[Recommendations about immunizations in patients with inborn errors of immunity]. / Recomendaciones para la inmunización de pacientes con errores innatos de la inmunidad.

Inborn errors of immunity (IEI) are a heterogeneous group of hereditary disorders that affect in number and/or function different components of the immune system, resulting in an increased risk and severity of infections, autoimmune diseases, allergic manifestations, autoinflammation and malignancy. Inactivated vaccines are generally safe in these patients, but may be ineffective in some cases, due to difference in immunogenicity. However, live viral and bacterial vaccines may lead to disease, with high morbidity and mortality, so it is essential a previous immunological work-out. In this document, the Pediatric Immunology Work Group of the Sociedad Argentina de Pediatría summarizes recommendations about immunizations in patients with IEI, their household contacts, as well as in patients under immunosuppressive treatment and hematopoietic stem cell transplant recipients.

Los errores innatos de la inmunidad (EII) constituyen un grupo heterogéneo de enfermedades hereditarias que afectan el número y/o la función de los distintos componentes del sistema inmune, lo que predispone a un incremento de la tasa y gravedad de infecciones, enfermedades autoinmunes, manifestaciones alérgicas, autoinflamación y malignidad. En estos pacientes, la inmunización con vacunas inactivadas es generalmente segura, pero puede no ser efectiva en determinados grupos de EII, sin generar el efecto protector deseado. La aplicación de vacunas vivas atenuadas (virales y bacterianas) puede llevar al desarrollo de enfermedad asociada a la inmunización, con elevada morbimortalidad, por lo que amerita previamente consultar al especialista. El presente informe resume las conclusiones del Grupo de Trabajo de Inmunología de la Sociedad Argentina de Pediatría respecto a la vacunación en pacientes con EII y sus convivientes, en pacientes bajo inmunosupresión farmacológica y en receptores de trasplante de células precursoras hematopoyéticas.

Ataxia-telangiectasia in Latin America: clinical features, immunodeficiency, and mortality in a multicenter study.

Ataxia-telangiectasia (AT) is a rare genetic disorder leading to neurological defects, telangiectasias, and immunodeficiency. We aimed to study the clinical and immunological features of Latin American patients with AT and analyze factors associated with mortality. Referral centers from 9 Latin American countries participated in this retrospective cohort study, and 218 patients were included. Median (IQR) ages at symptom onset and diagnosis were 1.0 (1.0-2.0)  and 5.0 (3.0-8.0) years, respectively. Most patients presented recurrent airway infections, which was significantly associated with IgA deficiency. IgA deficiency was observed in 60.8% of patients and IgG deficiency in 28.6%. T- and B-lymphopenias were also present in most cases. Mean survival was 24.2 years, and Kaplan-Meier 20-year-survival rate was 52.6%, with higher mortality associated with female gender and low IgG levels. These findings suggest that immunologic status should be investigated in all patients with AT.

Clinical, immunological, and genetic description of a Mexican cohort of patients with DOCK8 deficiency.

PURPOSE: We aimed to describe the clinical, immunological, and genetic features of patients with DOCK8 deficiency (DOCK8-Def) in a tertiary care center for children. METHODS: Retrospective chart review of patients' clinical, immunological, and genetic characteristics with DOCK8-Def. Genetic analysis was performed with targeted- or whole-exome sequencing; we also assessed DOCK8 protein expression and a lymphoproliferation assay and analyzed survival by the Kaplan-Meier method. RESULTS: We described 11 patients from 8 unrelated kindreds. The median age at symptoms' onset was 10 months (range 1-54 months). The median follow-up time was 53.4 months (4.8-118.8). All patients presented eczema and recurrent sinopulmonary and cutaneous infections. Besides those symptoms, the most frequent manifestations were bronchiectases (8/11), food allergies (6/11), and severe infections (6/11). Infrequent characteristics were detection of CMV in bronchial lavage, C. parvum-driven sclerosing cholangitis, Takayasu vasculitis, neurological syndromes, pulmonary tuberculosis, and lymphomatoid granulomatosis. CONCLUSION: DOCK8-Def has a broad spectrum of manifestations, including allergy, autoimmunity, inflammation, infection, and cancer. The hallmark of this inborn error of immunity is IEI-associated eczema with eosinophilia and increased IgE. Here, we report six new mutations causing human DOCK8 deficiency and symptoms previously unrecognized to occur in DOCK8-Def. Therefore, an early diagnosis of DOCK8-Def is essential to facilitate an adequate treatment such as HSCT.

ASIA and BIA-ALCL as adverse reactions to silicone breast implants / ASIA e BIA-ALCL como reações adversas aos implantes mamários de silicone

Adjuvant-induced autoimmune/inflammatory syndrome leads to capsular contracture and fibrosis from the oxidation that takes place in silicone. Anaplastic large cell lymphoma occurs through the development of a seroma, with the formation of a periprosthetic effusion, or through the infiltration of the condition itself. To analyze these conditions, a review of the literature was carried out on the symptoms and pathophysiology of the autoimmune/inflammatory syndrome induced by adjuvants and anaplastic large cell lymphoma, searched using the terms "ASIA breast silicone," "Lymphoma," "Adjuvants" "Immunologic" " Breast Implants" on the PubMed platform. Analyzing the data obtained, it was noted that the symptoms of the autoimmune/inflammatory syndrome induced by adjuvants are nonspecific, such as fatigue, myalgia, arthralgia, morning stiffness, and night sweats, and therefore need attention. Anaplastic large cell lymphoma presents with breast pain, periprosthetic effusion, and palpable mass, among other characteristics. Because of these aspects, it is concluded that a good investigation should be carried out when nonspecific symptoms appear, regardless of the time the surgery was performed since these complications can occur years later.

A síndrome autoimune/inflamatória induzida por adjuvantes leva à contratura capsular e fibrose pela oxidação que acontece no silicone. O linfoma anaplásico de grandes células ocorre através do desenvolvimento de um seroma, com a formação de derrame periprotético ou por uma infiltração da própria afecção. Para análise destes acometimentos, foi realizada uma revisão da literatura acerca da sintomatologia e fisiopatologia da síndrome autoimune/inflamatória induzida por adjuvantes e linfoma anaplásico de grandes células, pesquisada através dos termos "ASIA breast silicone" "Lymphoma" "Adjuvants" "Immunologic" "Breast Implants" na plataforma PubMed. Analisando os dados obtidos, notou-se que os sintomas da síndrome autoimune/inflamatória induzida por adjuvantes são inespecíficos, como fadiga, mialgia, artralgia, rigidez matinal e suores noturnos, e, portanto, necessitam de atenção. Já o linfoma anaplásico de grandes células se apresenta com dor mamária, derrame periprotético, massa palpável, dentre outras características. Em vista destes aspectos, conclui-se que uma boa investigação deve ser realizada ao surgirem sintomas inespecíficos, independentemente do tempo que a cirurgia foi realizada, uma vez que estas complicações podem ocorrer anos após a cirurgia.

Eosinophilia and elevated IgE serum levels: a red flag: when your diagnosis is not a common atopic eczema or common allergy.

OBJECTIVE AND DESIGN: The hallmark of type 2 inflammation is eosinophilia and/or high IgE serum levels, mostly in atopic dermatitis. Nevertheless, many dermatoses may present similar findings. Our aim is to explore the biological and clinical spectrum of cutaneous manifestations involving tissue and/or systemic eosinophilia, and distinct serum levels of IgE, where atopic dermatitis or other primary allergic eczema, not always is the definitive diagnosis. MATERIALS/METHODS: A total of 37 scientific papers were enrolled in this narrative review. RESULTS: A diagnostic approach for patients with elevated serum IgE level and a list of conditions not related to atopic dermatitis that runs through inborn errors of immunity, inflammatory disorders, lung disorders, malignancy, infections/infestations are displayed. Regarding to peripheral eosinophilia, differential diagnosis is also explored and clinical patterns of skin diseases associated with tissue eosinophilia are listed, to facilitate our diagnosis. CONCLUSIONS: We should maintain a high level of suspicion about other differential diagnosis involving eosinophilia and IgE dysregulation, especially in patients very young (when innate errors of the immunity may present) and in middle to elderly patients classified as having atopic dermatitis, due to the possibility of cutaneous hematological malignancies, paraneoplasia or autoimmune blistering diseases.

Macrophage Activation Syndrome as a Complication of Chronic Granulomatous Disease: A Case Report.

Chronic granulomatous disease (CGD) presents with granuloma formation and lethal infections. It is inherited in an autosomal or X-linked recessive pattern. We describe a 10-month-old patient with a fatal secondary HLH as a CGD primary manifestation. We carried out an autopsy and found noncaseating granulomas, an aspergilloma in the lung, and hemophagocytosis. We performed a DHR assay on the patient's mother and grandmother, showing a bimodal pattern conclusive of X-linked CGD. Thus, our definitive diagnosis was CGD complicated by macrophage activation syndrome. CGD is caused by phagocytes' inability to control pathogens, resulting in granulomas. Secondary HLH is a severe complication and could be characterized by the proliferation of macrophages and T lymphocytes and the production of proinflammatory cytokines. The early suspicion of this presentation helps establish a specific treatment, and the study of the carriers helps determine the etiology.

Manejo clínico y diagnóstico para pacientes con enfermedades de inmunodeficiencia primaria por déficit de producción de anticuerpos / Clinical management and diagnosis for patients with primary immunodeficiency diseases due to deficiency of antibody production

1. INTRODUCCIÓNLas inmunodeficiencias primarias son un grupo de más de 400 enfermedades, en las cuales el sistema inmune pierde sus funciones de reconocimiento de patógenos o funciona de forma inapropiada. Algunas de ellas son relativamente comunes; mientras otras son raras. Estas enfermedades son en ocasiones de por vida, debilitantes y costosas1,2.Sin embargo, muchos progresos se han hecho desde su des-cripción original en el año de 1952. Se han dado grandes pasos en cuanto a su entendimiento de las Inmunodeficiencias Pri-marias a nivel genético, de sus características, y tratamiento. Algunos tipos afectan un único tipo de célula; otros afectan más de un componente del sistema inmune2,3.Tomando en cuenta que la aproximación es entre 1-2% de la población, a nivel país se puede decir que un aproximado entre 170 000 a 340 000 pacientes en el país no cuentan con un diagnóstico y muchos mueren por falta de este. El número de afiliados al Instituto Ecuatoriano de Seguridad Social hasta julio de 2021 es de 3 672,611 por lo que se considera que un estimado de 36 726 a 73 452 pacientes podrían presentar este tipo de enfermedades y requerir de atención por infecciones a repetición, enfermedad autoinmune y enfermedades linfopro-liferativas, además de que sin un tratamiento específico po-drían fallecer debido a infecciones graves o tener discapacidad permanente, lo que implica mayor carga para el sistema de Seguridad Social en subsidios y menores ingresos. Ecuador, cuenta con 86 pacientes diagnosticados, según la base de datos de la Sociedad Latino-Americana de Inmunodeficiencias4.Algunas terapias, como la de reemplazo para inmunoglobu-linas, a la que es tributaria más del 60% de estas patologías permite que la esperanza de vida y la morbilidad casi alcancen a aquellos que no presentan la enfermedad5­7.

1. INTRODUCTIONPrimary immunodeficiencies are a group of more than 400 diseases, in which the immune system loses its pathogen recog-nition functions or functions inappropriately. Some of them are relatively common, while others are rare. These diseases are sometimes lifelong, debilitating, and costly1,2. However, much progress has been made since its original description in 1952. Great strides have been made in understanding Primary Immunodeficiencies at the genetic level, their characteristics, and treatment. Some types affect only one type of cell; others affect more than one component of the immune system2,3. Considering that the approximation is between 1 to 2% of the population, at the country level we could say that approximately between 170 000 to 340 000 patients in the country do not have a diagnosis and many die due to lack of it. The number of social security affiliates until July 2021 is 3 672,611, so we could consider that approximately 36 726 to 73 452 patients could present this type of disease and require care for recurrent infections, autoimmune disease and lymphoproliferative diseases, in addition to the fact that without specific treatment they could die due to serious infections or have permanent disability, which implies a greater burden for the social security system in subsidies and lower income. Currently the country has 86 diagnosed patients, according to the database of the Latin American Society of Immunodeficiencies4. Many of the therapies, such as immunoglobulin replacement therapy, to which more than 60% of these pathologies are de-pendent, allow life expectancy and morbidity to almost reach those who do not have the disease 5­7.

Knowledge and clinical practices of orthodontists regarding the treatment of patients with aids. A nationwide study

Aim: To evaluate orthodontists' knowledge and clinical practices regarding the treatment of patients with HIV/AIDS. Methods: Cross-sectional study performed with 655 Brazilian orthodontists based on a previously calculated sample size. Self-administered questionnaires were sent to orthodontists to collect information on knowledge and clinical conduct regarding the care of patients with HIV/AIDS. The study evaluated the awareness of possible risk factors for contamination, oral manifestations of HIV, need for more information on the care of HIV-positive patients, whether orthodontic treatment is indicated in HIV-positive patients, and whether they had knowingly performed orthodontic treatment in HIV-positive patients. Simple regression models were adjusted, and crude Odds Ratios estimated the associations with 95% confidence intervals. The variables with P < 0.20 in the crude analysis were tested in multiple logistic regression models, and those with P ≤ 0.05 were maintained in the final model. Magnitudes were estimated by adjusted Odds Ratios values, with 95% confidence intervals. Results: Orthodontists who were aware of the oral manifestations of HIV/AIDS, those having work experience of more than 20 years, and those who believed that orthodontic treatment could be indicated for these patients were 3.30 (1.79-6.10), 2.74 (1.36-5.52) and 1.92 (1.13-3.24) times more likely to perform orthodontic treatment in HIV-positive patients, respectively. Most orthodontists (92.9%) reported they needed to obtain more information about orthodontic care in patients with HIV/AIDS. Conclusion: Although orthodontists reported feeling able and qualified to provide dental care to patients with HIV/AIDS, gaps in their knowledge need to be addressed with further training

Criptococosis meníngea en un paciente con linfopenia T-CD4+ idiopática / Cryptococcal meningitis in a patient with idiopathic CD4+ T lymphopenia

RESUMEN La infección por el virus de la inmunodeficiencia humana es el factor de riesgo principal para desarrollar criptococosis meníngea; sin embargo, existe una entidad poco conocida, la linfopenia T-CD4+ idiopática, que genera un inexplicable déficit de células T-CD4+ circulantes predisponiendo a variadas complicaciones, entre ellas la infección por gérmenes oportunistas. Presentamos el caso de un paciente con criptococosis meníngea secundaria a una linfopenia T-CD4+ idiopática, que a nuestro conocimiento es el primer caso reportado en el Perú. Esta enfermedad debería considerarse en pacientes negativos para el virus de inmunodeficiencia humana, que cursen con infecciones infrecuentes del sistema nervioso central, ya que la evolución, manejo y pronóstico podrían ser distintos en pacientes con esta condición.

ABSTRACT Infection with the human immunodeficiency virus (HIV) is the main risk factor for developing cryptococcal meningitis. However, there is a poorly known entity, idiopathic CD4+ T-cell lymphopenia, which leads to an unexplainable CD4+ circulating T-cell deficit, predisposing patients to many complications, including infections caused by opportunistic microorganisms. We present the case of a patient with cryptococcal meningitis secondary to idiopathic T-CD4+ lymphopenia, which, as far as we know, is the very first case of its kind reported in Peru. This entity should be considered in patients negative for HIV infection developing non-common infections of the central nervous system, since outcome, management, and prognosis may be different in patients with this condition.

Atualizando e expandindo o universo de: "Uma nova classe de doenças ­ doenças autoinflamatórias" / Updating and expanding the universe of: "A new class of diseases ­ autoinflammatory disorders"

As síndromes autoinflamatórias são doenças raras, genéticas de envolvimento prioritário da imunidade inata. Avanços nas técnicas de sequenciamento genético permitiram dissecar os genes envolvidos nestas doenças, continuamente organizando o quebra-cabeça genético e fisiopatológico de tais desordens. Este artigo revisa os últimos achados genéticos com seus respectivos fenótipos, código OMIM e ORPHA. Além disso, sugere cautela na triagem clínica e na indicação de métodos restritivos de sequenciamentos genéticos.

Autoinflammatory diseases comprise a group of rare, genetic disorders with priority involvement of innate immunity. Advances in genetic sequencing techniques allowed genetic dissection of genes involved in these diseases, with continuous organization of the genetic and pathophysiologic puzzle of these disorders. This article reviews the most recent genetic findings linked to respective phenotypes and OMIM and ORPHA codes. Moreover, it suggests caution in clinical screening and genetic sequencing indication with restrictive genetic panels.

CD40 Ligand Deficiency.

CD40 ligand deficiency (CD40L), currently classified as an inborn error of immunity affecting cellular and humoral immunity, prevalently emerges in boys within the first two years of life. It manifests itself as a decrease in serum IgG, IgA and IgE, with normal or high IgM, defects in T cell proliferation, and decrease in soluble CD40L. These accompany sinopulmonary and/or gastrointestinal infections, and there may be infections caused by pyogenic bacteria, opportunistic infections, autoimmune diseases, and neoplasms. Mild and moderate cases of this deficiency may respond well to prophylactic antibiotic therapy or to human immunoglobulin replacement therapy, in addition to the early treatment of infections. Severe cases can be treated with hematopoietic stem cell transplantation, which allows the healing of such patients, rather than sequelae and a poor progression. Thus, its differential diagnosis with other inborn errors of immunity is essential, especially CD40 deficiency and variable common immunodeficiency; the reason why we have proposed the present literature review.

Neuroendocrine tumor in a child with common variable immunodeficiency / Tumor neuroendócrino em criança com imunodeficiência comum variável

ABSTRACT Objective: To report a case of a child with primary immunodeficiency who at eight years developed digestive symptoms, culminating with the diagnosis of a neuroendocrine tumor at ten years of age. Case description: One-year-old boy began to present recurrent pneumonias in different pulmonary lobes. At four years of age, an immunological investigation showed a decrease in IgG and IgA serum levels. After the exclusion of other causes of hypogammaglobinemia, he was diagnosed with a Common Variable Immunodeficiency and started to receive monthly replacement of human immunoglobulin. The patient evolved well, but at 8 years of age began with epigastrium pain and, at 10 years, chronic persistent diarrhea and weight loss. After investigation, a neuroendocrine tumor was diagnosed, which had a rapid progressive evolution to death. Comments: Medical literature has highlighted the presence of gastric tumors in adults with Common Variable Immunodeficiency, emphasizing the importance of early diagnosis and the investigation of digestive neoplasms. Up to now there is no description of neuroendocrine tumor in pediatric patients with Common Variable Immunodeficiency. We believe that the hypothesis of digestive neoplasm is important in children with Common Variable Immunodeficiency and with clinical manifestations similar to the case described here in the attempt to improve the prognosis for pediatric patients.

RESUMO Objetivo: Relatar um caso de criança portadora de imunodeficiência primária que, aos oito anos, desenvolveu sintomas digestivos, culminando com o diagnóstico de tumor neuroendócrino aos dez anos de idade. Descrição do caso: Menino, com um ano de idade, começou a apresentar pneumonias de repetição em diferentes lobos pulmonares. Aos quatro anos, a investigação imunológica mostrou diminuição dos níveis séricos de IgG e IgA. Após exclusão de outras causas de hipogamaglobulinemia, teve diagnóstico de imunodeficiência comum variável, passando a receber reposição mensal de imunoglobulina humana. Evoluiu bem, porém, aos oito anos, começou com epigastralgia e, aos dez anos, diarreia crônica persistente e perda de peso. O quadro culminou com o diagnóstico de tumor neuroendócrino intestinal, de rápida progressão, com óbito do paciente. Comentários: A literatura tem chamado a atenção para tumores gástricos em adultos com imunodeficiência comum variável, alertando para a importância do diagnóstico precoce e da pesquisa de neoplasias digestivas. Até o momento, não há descrição de tumor neuroendócrino em pacientes pediátricos portadores de imunodeficiência comum variável. Acredita-se ser importante a hipótese de neoplasia digestiva diante de crianças com imunodeficiência comum variável e com manifestações clínicas semelhantes ao caso descrito, na tentativa de melhorar o prognóstico para pacientes pediátricos.

Transfusion-related acute lung injury associated to intravenous immunoglobulin infusion in a pediatric patient / Lesão pulmonar aguda relacionada à transfusão associada com infusão de imunoglobulina intravenosa em paciente pediátrico

ABSTRACT Case report of a patient with an immunodeficiency who demands regular replacement of intravenous immunoglobulin. She presented an episode of transfusion-related acute lung injury shortly after using an immunoglobulin product different than the one she usually received. The patient evolved with respiratory changes (hypoxia, dyspnea, change in pulmonary auscultation) minutes after the end of the infusion, and received non-invasive respiratory support. She was discharged after 36 hours with good outcome. The patient achieved full recovery, showing no further reactions in subsequent immunoglobulin infusions (no longer receiving the product that was used when she had the episode of transfusion-related acute lung injury). Although rare, this reaction is potentially serious and has no specific treatment other than supportive therapy. The literature is scarce regarding the risk of recurrence. The decision on whether to proceed with immunoglobulin therapy after this adverse effect should be analyzed individually, assessing the possible risks and benefits for the patient.

RESUMO Relato de caso de paciente com imunodeficiência que necessitava de reposição regular de imunoglobulina endovenosa. Ela apresentou um episódio de lesão pulmonar aguda relacionada à transfusão após uso de produto de imunoglobulina diferente daquele que recebia habitualmente. Evoluiu com alterações respiratórias (hipóxia, dispneia e alteração de ausculta pulmonar) minutos após o fim da infusão, necessitando de suporte respiratório não invasivo. A paciente recebeu alta hospitalar após 36 horas, com boa evolução. Obteve recuperação total dos sintomas, sem mais reações nas infusões subsequentes de imunoglobulina (sendo optado por não mais prescrever o produto que foi usado quando ocorreu o episódio de lesão pulmonar aguda relacionada à transfusão). Apesar de rara, essa reação é potencialmente grave, não possui tratamento específico além de terapia de suporte, e há pouca informação na literatura sobre o risco de recorrência. A decisão sobre o seguimento da terapia com imunoglobulina após esse efeito adverso deve ser analisada individualmente, avaliando os possíveis riscos e benefícios para o paciente.

Deficiência de anticorpos específicos antipolissacarídeos / Specific polysaccharide antibody deficiency

A deficiência de anticorpos específicos antipolissacarídeos é um dos erros inatos da imunidade predominantemente de anticorpos, destacando-se entre os defeitos mais frequentes. É caracterizada por uma permanência de imaturidade da resposta imunológica a antígenos polissacarídeos, estando normais linfócitos B, classes e subclasses de imunoglobulinas. O paciente apresenta maior suscetibilidade a infecções por bactérias encapsuladas, especialmente Streptococcus pneumoniae e Haemophilus influenzae. As principais manifestações clínicas são otites, sinusites, traqueobronquites e pneumonias de repetição; pode haver meningite pneumocócica e septicemia. A investigação é feita por titulação de anticorpos antipolissacarídeos antes e após a aplicação da vacina pneumocócica não conjugada. Até dois anos, há imaturidade fisiológica desse setor da imunidade, por isso, o diagnóstico não pode ser feito antes desta idade. O tratamento, além de antibiótico precoce em vigência de quadros infecciosos, inclui antibióticos profiláticos, aplicação de vacina conjugada com proteínas e/ou reposição de imunoglobulina humana endovenosa ou subcutânea. O diagnóstico e o tratamento precoce melhoram a qualidade de vida do paciente, diminuindo o risco de sequelas e até de óbito por infecção, e quando não são precoces, é possível que haja sequelas como bronquiectasias, hipoacusia ou danos neurológicos.

Specific polysaccharide antibody deficiency is an inborn error of immunity predominantly affecting antibodies, being one of the most frequent primary immunodeficiencies of childhood. It is characterized by persistent immaturity of the immune response to polysaccharide antigens, with normal levels of B lymphocytes, immunoglobulin classes and subclasses. Patients are more susceptible to infections by encapsulated bacteria, especially Streptococcus pneumoniae and Haemophilus influenzae. The main clinical manifestations are recurrent otitis, sinusitis, tracheobronchitis and pneumonia; there may be pneumococcal meningitis and septicemia. The investigation is done by dosages of polysaccharide antibodies before and after unconjugated pneumococcal vaccination. As this area of immunity is physiologically immature until two years of age, diagnosis cannot be made earlier. Treatment, in addition to antibiotics as soon as infections are detected, includes prophylactic antibiotic therapy, use of pneumococcal vaccine conjugated to protein and/or replacement of intravenous or subcutaneous human immunoglobulin. Early diagnosis and treatment improve patients' quality of life, reducing the risk of sequelae and even death from infection, while lack of early measures can lead to sequelae such as bronchiectasis, hearing loss and neurological damage.

Primary immunodeficiency and autoimmunity: A comprehensive review.

The primary immunodeficiency diseases (PIDs) include many genetic disorders that affect different components of the innate and adaptive responses. The number of distinct genetic PIDs has increased exponentially with improved methods of detection and advanced laboratory methodology. Patients with PIDs have an increased susceptibility to infectious diseases and non-infectious complications including allergies, malignancies and autoimmune diseases (ADs), the latter being the first manifestation of PIDs in several cases. There are two types of PIDS. Monogenic immunodeficiencies due to mutations in genes involved in immunological tolerance that increase the predisposition to develop autoimmunity including polyautoimmunity, and polygenic immunodeficiencies characterized by a heterogeneous clinical presentation that can be explained by a complex pathophysiology and which may have a multifactorial etiology. The high prevalence of ADs in PIDs demonstrates the intricate relationships between the mechanisms of these two conditions. Defects in central and peripheral tolerance, including mutations in AIRE and T regulatory cells respectively, are thought to be crucial in the development of ADs in these patients. In fact, pathology that leads to PID often also impacts the Treg/Th17 balance that may ease the appearance of a proinflammatory environment, increasing the odds for the development of autoimmunity. Furthermore, the influence of chronic and recurrent infections through molecular mimicry, bystander activation and super antigens activation are supposed to be pivotal for the development of autoimmunity. These multiple mechanisms are associated with diverse clinical subphenotypes that hinders an accurate diagnosis in clinical settings, and in some cases, may delay the selection of suitable pharmacological therapies. Herein, a comprehensively appraisal of the common mechanisms among these conditions, together with clinical pearls for treatment and diagnosis is presented.

Enfermedad granulomatosa crónica: infecciones múltiples como forma de presentación. Caso clínico pediátrico / Chronic granulomatous disease: multiple infections as clinical presentation. Pediatric case report

La enfermedad granulomatosa crónica es una inmunodeficiencia primaria infrecuente, debida a un defecto en la actividad microbicida de los fagocitos, originada por mutaciones en los genes que codifican alguna de las subunidades del complejo enzimático nicotinamida adenina dinucleótido fosfato oxidasa. La incidencia estimada es 1 en 250 000 recién nacidos vivos. Puede presentarse desde la infancia hasta la adultez, por lo general, en menores de 2 años. Las infecciones bacterianas y fúngicas, en conjunto con las lesiones granulomatosas, son las manifestaciones más habituales de la enfermedad. Los microorganismos aislados más frecuentemente son Aspergillus spp., Staphylococcus aureus, Serratia marcescens, Nocardia spp. Se reporta el caso clínico de un varón de 1 año de vida en el que se diagnosticó enfermedad granulomatosa crónica a partir de infecciones múltiples que ocurrieron simultáneamente: aspergilosis pulmonar invasiva, osteomielitis por Serratia marcescens y granuloma cervical por Enterobacter cloacae.

Chronic granulomatous disease is an uncommon primary immunodeficiency due to a defect of the killing activity of phagocytes, caused by mutations in any of the genes encoding subunits of the superoxide-generating phagocyte NADPH oxidase system. The incidence is 1 in 250 000 live births. It can occur from infancy to adulthood, usually in children under 2 years. Bacterial and fungal infections in association with granuloma lesions are the most common manifestations of the disease. Aspergillus species, Staphylococcus aureus, Serratia marcescens, Nocardia species are the most common microorganisms isolated. We describe here a case of a 1-year-old boy with chronic granulomatous disease and invasive pulmonary aspergillosis, Serratia marcescens osteomyelitis and Enterobacter cloacae cervical granuloma.

[Chronic granulomatous disease: multiple infections as clinical presentation. Pediatric case report]. / Enfermedad granulomatosa crónica: infecciones múltiples como forma de presentación. Caso clínico pediátrico.

Chronic granulomatous disease is an uncommon primary immunodeficiency due to a defect of the killing activity of phagocytes, caused by mutations in any of the genes encoding subunits of the superoxide-generating phagocyte NADPH oxidase system. The incidence is 1 in 250 000 live births. It can occur from infancy to adulthood, usually in children under 2 years. Bacterial and fungal infections in association with granuloma lesions are the most common manifestations of the disease. Aspergillus species, Staphylococcus aureus, Serratia marcescens, Nocardia species are the most common microorganisms isolated. We describe here a case of a 1-year-old boy with chronic granulomatous disease and invasive pulmonary aspergillosis, Serratia marcescens osteomyelitis and Enterobacter cloacae cervical granuloma.

La enfermedad granulomatosa crónica es una inmunodeficiencia primaria infrecuente, debida a un defecto en la actividad microbicida de los fagocitos, originada por mutaciones en los genes que codifican alguna de las subunidades del complejo enzimático nicotinamida adenina dinucleótido fosfato oxidasa. La incidencia estimada es 1 en 250 000 recién nacidos vivos. Puede presentarse desde la infancia hasta la adultez, por lo general, en menores de 2 años. Las infecciones bacterianas y fúngicas, en conjunto con las lesiones granulomatosas, son las manifestaciones más habituales de la enfermedad. Los microorganismos aislados más frecuentemente son Aspergillus spp., Staphylococcus aureus, Serratia marcescens, Nocardia spp. Se reporta el caso clínico de un varón de 1 año de vida en el que se diagnosticó enfermedad granulomatosa crónica a partir de infecciones múltiples que ocurrieron simultáneamente: aspergilosis pulmonar invasiva, osteomielitis por Serratia marcescens y granuloma cervical por Enterobacter cloacae.

Signos de alarma para el diagnóstico de las inmunodeficiencias primarias. Una propuesta adaptada a la provincia de Cienfuegos / Alarm sings for primary immunodeficiency diagnosis. A proposal adapted to the Cienfuegos province

Fundamento: las enfermedades por inmunodeficiencias son un grupo heterogéneo de trastornos que reflejan un déficit cuantitativo y/o cualitativo en uno o más componentes del sistema inmune. La rápida remisión de estos casos a la consulta de inmunología disminuye la morbilidad y mortalidad.Objetivo: establecer los signos de alarma para el diagnóstico de una inmunodeficiencia primaria, que servirán de criterio de remisión en la provincia de Cienfuegos.Métodos: se revisaron 11 artículos sobre los signos de alarma para el diagnóstico de las inmunodeficiencias primarias, publicados por asociaciones y organizaciones internacionales dedicadas a la inmunología. Se determinó del valor diagnóstico del signo como criterio para su inclusión en la relación de signos de alarma de esta enfermedad. Resultados: se establecieron 15 signos de alarma basados en su frecuencia de reporte y/o valor diagnóstico atribuido.Conclusiones: los signos de alarma establecidos por el grupo provincial de inmunología de Cienfuegos se tomarán como criterios de remisión a consulta de inmunología por sospecha de inmunodeficiencia primaria, lo que podrá contribuir a disminuir su morbilidad.

Foundation: immunodeficiency diseases are a heterogeneous group of disorders that reflect one or more components of the immune system quantitative and / or qualitative deficit. The fast reference of these cases to the immunology consultation decreases morbidity and mortality. Objective: to establish the alarm signs for a primary immunodeficiency diagnosis, that will be a referral criterion in the province of Cienfuegos. Methods: eleven articles on alarm signs for primary immunodeficiencies diagnosis, published by associations and international organizations dedicated to immunology were reviewed. The sign diagnostic value was determined as a criterion for inclusion in the disease warning signs list. Results: Fifteen alarm signs were established based on their reporting frequency and / or assigned diagnostic value. Conclusion: alarm signs established by the Cienfuegos provincial immunology group will be taken as referral criteria for immunology consultation due to primary immunodeficiency suspicion, which may contribute to decrease its morbidity.

Diagnostic Delay of Primary Immunodeficiencies at a Tertiary Care Hospital in Peru- Brief Report.

OBJECTIVE: The aim of the study was to assess the diagnostic delay in pediatric patients with primary immunodeficiencies (PID) at a tertiary care hospital in Peru. METHODS: A descriptive study was carried out in which patients from a third-level referral center in Peru were included. Those without a specific diagnosis of PID were excluded. Data was collected by reviewing the medical records and interviewing patients' family members. RESULTS: A total of 45 patients with a mean of 7.4 years (SD = 4.3) were studied. The most frequent diagnosis was predominant antibody defects (35.5%), and the diagnostic delay had a median of 12.17 months (IQR 5.1-30.3). CONCLUSIONS: The most frequently diagnosed group of PID was predominant antibody deficiency. The overall median diagnostic delays for PID and predominant antibody deficiency were 12 and 14 months, respectively. Even though early detection of PIDs is crucial for effective treatment, current available laboratory tests required for PID diagnosis are both complex and expensive. Early detection and management of these pathologies cannot be achieved without training non-specialist health professionals in the diagnosis of PID, as well as integrating multidisciplinary and multi-center cooperation at both national and international levels.

TRIAGEM NEONATAL DE IMUNODEFICIÊNCIAS GRAVES COMBINADAS POR MEIO DE TRECS E KRECS: SEGUNDO ESTUDO PILOTO NO BRASIL / NEWBORN SCREENING FOR SEVERE COMBINED IMMUNODEFICIENCIES USING TRECS AND KRECS: SECOND PILOT STUDY IN BRAZIL

RESUMO Objetivo: Validar a quantificação de T-cell receptor excision circles (TRECs) e kappa-deleting recombination circles (KRECs) por reação em cadeia de polimerase (polymerase chain reaction, PCR) em tempo real (qRT-PCR), para triagem neonatal de imunodeficiências primárias que cursam com defeitos nas células T e/ou B no Brasil. Métodos: Amostras de sangue de recém-nascidos (RN) e controles foram coletadas em papel-filtro. O DNA foi extraído e os TRECs e KRECs foram quantificados por reação duplex de qRT-PCR. O valor de corte foi determinado pela análise de Receiver Operating Characteristics Curve, utilizando-se o programa Statistical Package for the Social Sciences (SSPS) (IBM®, Armonk, NY, EUA). Resultados: 6.881 amostras de RN foram analisadas quanto à concentração de TRECs e KRECs. Os valores de TRECs variaram entre 1 e 1.006 TRECs/µL, com média e mediana de 160 e 139 TRECs/µL, respectivamente. Três amostras de pacientes diagnosticados com imunodeficiência grave combinada (severe combined immunodeficiency, SCID) apresentaram valores de TRECs abaixo de 4/µL e um paciente com Síndrome de DiGeorge apresentou TRECs indetectáveis. Os valores de KRECs encontraram-se entre 10 e 1.097 KRECs/µL, com média e mediana de 130 e 108 KRECs/µL, e quatro pacientes com diagnóstico de agamaglobulinemia tiveram resultados abaixo de 4 KRECs/µL. Os valores de corte encontrados foram 15 TRECs/µL e 14 KRECs/µL, e foram estabelecidos de acordo com a análise da Receiver Operating Characteristics Curve, com sensibilidade de 100% para detecção de SCID e agamaglobulinemia, respectivamente. Conclusões: A quantificação de TRECs e KRECs foi capaz de diagnosticar crianças com linfopenias T e/ou B em nosso estudo, validando a técnica e dando o primeiro passo para a implementação da triagem neonatal em grande escala no Brasil.

ABSTRACT Objective: To validate the quantification of T-cell receptor excision circles (TRECs) and kappa-deleting recombination excision circles (KRECs) by real-time polymerase chain reaction (qRT-PCR) for newborn screening of primary immunodeficiencies with defects in T and/or B cells in Brazil. Methods: Blood samples from newborns and controls were collected on filter paper. DNA was extracted and TRECs, and KRECs were quantified by a duplex real-time PCR. The cutoff values were determined by receiver operating characteristic curve analysis using SPSS software (IBM®, Armonk, NY, USA). Results: Around 6,881 samples from newborns were collected and TRECs and KRECs were quantified. The TRECs values ranged between 1 and 1,006 TRECs/µL, with mean and median of 160 and 139 TRECs/µL, respectively. Three samples from patients with severe combined immunodeficiency (SCID) showed TRECs below 4/µL and a patient with DiGeorge syndrome showed undetectable TRECs. KRECs values ranged from 10 to 1,097 KRECs/µL, with mean and median of 130 and 108 KRECs/µL. Four patients with agammaglobulinemia had results below 4 KRECs/µL. The cutoff values were 15 TRECs/µL and 14 KRECs/µL and were established according to the receiver operating characteristic curve analysis, with 100% sensitivity for SCID and agammaglobulinemia detection, respectively. Conclusions: Quantification of TRECs and KRECs was able to diagnose children with T- and/or B-cell lymphopenia in our study, which validated the technique in Brazil and enabled us to implement the newborn screening program for SCID and agammaglobulinemia.