targeted Next Generation Sequencing (t-NGS) and confirmed by Sanger sequencing using specific primers of exons 53. Then, bioinformatics analysis and protein modeling for the novel founded mutations were also performed. The genotype, phenotype correlation was done according to the molecular findings and clinical features. RESULTS: We report an unusual case of a female patient born of a consanguineous marriage, presented with severe anaemia and jaundice with a history of multiple blood transfusions of unknown cause up to the age of 5 yrs. She had hepatosplenomegaly with recurrent viral and bacterial infections. Tests for hemoglobinopathies, enzymopathies, and hereditary spherocytosis were within the normal limits. The t-NGS revealed a novel homozygous missense variation in exon 53 of the LRBA gene (chr4:151231464C > T; c.7799G > A) (p.C2600Y), and the parents were heterozygous. The further immunological analysis is suggestive of hypogammaglobulinaemia and autoimmune haemolytic anaemia. The bioinformatics tools are suggestive of deleterious and disease-causing variants. CONCLUSION: This study concludes the importance of a timely decision of targeted exome sequencing for the molecular diagnostic tool of unexplained haemolytic anaemia with heterogeneous clinical phenotypes.
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Proteínas Adaptadoras Transductoras de Señales , Anemia Hemolítica Autoinmune , Hemólisis , Anemia Hemolítica Autoinmune/sangre , Anemia Hemolítica Autoinmune/genética , Anemia Hemolítica Autoinmune/patología , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , MutaciónRESUMEN
PURPOSE: To call attention to the central clues for primary immunodeficiency in the cases reported by María Nieves-Moreno et. al where chalazia in the reported cases is undoubtedly an important clue but is a late clinical manifestation.
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Chalazión , Enfermedades de Inmunodeficiencia Primaria , HumanosRESUMEN
Phaeohypomycosis is a rare cutaneous and subcutaneous fungal infection caused by dematiaceous fungi. They have a widespread global distribution occasionally affecting humans. A 26-year-old woman presented with multiple skin lesions over her face and extremities for last 7 years, unresponsive to systemic amphotericin B and itraconazole. Further investigations revealed CARD9 mutation and phaeohyphomycosis caused by the pigmented fungus Exserohilum rosatratum. Lesions subsequently improved with oral flucytosine and itraconazole.
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Ascomicetos , Proteínas Adaptadoras de Señalización CARD/genética , Mutación , Feohifomicosis/microbiología , Adulto , Antifúngicos/uso terapéutico , Femenino , Flucitosina/uso terapéutico , Humanos , Itraconazol/uso terapéutico , Feohifomicosis/tratamiento farmacológicoRESUMEN
BACKGROUND: The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic has resulted in occupational exposure among Healthcare Workers (HCWs) and a high risk of nosocomial transmission. Asymptomatic infection and transmission of infection before the development of symptoms are well-recognized factors contributing to the spread of infection. We conducted a cross-sectional observational study to understand the seroprevalence of SARS-CoV-2 infection among HCWs and to verify the appropriateness of infection control measures, particularly Hydroxychloroquine (HCQ) prophylaxis. METHODS: A cross-sectional sero-surveillance study was conducted among 500 HCWs in Dombivli and surrounding Mumbai Metropolitan area (Maharashtra, India) between 21st July and 3rd August 2020. The vulnerability of the study participants to SARS-CoV-2 infection was ascertained through a history of (i) involvement in direct care, (ii) exposure to aerosol-generating procedures, (iii) co-morbidities, (iv) Personal Protective Equipment (PPE) use, and (v) HCQ prophylaxis. SARS-CoV-2 IgG antibodies were tested using COVID KAVACH anti-SARS-CoV-2 IgG antibody detection enzyme-linked immunosorbent assay (ELISA) from Zydus Cadila. A systematic analysis of the correlation between the development of antibodies and factors affecting vulnerability to infection was performed. RESULTS: The overall SARS-CoV-2 seroprevalence in the study population was 11%. Providing direct care to COVID-19 patients (Adjusted OR 16.4, 95% CI 3.3-126.9, p = 0.002) for long hours and irregular use of PPE (Adjusted OR 3.78, 95% CI 1.1-11.9, p = 0.02) were associated with an increased incidence of seropositivity. Prophylaxis with HCQ may have a role in reducing the vulnerability to infection as depicted by univariate and multivariate analysis (Adjusted OR 0.55, 95% CI 0.3-0.9, p = 0.047). It was also noted that those not on HCQ prophylaxis were threefold more prone to infection and developed severe disease as compared to those on HCQ prophylaxis. CONCLUSION: Prophylaxis with HCQ may have a role in mitigating the incidence and severity of SARS-CoV-2 infection. Although vaccination is the most robust strategy to safeguard against COVID-19, it will be months before vaccination percolates to the masses. In the face of the second wave of COVID-19, the use of HCQ prophylaxis in combination with use of face-masks regularly may be considered as a cost-effective measure for population dense areas like urban slums where social distancing is not possible.