The Latin American Society for Immunodeficiencies Registry.

Purpose - The Latin American Society of Immunodeficiencies (LASID) Registry was established in 2009 to collect data on Inborn Errors of Immunity (IEI) patients in the region. Although several reports have been published regarding LASID data, this is the first report of the entire dataset. Methods - The European Society of Immunodeficiencies (ESID) donated the online platform in 2008. Data was collected from participating centers from Apr 13, 2009, to Dec 31, 2022, and included demographic, clinical, and follow-up information. Results - A total of 9307 patients were included in the database. At the end of the study period, 8,805 patients were alive or lost to follow-up, and 502 were deceased. The most common type of IEI was predominantly antibody deficiency (PAD, 60.35%), and selective IgA deficiency was the most frequent diagnosis (1627 patients, 17.48%), followed by Common Variable Immune Deficiency (CVID, 1191 patients). Most patients (78.16%) were ≤ 18 years old at inclusion, and the median age at diagnosis was 4.77 years. The median time to diagnosis was 5.04 years. Antibiotics were prescribed in 32.3% of visits, followed by immunoglobulins (29.49% ). Hematopoietic stem cell transplantation was performed in 5.03% of patients. Omenn syndrome was the most common disease in deceased patients, with a mortality rate of 52.63%. Conclusion - This study contributes to our understanding of IEIs in Latin America and highlights the importance of early diagnosis, appropriate treatments, and improved data collection to optimize patient outcome.

SCID and Other Inborn Errors of Immunity with Low TRECs - the Brazilian Experience.

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.

Baked Tolerance in Cow's Milk Allergy: Quite Frequent, Hard to Predict!

INTRODUCTION: Cow's milk protein allergy (CMA) is the most common type of food allergy in childhood and exclusion diet is a challenge for patients. OBJECTIVE: The study aim was to investigate the frequency of tolerance to baked foods containing milk and evaluate immediate skin prick test (SPT) and specific IgEs for different cow's milk (CM) protein types as predictors of tolerance to baked foods containing milk for CMA patients. METHODS: A cross-sectional study was performed. Fifty-four CMA patients were enrolled and oral food challenge (OFC) was performed with baked product, 6 different milk SPTs and specific IgEs to CM, casein, α-lactalbumin, and ß-lactoglobulin. RESULTS: Thirty-nine (72.2%) patients tolerated OFC with baked milk cupcake. CM-specific IgE and casein SPT showed statistical difference between positive and negative OFC groups. Probability curves for baked milk tolerance were created for specific CM IgE (Z = 2.542, p < 0.0110) and casein SPT (Z = 2.290, p < 0.0220) using logistic regression. CONCLUSIONS: The high percentage of patients able to tolerate baked goods enables an improvement in intake possibilities and quality of life of CMA patients and families. Specific CM IgE and casein SPT demonstrated to be useful predictors in relation to baked milk tolerance.

Different immunological patterns of Down syndrome patients with and without recurrent infections.

OBJECTIVE: Individuals with Down Syndrome (DS) exhibit a higher susceptibility to infections, suggesting potential immunological alterations within this population. Consequently, this study aims to assess the immune response profile in children with DS to identify potential immune dysfunctions associated with recurrent infections. METHODS: The authors conducted a retrospective analysis involving 49 DS patients, examining various epidemiological, clinical, cytogenetic, and laboratory variables. The study's sample comprised patients aged 2-20 years, with a predominance of males. These patients were categorized into two groups based on the presence or absence of recurrent infections, as indicated by the Jeffrey Modell Foundation alert signs. RESULTS: Immunoglobulin (Ig) A, G, and M levels were deemed normal, although individuals with DS experiencing recurrent infections exhibited significantly lower IgA levels. Additionally, CD3, CD4, CD8, and CD19 lymphocyte counts were found to be within normal ranges, with no significant differences between the two groups. While overall data indicated normal seroconversion levels of pneumococcal polysaccharide antibodies, a notable impairment in seroconversion was observed among DS patients with recurrent infections compared to those without such infections. CONCLUSION: The deficiency of anti-polysaccharide antibodies in individuals with DS may constitute an important immunological comorbidity. Therefore, it warrants further investigation, particularly among individuals with recurrent infections.

Genetic-molecular characterization in the diagnosis of primary immunodeficiencies.

OBJECTIVES: To rescue medical genetics concepts that are necessary to understand the advances in the genetic-molecular characterization of primary immunodeficiencies, to help in the understanding and adequate interpretation of their results. SOURCE OF DATA: Non-systematic literature review, searching for articles since 2000 on PubMed using the terms "genetic evaluation" OR "whole exome sequence" or "whole genome sequence" OR "next generation sequence" AND "immunologic deficiency syndromes" OR "Immune deficiency disease" OR "immune deficiency" NOT HIV. SUMMARY OF THE DATA: Knowledge of medical genetics is essential for the understanding of the principles of heredity and disease inheritance patterns, types of genetic variants, types of genetic sequencing and interpretation of their results. The clinical and immunophenotypic evaluation of each patient is essential for the correlation with the genetic variants observed in the genetic study of patients with primary immunodeficiencies. The discussion of the benefits and limitations of genetic tests should always guide the performance of genetic tests. CONCLUSIONS: There are many evident benefits of genetic analysis, such as the definitive diagnosis of the disease, family genetic counseling, and the possibility of a more adequate and accurate management. Cost, access and interpretation of genetic test results are limitations that need continuous improvement. The understanding of the benefits and limits of the several genetic assessment methodologies related to primary immunodeficiencies is essential to obtain more effective results from the sequencing.

Treatment of patients with immunodeficiency: Medication, gene therapy, and transplantation.

OBJECTIVES: To provide an overview of drug treatment, transplantation, and gene therapy for patients with primary immunodeficiencies. SOURCE OF DATA: Non-systematic review of the literature in the English language carried out at PubMed. SYNTHESIS OF DATA: The treatment of patients with primary immunodeficiencies aims to control their disease, especially the treatment and prevention of infections through antibiotic prophylaxis and/or immunoglobulin replacement therapy. In several diseases, it is possible to use specific medications for the affected pathway with control of the condition, especially in autoimmune or autoinflammatory processes associated with inborn immunity errors. In some diseases, treatment can be curative through hematopoietic stem cell transplantation (HSCT); more recently, gene therapy has opened new horizons through new technologies. CONCLUSIONS: Immunoglobulin replacement therapy remains the main therapeutic tool. Precision medicine with specific drugs for altered immune pathways is already a reality for several immune defects. Advances in the management of HSCT and gene therapy have expanded the capacity for curative treatments in patients with primary immunodeficiencies.

Baked egg tolerance: is it possible to predict?

OBJECTIVE: To assess the frequency of baked egg tolerance in IgE-mediated egg allergy patients through the oral food challenge and to assess the tolerance predictability of different skin prick tests, as well as specific serum IgE measurement to egg proteins. METHODS: In this cross-sectional study, 42 patients with a diagnosis of egg allergy were submitted to different skin prick tests with egg (in natura, boiled, muffin, ovalbumin, and ovomucoid), and specific IgE to egg white, ovalbumin, and ovomucoid; as well as to the oral food challenge with food containing egg, extensively baked in a wheat matrix. RESULTS: Of the total, 66.6% of patients tolerated the ingestion of egg-containing foods in the oral food challenge. A comparative analysis with positive and negative oral food challenge found no significant differences regarding age, gender, other food allergies, or even specific skin prick tests and IgE values between the groups. CONCLUSIONS: The study demonstrated an elevated frequency of baked egg food-tolerant individuals among egg allergy patients. None of the tested markers, skin prick tests, or specific IgE, were shown to be good predictors for identifying baked egg-tolerant patients. The oral food challenge with egg baked in a matrix is central to demonstrate tolerance and the early introduction of baked foods, improving patients' and families' quality of life and nutrient intake.

Diversity of allergen exposure: implications for the efficacy of environmental control.

UNLABELLED: The prevalence of allergic diseases such as asthma, rhinitis, allergic conjunctivitis and atopic dermatitis has increased in the last decades. The relationship between allergen exposure, atopic sensitization and development of allergic diseases is widely described in the literature. AIM: To evaluate measures for reducing allergen exposure as part of the treatment of allergic diseases. METHODS: An analysis was made of previous studies on allergen exposure done with a similar methodology in the central region of Brazil; the study included homes, hotels, cinemas, cars, taxis, buses and scholar transportation. RESULTS: High levels of Der p 1 and Der f 1 mite allergens were found in a large proportion of the sample in most of the environments included in those studies; there were higher levels of pet allergens in cars and school transportation vehicles. CONCLUSION: The diversity of allergen exposure demonstrates the need for education about allergic diseases for patients and their families, as well as measures of reducing allergens in homes. This should be part of a global strategy of the management of allergic diseases, given that individuals live in society, not only in their houses.

Repercussions of inborn errors of immunity on growth.

OBJECTIVES: This study aimed to review the literature on the repercussions of the different inborn errors of immunity on growth, drawing attention to the diagnosis of this group of diseases in patients with growth disorders, as well as to enable the identification of the different causes of growth disorders in patients with inborn errors of immunity, which can help in their treatment. DATA SOURCES: Non-systematic review of the literature, searching articles since 2000 in PubMed with the terms "growth", "growth disorders", "failure to thrive", or "short stature" AND "immunologic deficiency syndromes", "immune deficiency disease", or "immune deficiency" NOT HIV. The Online Mendelian Inheritance in Man (OMIN) database was searched for immunodeficiencies and short stature or failure to thrive. DATA SUMMARY: Inborn errors of immunity can affect growth in different ways, and some of them can change growth through multiple simultaneous mechanisms: genetic syndromes; disorders of the osteoarticular system; disorders of the endocrine system; reduction in caloric intake; catabolic processes; loss of nutrients; and inflammatory and/or infectious conditions. CONCLUSIONS: The type of inborn errors of immunity allows anticipating what type of growth disorder can be expected. The type of growth disorder can help in the diagnosis of clinical conditions related to inborn errors of immunity. In many inborn errors of immunity, the causes of poor growth are mixed, involving more than one factor. In many cases, impaired growth can be adjusted with proper inborn errors of immunity treatment or proper approach to the mechanism of growth impairment.

Flow Cytometry Contributions for the Diagnosis and Immunopathological Characterization of Primary Immunodeficiency Diseases With Immune Dysregulation.

Almost 70 years after establishing the concept of primary immunodeficiency disorders (PIDs), more than 320 monogenic inborn errors of immunity have been identified thanks to the remarkable contribution of high-throughput genetic screening in the last decade. Approximately 40 of these PIDs present with autoimmune or auto-inflammatory symptoms as the primary clinical manifestation instead of infections. These PIDs are now recognized as diseases of immune dysregulation. Loss-of function mutations in genes such as FOXP3, CD25, LRBA, IL-10, IL10RA, and IL10RB, as well as heterozygous gain-of-function mutations in JAK1 and STAT3 have been reported as causative of these disorders. Identifying these syndromes has considerably contributed to expanding our knowledge on the mechanisms of immune regulation and tolerance. Although whole exome and whole genome sequencing have been extremely useful in identifying novel causative genes underlying new phenotypes, these approaches are time-consuming and expensive. Patients with monogenic syndromes associated with autoimmunity require faster diagnostic tools to delineate therapeutic strategies and avoid organ damage. Since these PIDs present with severe life-threatening phenotypes, the need for a precise diagnosis in order to initiate appropriate patient management is necessary. More traditional approaches such as flow cytometry are therefore a valid option. Here, we review the application of flow cytometry and discuss the relevance of this powerful technique in diagnosing patients with PIDs presenting with immune dysregulation. In addition, flow cytometry represents a fast, robust, and sensitive approach that efficiently uncovers new immunopathological mechanisms underlying monogenic PIDs.

Frequency of Esophageal Eosinophilia in a Pediatric Population from Central Brazil.

Here we report a retrospective cross-sectional study on Esophageal eosinophilia (EsEo) frequency in Brazil, for 2, 425 pediatric patients with symptoms associated with gastroesophageal diseases in 2012. EsEo is defined by ≥15 eosinophils per high power field (400x) and confirmed through histological analyses of esophageal biopsies. Overall, 126 patients had EsEo equating to a frequency of 5.2%. There was a significant difference between the endoscopic features of patients with EsEo, where 10.7% had erosive esophagitis, 3.0% had non-erosive esophagitis and 1% showed normal esophageal mucosa. According to the interaction of the variables in the Classification and Regression Tree Analysis, most patients diagnosed with EsEo were older males with erosive esophagitis. On the other hand, the lowest frequency of EsEo was found among younger females with non-erosive esophagitis/normal mucosa. Environmental conditions, including climate variation and changes, were observed in association with EsEo, supporting a potential role for environmental factors in its pathogenesis. There was an inverse correlation between the number of EsEo, rainfall and humidity. EsEo is a relatively frequent finding in the pediatric population of Brazil with symptoms of gastroesophageal diseases. Both clinical and histological examinations of patients are important for a reliable diagnostic of EsEo cases and to patient care.

[Indoor allergen sensitization profile in allergic patients of the allergy clinic in the University Hospital in Uberlândia, Brazil]. / Perfil de sensibilização a alérgenos domiciliares em pacientes ambulatoriais.

OBJECTIVE: To evaluate allergens among patients with allergic respiratory disease attended at the Allergy Clinic of the University Hospital-Federal University of Uberlândia. METHODS: A retrospective study was performed using medical records. Patients were included if their ISAAC questionnaires were correctly filled out and their skin prick tests were positive to at least one of the allergens from Dermatophagoides pteronyssinus (Der p), Dermatophagoides farinae (Der f), Blomia tropicalis (Blo t), Canis familiaris (Can f), Felis domesticus (Fel d), Blattella germanica (Bla g) and Alternaria alternata. RESULTS: Two-hundred and twelve medical records fulfilled the inclusion criteria. Allergic rhinitis was the main clinical diagnosis (32%), followed by concomitant manifestation of asthma and rhinitis (29.7%), and asthma, rhinitis and atopic dermatitis (9.4%). Asthma alone was found only in 1.9% of patients. The total sensitization observed was 73.5%, of which 61.7%, 59.9%, 54.7%, 45.7%, 38.2%, 33.3%, 9.9% were sensitized to Der p, Der f, Blo t, Bla g, Can f, Fel d and Alternaria, respectively. No significant difference was found between allergic disease types and source of allergen sensitization. CONCLUSION: The highest sensitization in allergic patients under study was to dust mites, especially Der p and Der f. It is noteworthy that the number of patients sensitized to cockroach extract was uncommonly high when compared to previous studies.

Diretriz Latino-americana sobre o Diagnóstico e Tratamento da Alergia Ocular ­ Em nome da Sociedade Latinoamericana de Alergia, Asma e Imunologia (SLAAI) / Latin American Guideline on the Diagnosis and Treatment of Ocular Allergy ­ On behalf of the Latin American Society of Allergy, Asthma and Immunology (SLAAI)

A alergia ocular, também conhecida como conjuntivite alérgica (CA), é uma reação de hipersensibilidade mediada por imunoglobulina E (IgE) do olho desencadeada por aeroalérgenos, principalmente ácaros da poeira doméstica e pólen de gramíneas. Os sintomas geralmente consistem em prurido ocular ou periocular, lacrimejamento e olhos vermelhos que podem estar presentes durante todo o ano ou sazonalmente. A alergia ocular tem frequência elevada, é subdiagnosticada e pode ser debilitante para o paciente. É potencialmente danosa para a visão, nos casos em que ocasiona cicatrização corneana grave, e na maioria dos pacientes associa-se a outros quadros alérgicos, principalmente rinite, asma e dermatite atópica. É classificada em conjuntivite alérgica perene, conjuntivite alérgica sazonal, ceratoconjuntivite atópica e ceratoconjuntivite vernal. O diagnóstico procura evidenciar o agente etiológico e a confirmação se dá pela realização do teste de provocação conjuntival. O tratamento baseia-se em evitar o contato com os desencadeantes, lubrificação, anti-histamínicos tópicos, estabilizadores de mastócitos, imunossupressores e imunoterapia específica com o objetivo de obter o controle e prevenir as complicações da doença.

Ocular allergy, also known as allergic conjunctivitis, is an immunoglobulin E-mediated hypersensitivity reaction of the eye triggered by airborne allergens, primarily house dust mites and grass pollen. Symptoms usually consist of ocular or periocular itching, watery eyes, and red eyes that may be present year-round or seasonally. Ocular allergy has a high frequency, is underdiagnosed, and can be debilitating for the patient. It is potentially harmful to vision in cases of severe corneal scarring, and in most patients, it is associated with other allergic conditions, especially rhinitis, asthma, and atopic dermatitis. It is classified as perennial allergic conjunctivitis, seasonal allergic conjunctivitis, atopic keratoconjunctivitis, and vernal keratoconjunctivitis. Diagnosis seeks to identify the etiologic agent, and confirmation is given by conjunctival provocation testing. Treatment is based on avoiding contact with triggers, lubrication, topical antihistamines, mast cell stabilizers, immunosuppressants, and specific immunotherapy with the aim of achieving control and preventing disease complications.

Genetic-molecular characterization in the diagnosis of primary immunodeficiencies

Abstract Objectives: To rescue medical genetics concepts that are necessary to understand the advances in the genetic-molecular characterization of primary immunodeficiencies, to help in the understanding and adequate interpretation of their results. Source of data: Non-systematic literature review, searching for articles since 2000 on PubMed using the terms "genetic evaluation" OR "whole exome sequence" or "whole genome sequence" OR "next generation sequence" AND "immunologic deficiency syndromes" OR "Immune deficiency disease" OR "immune deficiency" NOT HIV. Summary of the data: Knowledge of medical genetics is essential for the understanding of the principles of heredity and disease inheritance patterns, types of genetic variants, types of genetic sequencing and interpretation of their results. The clinical and immunophenotypic evaluation of each patient is essential for the correlation with the genetic variants observed in the genetic study of patients with primary immunodeficiencies. The discussion of the benefits and limitations of genetic tests should always guide the performance of genetic tests. Conclusions: There are many evident benefits of genetic analysis, such as the definitive diagnosis of the disease, family genetic counseling, and the possibility of a more adequate and accurate management. Cost, access and interpretation of genetic test results are limitations that need continuous improvement. The understanding of the benefits and limits of the several genetic assessment methodologies related to primary immunodeficiencies is essential to obtain more effective results from the sequencing.

Treatment of patients with immunodeficiency: Medication, gene therapy, and transplantation

Abstract Objectives: To provide an overview of drug treatment, transplantation, and gene therapy for patients with primary immunodeficiencies. Source of data: Non-systematic review of the literature in the English language carried out at PubMed. Synthesis of data: The treatment of patients with primary immunodeficiencies aims to control their disease, especially the treatment and prevention of infections through antibiotic prophylaxis and/or immunoglobulin replacement therapy. In several diseases, it is possible to use specific medications for the affected pathway with control of the condition, especially in autoimmune or autoinflammatory processes associated with inborn immunity errors. In some diseases, treatment can be curative through hematopoietic stem cell transplantation (HSCT); more recently, gene therapy has opened new horizons through new technologies. Conclusions: Immunoglobulin replacement therapy remains the main therapeutic tool. Precision medicine with specific drugs for altered immune pathways is already a reality for several immune defects. Advances in the management of HSCT and gene therapy have expanded the capacity for curative treatments in patients with primary immunodeficiencies.

Vacinas contra a COVID-19 e os erros inatos da imunidade (ou imunodeficiências primárias) / COVID-19 vaccines and inborn errors of immunity (or primary immunodeficiencies)

Desde o início da pandemia de COVID-19 iniciou-se a corrida por uma imunização ativa, eficaz e segura. Todas as vacinas desenvolvidas até o momento vêm demostrando boa eficácia na prevenção de casos graves de COVID-19, de hospitalizações e mortes. Muitos pacientes com erros inatos da imunidade (EII) não terão capacidade de desenvolver uma resposta imune semelhante ao indivíduo imunocompetente. Esses pacientes foram incluídos nos grupos prioritários definidos pelo Ministério da Saúde, como pessoas entre 18 a 59 anos com uma ou mais das comorbidades, incluindo as imunodeficiências primárias. Eles podem e devem receber as vacinas em uso contra o SARS-CoV-2, mas nem sempre apresentarão uma resposta imunológica satisfatória e protetora, e, portanto, seus contactantes também devem ser vacinados.

Since the beginning of the COVID-19 pandemic, the race for an active, effective, and safe immunization has started. All vaccines developed to date have shown good efficacy in preventing serious cases of COVID-19, hospitalization, and death. Many patients with inborn errors of immunity will not be able to develop an immune response similar to that of immunocompetent individuals. These patients were included in the priority groups defined by the Brazilian Ministry of Health, as people between 18 and 59 years of age with one or more comorbidities, including primary immunodeficiencies. They can and should receive the vaccines in use against SARS-CoV-2, but they will not always have a satisfactory and protective immune response, and, therefore, those in direct contact with them should also be vaccinated.