RESUMO
Severe combined immunodeficiency, SCID, is a pediatric emergency that represents the most critical group of inborn errors of immunity (IEI). Affected infants present with early onset life-threatening infections due to absent or non-functional T cells. Without early diagnosis and curative treatment, most die in early infancy. As most affected infants appear healthy at birth, newborn screening (NBS) is essential to identify and treat patients before the onset of symptoms. Here, we report 47 Brazilian patients investigated between 2009 and 2020 for SCID due to either a positive family history and/or clinical impression and low TRECs. Based on clinical presentation, laboratory finding, and genetic information, 24 patients were diagnosed as typical SCID, 14 as leaky SCID, and 6 as Omenn syndrome; 2 patients had non-SCID IEI, and 1 remained undefined. Disease onset median age was 2 months, but at the time of diagnosis and treatment, median ages were 6.5 and 11.5 months, respectively, revealing considerable delay which affected negatively treatment success. While overall survival was 51.1%, only 66.7% (30/45) lived long enough to undergo hematopoietic stem-cell transplantation, which was successful in 70% of cases. Forty-three of 47 (91.5%) patients underwent genetic testing, with a 65.1% success rate. Even though our patients did not come from the NBS programs, the diagnosis of SCID improved in Brazil during the pilot programs, likely due to improved medical education. However, we estimate that at least 80% of SCID cases are still missed. NBS-SCID started to be universally implemented in the city of São Paulo in May 2021, and it is our hope that other cities will follow, leading to early diagnosis and higher survival of SCID patients in Brazil.
Assuntos
Imunodeficiência Combinada Severa , Brasil/epidemiologia , Criança , DNA/genética , Humanos , Lactente , Recém-Nascido , Triagem Neonatal , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/epidemiologia , Imunodeficiência Combinada Severa/genética , Linfócitos TRESUMO
CD40 ligand (CD40L) deficiency is a rare inborn error of immunity presenting with heterogeneous clinical manifestations. While a detailed characterization of patients affected by CD40L deficiency is essential to an accurate diagnosis and management, information about this disorder in Latin American patients is limited. We retrospectively analyzed data from 50 patients collected by the Latin American Society for Immunodeficiencies registry or provided by affiliated physicians to characterize the clinical, laboratory, and molecular features of Latin American patients with CD40L deficiency. The median age at disease onset and diagnosis was 7 months and 17 months, respectively, with a median diagnosis delay of 1 year. Forty-seven patients were genetically characterized revealing 6 novel mutations in the CD40LG gene. Pneumonia was the most common first symptom reported (66%). Initial immunoglobulin levels were variable among patients. Pneumonia (86%), upper respiratory tract infections (70%), neutropenia (70%), and gastrointestinal manifestations (60%) were the most prevalent clinical symptoms throughout life. Thirty-five infectious agents were reported, five of which were not previously described in CD40L deficient patients, representing the largest number of pathogens reported to date in a cohort of CD40L deficient patients. The characterization of the largest cohort of Latin American patients with CD40L deficiency adds novel insights to the recognition of this disorder, helping to fulfill unmet needs and gaps in the diagnosis and management of patients with CD40L deficiency.
Assuntos
Ligante de CD40 , Síndromes de Imunodeficiência , Ligante de CD40/genética , Estudos de Coortes , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , América Latina/epidemiologia , Estudos RetrospectivosRESUMO
PURPOSE: There is still scarce data on SARS-CoV-2 infection in patients with Inborn Errors of Immunity (IEI) and many unresolved questions. We aimed to describe the clinical outcome of SARS-CoV-2 infection in Brazilian IEI patients and identify factors influencing the infection. METHODS: We did a cross-sectional, multicenter study that included patients of any age affected by IEI and SARS-CoV-2 infection. The variables studied were sex, age, type of IEI, comorbidities (number and type), treatment in use for IEI, clinical manifestations and severity of SARS-CoV-2 infection. RESULTS: 121 patients were included: 55.4% female, ages from six months to 74 yo (median age = 25.1 yo). Most patients had predominantly antibody deficiency (n = 53). The infection was mostly asymptomatic (n = 21) and mild (n = 66), and one child had multisystem inflammatory syndrome (MIS-C). We could not observe sex-related susceptibility, and there was a weak correlation between age and severity of infection. The number of comorbidities was higher in severe cases, particularly bronchiectasis and cardiopathy. There were no severe cases in hereditary angioedema patients. Six patients aged 2 to 74 years died, three of them with antibody deficiency. CONCLUSION: The outcome was mild in most patients, but the Case Fatality Ratio was higher than in the general population. However, the type of IEI was not a determining factor for severity, except for complement deficiencies linked to milder COVID-19. The severity of SARS-CoV-2 infection seems to be more related to older age, a higher number of comorbidities and type of comorbidities (bronchiectasis and cardiopathy).
Assuntos
COVID-19/diagnóstico , Doenças da Imunodeficiência Primária/diagnóstico , SARS-CoV-2/fisiologia , Síndrome de Resposta Inflamatória Sistêmica/diagnóstico , Adulto , Doenças Assintomáticas , Brasil , COVID-19/mortalidade , Estudos Transversais , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças da Imunodeficiência Primária/mortalidade , Índice de Gravidade de Doença , Análise de Sobrevida , Síndrome de Resposta Inflamatória Sistêmica/mortalidade , Adulto JovemRESUMO
BACKGROUND: Patients with X-linked hyper-IgM syndrome caused by CD40 ligand (CD40L) deficiency often present with episodic, cyclic, or chronic neutropenia, suggesting abnormal neutrophil development in the absence of CD40L-CD40 interaction. However, even when not neutropenic and despite immunoglobulin replacement therapy, CD40L-deficient patients are susceptible to life-threatening infections caused by opportunistic pathogens, suggesting impaired phagocyte function and the need for novel therapeutic approaches. OBJECTIVES: We sought to analyze whether peripheral neutrophils from CD40L-deficient patients display functional defects and to explore the in vitro effects of recombinant human IFN-γ (rhIFN-γ) on neutrophil function. METHODS: We investigated the microbicidal activity, respiratory burst, and transcriptome profile of neutrophils from CD40L-deficient patients. In addition, we evaluated whether the lack of CD40L in mice also affects neutrophil function. RESULTS: Neutrophils from CD40L-deficient patients exhibited defective respiratory burst and microbicidal activity, which were improved in vitro by rhIFN-γ but not soluble CD40L. Moreover, neutrophils from patients showed reduced CD16 protein expression and a dysregulated transcriptome suggestive of impaired differentiation. Similar to CD40L-deficient patients, CD40L knockout mice were found to have impaired neutrophil responses. In parallel, we demonstrated that soluble CD40L induces the promyelocytic cell line HL-60 to proliferate and mature by regulating the expression of genes of the same Gene Ontology categories (eg, cell differentiation) when compared with those dysregulated in peripheral blood neutrophils from CD40L-deficient patients. CONCLUSION: Our data suggest a nonredundant role of CD40L-CD40 interaction in neutrophil development and function that could be improved in vitro by rhIFN-γ, indicating a potential novel therapeutic application for this cytokine.
Assuntos
Ligante de CD40/deficiência , Interferon gama/farmacologia , Neutrófilos/efeitos dos fármacos , Animais , Ligante de CD40/imunologia , Feminino , Células HL-60 , Humanos , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Neutrófilos/fisiologia , Paracoccidioides , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes/farmacologia , Explosão Respiratória/efeitos dos fármacos , Staphylococcus aureus , Acetato de Tetradecanoilforbol/farmacologia , Transcriptoma/efeitos dos fármacosRESUMO
INTRODUÇÃO: O leite de vaca é a maior causa de alergia alimentar na infância. O teste de provocação oral duplo cego placebo controlado (TPODCPC) é considerado padrão ouro no diagnóstico, mas dificuldades relacionadas à sua realização têm estimulado a utilização dos testes cutâneos de leitura imediata (TCLI) complementando a história clínica como alternativa no diagnóstico. OBJETIVO: avaliar a efetividade deste meio diagnóstico em crianças com alergia às proteínas do leite de vaca (APLV) atendidas em hospital terciário. MÉTODOS: os dados de anamnese e os resultados dos TCLI foram extraídos dos registros dos prontuários médicos em estudo observacional, transversal, retrospectivo. Os reagentes utilizados foram extrato alergênico comercial e leite de vaca in natura. RESULTADOS: Foram incluídas 103 crianças, com mediana de idade de 41,2 (24,0;72,0) meses. Como desfecho, avaliou-se a presença de sintomas relacionados à alergia ao leite de vaca mediante seu consumo. A maioria das crianças com história pouco sugestiva de APLV e resultados dos testes negativos (79 crianças) foi orientada a introduzir o leite de vaca em domicílio. Entre elas, três (3,8%) apresentaram reações leves (diarreia e eczema) e não houve relato de anafilaxia. Considerando o valor de cut off de 3 mm para os TCLI, os dois extratos alergênicos demostraram ser úteis na avaliação das crianças com APLV, mas o leite de vaca in natura mostrou melhor sensibilidade (86,4%) e maior valor preditivo negativo (96,2%) quando comparado ao extrato alergênico comercial (IC95%). A análise da história clínica complementada pelos resultados dos TCLI possibilitou reintroduzir o leite de vaca em 81 crianças (78,6%), sem necessidade de teste de provocação...(AU)
Assuntos
Humanos , Masculino , Feminino , Criança , Sistema Único de Saúde , Brasil , Saúde Pública , Hipersensibilidade a LeiteRESUMO
Abstract Objective To apply, in Brazil, the T-cell receptor excision circles (TRECs) quantification technique using real-time polymerase chain reaction in newborn screening for severe combined immunodeficiency and assess the feasibility of implementing it on a large scale in Brazil. Methods 8715 newborn blood samples were collected on filter paper and, after DNA elution, TRECs were quantified by real-time polymerase chain reaction. The cutoff value to determine whether a sample was abnormal was determined by ROC curve analysis, using SSPS. Results The concentration of TRECs in 8,682 samples ranged from 2 to 2,181 TRECs/µL of blood, with mean and median of 324 and 259 TRECs/µL, respectively. Forty-nine (0.56%) samples were below the cutoff (30 TRECs/µL) and were reanalyzed. Four (0.05%) samples had abnormal results (between 16 and 29 TRECs/µL). Samples from patients previously identified as having severe combined immunodeficiency or DiGeorge syndrome were used to validate the assay and all of them showed TRECs below the cutoff. Preterm infants had lower levels of TRECs than full-term neonates. The ROC curve showed a cutoff of 26 TRECs/µL, with 100% sensitivity for detecting severe combined immunodeficiency. Using this value, retest and referral rates were 0.43% (37 samples) and 0.03% (3 samples), respectively. Conclusion The technique is reliable and can be applied on a large scale after the training of technical teams throughout Brazil.
Resumo Objetivo Aplicar no Brasil a técnica de quantificação de T-cell Receptor Excision Circles (TRECs) por PCR em tempo real para triagem neonatal de imunodeficiência combinada grave (SCID) e avaliar se é possível fazê-la em grande escala em nosso país. Métodos Foram coletadas em papel filtro 8.715 amostras de sangue de recém-nascidos e, após eluição do DNA, os TRECs foram quantificados por PCR em tempo real. O valor de corte para determinar se uma amostra é anormal foi determinado pela análise de curva ROC com o programa SSPS. Resultados A concentração de TRECs em 8.682 amostras analisadas variou entre 2 e 2.181 TRECs/µL de sangue, com média e mediana de 324 e 259 TRECs/µL, respectivamente. Das amostras, 49 (0,56%) ficaram abaixo do valor de corte (30 TRECs/µL) e foram requantificadas. Quatro (0,05%) mantiveram resultados anormais (entre 16 e 29 TRECs/µL). Amostras de pacientes com diagnóstico clínico prévio de SCID e síndrome de DiGeorge foram usadas para validar o ensaio e todas apresentaram concentração de TRECs abaixo do valor de corte. Recém-nascidos prematuros apresentaram menores níveis de TRECs comparados com os nascidos a termo. Com o uso da curva ROC em nossos dados, chegamos ao valor de corte de 26 TRECs/µL, com sensibilidade de 100% para detecção de SCID. Com o uso desse valor, as taxas de repetição e encaminhamento ficaram em 0,43% (37 amostras) e 0,03% (3 amostras), respectivamente. Conclusão A técnica é factível e pode ser implantada em grande escala, após treinamento técnico das equipes envolvidas.
Assuntos
Humanos , Masculino , Feminino , Recém-Nascido , Receptores de Antígenos de Linfócitos T/sangue , Triagem Neonatal/métodos , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/sangue , Valores de Referência , Fatores de Tempo , Brasil , Receptores de Antígenos de Linfócitos T/genética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Fatores Etários , Estatísticas não Paramétricas , Teste em Amostras de Sangue Seco , Reação em Cadeia da Polimerase em Tempo RealRESUMO
OBJECTIVE: To apply, in Brazil, the T-cell receptor excision circles (TRECs) quantification technique using real-time polymerase chain reaction in newborn screening for severe combined immunodeficiency and assess the feasibility of implementing it on a large scale in Brazil. METHODS: 8715 newborn blood samples were collected on filter paper and, after DNA elution, TRECs were quantified by real-time polymerase chain reaction. The cutoff value to determine whether a sample was abnormal was determined by ROC curve analysis, using SSPS. RESULTS: The concentration of TRECs in 8,682 samples ranged from 2 to 2,181TRECs/µL of blood, with mean and median of 324 and 259TRECs/µL, respectively. Forty-nine (0.56%) samples were below the cutoff (30TRECs/µL) and were reanalyzed. Four (0.05%) samples had abnormal results (between 16 and 29TRECs/µL). Samples from patients previously identified as having severe combined immunodeficiency or DiGeorge syndrome were used to validate the assay and all of them showed TRECs below the cutoff. Preterm infants had lower levels of TRECs than full-term neonates. The ROC curve showed a cutoff of 26TRECs/µL, with 100% sensitivity for detecting severe combined immunodeficiency. Using this value, retest and referral rates were 0.43% (37 samples) and 0.03% (3 samples), respectively. CONCLUSION: The technique is reliable and can be applied on a large scale after the training of technical teams throughout Brazil.
Assuntos
Triagem Neonatal/métodos , Receptores de Antígenos de Linfócitos T/sangue , Imunodeficiência Combinada Severa/sangue , Imunodeficiência Combinada Severa/diagnóstico , Fatores Etários , Brasil , Teste em Amostras de Sangue Seco , Feminino , Humanos , Recém-Nascido , Masculino , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Antígenos de Linfócitos T/genética , Valores de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Estatísticas não Paramétricas , Fatores de TempoRESUMO
Hyper-IgM (HIGM) syndrome is a heterogeneous group of disorders characterized by normal or elevated serum IgM levels associated with absent or decreased IgG, IgA and IgE. Here we summarize data from the HIGM syndrome Registry of the Latin American Society for Immunodeficiencies (LASID). Of the 58 patients from 51 families reported to the registry with the clinical phenotype of HIGM syndrome, molecular defects were identified in 37 patients thus far. We retrospectively analyzed the clinical, immunological and molecular data from these 37 patients. CD40 ligand (CD40L) deficiency was found in 35 patients from 25 families and activation-induced cytidine deaminase (AID) deficiency in 2 unrelated patients. Five previously unreported mutations were identified in the CD40L gene (CD40LG). Respiratory tract infections, mainly pneumonia, were the most frequent clinical manifestation. Previously undescribed fungal and opportunistic infections were observed in CD40L-deficient patients but not in the two patients with AID deficiency. These include the first cases of pneumonia caused by Mycoplasma pneumoniae, Serratia marcescens or Aspergillus sp. and diarrhea caused by Microsporidium sp. or Isospora belli. Except for four CD40L-deficient patients who died from complications of presumptive central nervous system infections or sepsis, all patients reported in this study are alive. Four CD40L-deficient patients underwent successful bone marrow transplantation. This report characterizes the clinical and genetic spectrum of HIGM syndrome in Latin America and expands the understanding of the genotype and phenotype of this syndrome in tropical areas.
Assuntos
Síndrome de Imunodeficiência com Hiper-IgM/epidemiologia , Ligante de CD40/deficiência , Ligante de CD40/genética , Pré-Escolar , Comorbidade , Citidina Desaminase/deficiência , Citidina Desaminase/genética , Feminino , Hispânico ou Latino , Humanos , Síndrome de Imunodeficiência com Hiper-IgM/complicações , Síndrome de Imunodeficiência com Hiper-IgM/diagnóstico , Síndrome de Imunodeficiência com Hiper-IgM/terapia , Lactente , Recém-Nascido , Infecções/diagnóstico , Infecções/etiologia , Pulmão/patologia , Masculino , Sistema de Registros , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
<p><b>OBJECTIVES</b>To examine nonylphenol (NP) and 4-t-octylphenol (OP) concentrations and general water quality indicators along a river in the greater Tokyo area and to specify the distribution and origin of alkylphenols.</p><p><b>METHODS</b>Water was sampled from the Edogawa River, a main river in the greater Tokyo area, which is a source of public drinking water; and the Sakagawa River system, a tributary of the Edogawa River. To determine alkylphenol in river water. NP and OP concentrations were quantified using gas chromatography-mass spectrometry (GC-MS).</p><p><b>RESULTS</b>The detection rates of NP above the detection limit were 100% in both rivers, and those of OP were 75.0% in the Edogawa River and 92.9% in the Sakagawa River system. The median NP and OP concentrations in the Edogawa River were 0.24 μg/1 and 0.066 μg/l, and those in the Sakagawa River system were 0.87 μg/l and 0.19 μg/l respectively. Alkylphenol concentrations are significantly higher in the Sakagawa River system than in the Edogawa River. In the Sakagawa River system, the NP and OP concentrations were highest in the water along the nonindustrial area with an underdeveloped sewerage system.</p><p><b>CONCLUSIONS</b>NP and OP were detected widely in the Edogawa River and Sakagawa River system. Endocrine-disrupting chemical (EDC) pollution in a river by the inflow of urban wastewater was demonstrated. A systematic monitoring of alkylphenols in tributary rivers and streams as well as in main rivers will help control EDC pollution and protect the source of drinking water in urban areas.</p>
RESUMO
Objectives: To examine nonylphenol (NP) and 4-t-octylphenol (OP) concentrations and general water quality indicators along a river in the greater Tokyo area and to specify the distribution and origin of alkylphenols. Methods: Water was sampled from the Edogawa River, a main river in the greater Tokyo area, which is a source of public drinking water; and the Sakagawa River system, a tributary of the Edogawa River. To determine alkylphenol in river water, NP and OP concentrations were quantified using gas chromatography-mass spectrometry (GC-MS). Results: The detection rates of NP above the detection limit were 100% in both rivers, and those of OP were 75.0% in the Edogawa River and 92.9% in the Sakagawa River system. The median NP and OP concentrations in the Edogawa River were 0.24 μg/l and 0.066 μg/l, and those in the Sakagawa River system were 0.87 μg/l and 0.19 μg/l respectively. Alkylphenol concentrations are significantly higher in the Sakagawa River system than in the Edogawa River. In the Sakagawa River system, the NP and OP concentrations were highest in the water along the nonindustrial area with an underdeveloped sewerage system. Conclusions: NP and OP were detected widely in the Edogawa River and Sakagawa River system. Endocrine-disrupting chemical (EDC) pollution in a river by the inflow of urban wastewater was demonstrated. A systematic monitoring of alkylphenols in tributary rivers and streams as well as in main rivers will help control EDC pollution and protect the source of drinking water in urban areas.