RESUMO
BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency. Infections of lung, skin, lymph nodes, and liver are the hallmark of CGD and frequently the initial manifestation of the disease. The aim of the present paper is to describe the sites of infections and their causative agents in 38 pediatric patients with CGD. METHODS: This retrospective, single-center cohort study included CGD patients followed at the allergy and immunology unit of a tertiary hospital in São Paulo, Brazil over the last 40 years. Sites of infections and their causative agents were described. RESULTS: Thirty-eight patients were included (36 males). The median age of onset of symptoms was 45 days (ranging from 7 days-7 years), and the median age at diagnosis was 23 months (ranging from 1 month-12 years). In all, 31.6% of the patients reported a family history of child deaths and 21% (eight cases) had another male family member with CGD. The most common infections were pneumonia (81.6%), skin infections (50.0%), adenitis (42.1%), and liver abscess (23.7%); 188 cultures were positive (85.6% bacteria; 14.4% fungi). The most prevalent bacterial agents were Staphylococcus sp. (12.4%), Staphylococcus aureus (11.2%), and Klebsiella pneumoniae (9.3%). Aspergillus sp. and Candida sp. were 56% and 22.2% of the isolated fungi, respectively. Mycobacterium tuberculosis was isolated in 5.6% and Mycobacterium bovis in one patient (0.9%). CONCLUSION: Staphylococcus sp., Staphylococcus aureus, and Aspergillus sp. were the most frequent agents found in this cohort. M. tuberculosis should be considered in endemic area. Detection of infectious agents drives to the adequate treatment and benefits the evolution of patients with CGD.
Assuntos
Infecções Bacterianas/microbiologia , Doença Granulomatosa Crônica/complicações , Micoses/microbiologia , Bactérias/imunologia , Bactérias/isolamento & purificação , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/imunologia , Brasil , Criança , Pré-Escolar , Estudos Transversais , Feminino , Fungos/imunologia , Fungos/isolamento & purificação , Doença Granulomatosa Crônica/imunologia , Humanos , Lactente , Masculino , Micoses/diagnóstico , Micoses/imunologia , Estudos RetrospectivosRESUMO
PURPOSE: Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by an inability of phagocytes to produce reactive oxygen species, impairing their killing of various bacteria and fungi. We summarize here the 93 cases of CGD diagnosed in Mexico from 2011 to 2019. METHODS: Thirteen Mexican hospitals participated in this study. We describe the genetic, immunological, and clinical features of the 93 CGD patients from 78 unrelated kindreds. RESULTS: Eighty-two of the patients (88%) were male. All patients developed bacterial infections and 30% suffered from some kind of fungal infection. Fifty-four BCG-vaccinated patients (58%) presented infectious complications of BCG vaccine. Tuberculosis occurred in 29%. Granulomas were found in 56% of the patients. Autoimmune and inflammatory diseases were present in 15% of patients. A biological diagnosis of CGD was made in 89/93 patients, on the basis of NBT assay (n = 6), DHR (n = 27), and NBT plus DHR (n = 56). The deficiency was complete in all patients. The median age of biological diagnosis was 17 months (range, 0-186 months). A genetic diagnosis was made in 83/93 patients (when material was available), corresponding to CYBB (n = 64), NCF1 (n = 7), NCF2 (n = 7), and CYBA (n = 5) mutations. CONCLUSIONS: The clinical manifestations in these Mexican CGD patients were similar to those in patients elsewhere. This cohort is the largest in Latin America. Mycobacterial infections are an important cause of morbidity in Mexico, as in other countries in which tuberculosis is endemic and infants are vaccinated with BCG. X-linked CGD accounted for most of the cases in Mexico, as in other Latin American countries. However, a significant number of CYBA and NCF2 mutations were identified, expanding the spectrum of known causal mutations.
Assuntos
Doença Granulomatosa Crônica/imunologia , Mutação/genética , Infecções por Mycobacterium/epidemiologia , Mycobacterium/fisiologia , NADPH Oxidase 2/genética , NADPH Oxidases/genética , Adolescente , Autoimunidade , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Genes Ligados ao Cromossomo X , Doença Granulomatosa Crônica/epidemiologia , Doença Granulomatosa Crônica/genética , Humanos , Lactente , Recém-Nascido , Inflamação , Masculino , México/epidemiologiaAssuntos
Antibacterianos/uso terapêutico , Dermatite Seborreica/imunologia , Doença Granulomatosa Crônica/complicações , NADPH Oxidases/genética , Infecções Estafilocócicas/imunologia , Análise Mutacional de DNA , Dermatite Seborreica/diagnóstico , Dermatite Seborreica/tratamento farmacológico , Dermatite Seborreica/microbiologia , Suscetibilidade a Doenças/imunologia , Quimioterapia Combinada/métodos , Feminino , Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/imunologia , Humanos , Índice de Gravidade de Doença , Irmãos , Infecções Estafilocócicas/diagnóstico , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/isolamento & purificação , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: Chronic granulomatous disease (CGD) is a disorder of phagocyte function, characterized by pyogenic infections and granuloma formation caused by defects in NADPH oxidase complex activity. Although the effect of CGD mainly reflects the phagocytic compartment, B cell responses are also impaired in patients with CGD. MATERIALS AND METHODS: Flow cytometric analysis was performed on peripheral blood samples from 35 CGD patients age-matched with healthy controls (HC). The target cells of our study were the naive (IgD+/CD27-), memory (IgD-/CD27+), and B1a (CD5+) cells. Immunoglobulins (Igs) were also measured. This study was performed in a Latin American cohort. RESULTS: We found significantly higher levels of naive B cells and B1a cells, but lower levels of memory B cells were found in CGD patients compared to HC. There was no significant difference of cell percentages per inheritance type. DISCUSSION: Our findings suggest that the deficiency of NADPH oxidase components can affect the differentiation of naive B cells to memory B cells. Consequently, memory cells will be low, which also influenced the expression of CD27 in memory B cells and as a result, the percentage of naive cells increases. An altered phenotype of B lymphocytes in CGD patients may contribute to the opportunistic infections and autoimmune disorders that are seen in this disease.
Assuntos
Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Doença Granulomatosa Crônica/imunologia , NADPH Oxidase 2/genética , Adolescente , Adulto , Separação Celular , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Citometria de Fluxo , Doença Granulomatosa Crônica/genética , Humanos , Memória Imunológica , Imunofenotipagem , Lactente , Masculino , México , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Adulto JovemRESUMO
Primary immunodeficiency diseases (PID) are congenital disorders secondary to an impaired immune response. Infections, autoimmune disorders, atopy, and lymphoproliferative syndromes are commonly associated with this disorder. OBJECTIVE: To present and discuss 3 infants diagnosed with PID. CLINICAL CASES: The cases are presented of three patients with PID diagnosed during their first admission to a Paediatric Intensive Critical Care Unit. The first patient, a 4-month-old infant affected by a severe pneumonia, and was diagnosed as a Severe Combined Immunodeficiency Disease. The second patient was an 8-month-old infant with Candida lusitaniae mesenteric adenitis, and diagnosed with a Chronic Granulomatous Disease. The last patient, a 6-month-old infant presented with ecthyma gangrenosum and X-linked agammaglobulinaemia. CONCLUSION: PID should be suspected when an infectious disease does not responde to the appropriate therapy within the expected period. An update of each disease is presented.
Assuntos
Agamaglobulinemia/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doença Granulomatosa Crônica/diagnóstico , Síndromes de Imunodeficiência/diagnóstico , Agamaglobulinemia/imunologia , Agamaglobulinemia/fisiopatologia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Doença Granulomatosa Crônica/imunologia , Doença Granulomatosa Crônica/fisiopatologia , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/fisiopatologia , Lactente , Unidades de Terapia Intensiva Pediátrica , Masculino , Índice de Gravidade de DoençaRESUMO
Las inmunodeficiencias primarias (IDP) son enfermedades congénitas causadas por alteraciones cuantitativas o funcionales de la respuesta inmunitaria. Se caracterizan por predisposición a infecciones, autoinmunidad, alergia y enfermedades linfoproliferativas. Objetivo: Reportar 3 casos de lactantes menores con IDP que se manifestaron como infecciones graves de curso inhabitual. Casos clínicos: Se presentan 3 pacientes diagnosticados como IDP en su estadía en la Unidad de Paciente Crítico Pediátrico. El primero corresponde a un lactante de 4 meses con neumonía multifocal extensa a quien se diagnosticó un síndrome de inmunodeficiencia combinada severa ligada a X; el segundo es un lactante de 8 meses que se manifestó como una adenitis mesentérica por Candida lusitaniae y que correspondió a enfermedad granulomatosa crónica, y el tercero se trata de un lactante de 6 meses que se presentó con un ectima por Pseudomona y se diagnosticó una agammaglobulinemia ligada a X. Conclusión: El diagnóstico de IDP debe sospecharse en presencia de una infección de evolución arrastrada que no responde a tratamiento habitual. Se discuten los casos y se presenta una puesta al día de las patologías diagnosticadas.
Primary immunodeficiency diseases (PID) are congenital disorders secondary to an impaired immune response. Infections, autoimmune disorders, atopy, and lymphoproliferative syndromes are commonly associated with this disorder. Objective: To present and discuss 3 infants diagnosed with PID. Clinical cases: The cases are presented of three patients with PID diagnosed during their first admission to a Paediatric Intensive Critical Care Unit. The first patient, a 4-month-old infant affected by a severe pneumonia, and was diagnosed as a Severe Combined Immunodeficiency Disease. The second patient was an 8-month-old infant with Candida lusitaniae mesenteric adenitis, and diagnosed with a Chronic Granulomatous Disease. The last patient, a 6-month-old infant presented with ecthyma gangrenosum and X-linked agammaglobulinaemia. Conclusion: PID should be suspected when an infectious disease does not responde to the appropriate therapy within the expected period. An update of each disease is presented.
Assuntos
Humanos , Masculino , Lactente , Agamaglobulinemia/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doença Granulomatosa Crônica/diagnóstico , Síndromes de Imunodeficiência/diagnóstico , Índice de Gravidade de Doença , Unidades de Terapia Intensiva Pediátrica , Agamaglobulinemia/fisiopatologia , Agamaglobulinemia/imunologia , Doença Granulomatosa Crônica/imunologia , Síndromes de Imunodeficiência/fisiopatologiaRESUMO
CD4+ T follicular helper cells (TFH) were assessed in adult patients with common variable immune deficiency (CVID) classified according to the presence of granulomatous disease (GD), autoimmunity (AI), or both GD and AI (Group I) or the absence of AI and GD (Group II). TFH lymphocytes were characterized by expression of CXCR5 and PD-1. TFH were higher (in both absolute number and percentage) in Group I than in Group II CVID patients and normal controls (N). Within CXCR5+CD4+ T cells, the percentage of PD-1 (+) was higher and that of CCR7 (+) was lower in Group I than in Group II and N. The percentages of Treg and TFH reg were similar in both CVID groups and in N. TFH responded to stimulation increasing the expression of the costimulatory molecules CD40L and ICOS as did N. After submitogenic PHA+IL-2 stimulation, intracellular expression of TFH cytokines (IL-10, IL-21) was higher than N in Group I, and IL-4 was higher than N in Group II. These results suggest that TFH are functional in CVID and highlight the association of increased circulating TFH with AI and GD manifestations.
Assuntos
Imunodeficiência de Variável Comum/imunologia , Regulação da Expressão Gênica/imunologia , Doença Granulomatosa Crônica/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Autoimunidade , Ligante de CD40/genética , Ligante de CD40/imunologia , Estudos de Casos e Controles , Imunodeficiência de Variável Comum/complicações , Imunodeficiência de Variável Comum/genética , Imunodeficiência de Variável Comum/patologia , Feminino , Doença Granulomatosa Crônica/complicações , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/patologia , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Proteína Coestimuladora de Linfócitos T Induzíveis/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-2/farmacologia , Interleucina-4/genética , Interleucina-4/imunologia , Interleucinas/genética , Interleucinas/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Fito-Hemaglutininas/farmacologia , Cultura Primária de Células , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Receptores CCR7/genética , Receptores CCR7/imunologia , Receptores CXCR5/genética , Receptores CXCR5/imunologia , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/patologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/patologiaAssuntos
Doença Granulomatosa Crônica/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Macrófagos/efeitos dos fármacos , Mitocôndrias/metabolismo , Fagocitose , Tiazolidinedionas/administração & dosagem , Adolescente , Adulto , Animais , Células Cultivadas , Criança , Modelos Animais de Doenças , Feminino , Doença Granulomatosa Crônica/imunologia , Humanos , Mediadores da Inflamação/metabolismo , Macrófagos/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , PPAR gama/metabolismo , Fagocitose/efeitos dos fármacos , Pioglitazona , Espécies Reativas de Oxigênio/metabolismo , Adulto JovemRESUMO
Chronic granulomatous disease is a primary immunodeficiency caused by mutations in the genes encoding subunits of the phagocytic NADPH oxidase system. Patients can present with severe, recurrent infections and noninfectious conditions. Among the latter, inflammatory manifestations are predominant, especially granulomas and colitis. In this article, we systematically review the possible mechanisms of hyperinflammation in this rare primary immunodeficiency condition and their correlations with clinical aspects.