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.

Severe combined immunodeficiency diagnosis and genetic defects.

Severe combined immunodeficiency (SCID) is a rare and life-threatening genetic disorder that severely impairs the immune system's ability to defend the body against infections. Often referred to as the "bubble boy" disease, SCID gained widespread recognition due to the case of David Vetter, a young boy who lived in a sterile plastic bubble to protect him from germs. SCID is typically present at birth, and it results from genetic mutations that affect the development and function of immune cells, particularly T cells and B cells. These immune cells are essential for identifying and fighting off infections caused by viruses, bacteria, and fungi. In SCID patients, the immune system is virtually non-existent, leaving them highly susceptible to recurrent, severe infections. There are several forms of SCID, with varying degrees of severity, but all share common features. Newborns with SCID often exhibit symptoms such as chronic diarrhea, thrush, skin rashes, and persistent infections that do not respond to standard treatments. Without prompt diagnosis and intervention, SCID can lead to life-threatening complications and a high risk of mortality. There are over 20 possible affected genes. Treatment options for SCID primarily involve immune reconstitution, with the most well-known approach being hematopoietic stem cell transplantation (HSCT). Alternatively, gene therapy is also available for some forms of SCID. Once treated successfully, SCID patients can lead relatively normal lives, but they may still require vigilant infection control measures and lifelong medical follow-up to manage potential complications. In conclusion, severe combined immunodeficiency is a rare but life-threatening genetic disorder that severely compromises the immune system's function, rendering affected individuals highly vulnerable to infections. Early diagnosis and appropriate treatment are fundamental. With this respect, newborn screening is progressively and dramatically improving the prognosis of SCID.

Antioxidant defense of children and adolescents with atopic dermatitis: Association with disease severity.

BACKGROUND: Atopic dermatitis (AD) is a relapsing, chronic cutaneous inflammatory disease with onset, in general, in early childhood. Chronic skin inflammation is associated with overproduction of reactive oxygen species (ROS) such as superoxide and hydrogen peroxide. Oxidative stress, an imbalance between the production of free radicals and antioxidant defense, results in tissue inflammation due to the upregulation of genes that encode inflammatory cytokines. This condition plays an important role in the pathogenesis of AD. OBJECTIVE: To compare the antioxidant defense in children and adolescents with AD with that of healthy individuals and to verify the association of antioxidant defense with disease severity and nutritional status. METHODS: Cross-sectional study that evaluated 48 children and adolescents with AD and 25 controls for nutritional assessment (body mass index z score [BMIZ] and height for age z score [HAZ]) and levels of vitamins A, C, E, and D, zinc (Zn), copper (Cu), antioxidant enzymes (superoxide dismutase [SOD], catalase [CAT], glutathione peroxidase [GPx]), high-sensitivity C-reactive protein (CRP) and interleukin 33 (IL-33). RESULTS: There was no significant difference in the comparison between AD and control groups for serum levels of vitamins (A, D, C, and E), copper, and antioxidant enzymes. Serum zinc levels were higher in the AD group (ß = 24.20; 95% CI 13.95-34.91; P < 0.001) even after adjusting the BMIZ, HAZ, gender, IL-33, and CRP. Children and adolescents with moderate or severe AD compared to mild AD (SCORAD - 36.7±17.4 vs 11.8 ± 3.9; P < 0.001) had lower values of the vitamin E/total lipid ratio (3.68 [0.29;12.63] vs 5.92 [3.27;17.37]; P = 0.013). CONCLUSION: Children and adolescents with AD had higher concentrations OF elevated levels of zinc compared to controls, a fact not observed for other biomarkers of antioxidant defense. AD in moderate or severe forms presented lower concentrations of vitamin E, a potent antioxidant fat soluble.

Egg allergy and yellow fever vaccination.

OBJECTIVE: Evaluate biomarkers capable of safely guiding Yellow fever vaccine (YFV) vaccination among individuals suspicious of hen's egg allergy, and identify factors associated with a higher risk for adverse events after immunization (AEAI). METHODS: Patients underwent skin prick test (SPT) for standardized allergens: whole egg, egg white, egg yolk; YFV (1:10 dilution; Biomanguinhos-Fiocruz), and intradermal test (IDT; YFV 0.02 mL, 1:100 dilution) and positive and negative controls. Serum levels of specific IgE (sIgE) for a whole egg, egg white, egg yolk, egg albumin, ovomucoid, lysozyme, and conalbumin (ImmunoCap®; ThermoFisher®) were obtained. Patients sensitized to YFV were submitted to YFV desensitization, and those negatives received YFV (0.5mL) and remained under surveillance for at least one hour. RESULTS: 103 patients were enrolled, 95% under 12 years old. 71% (81/103) of patients had reactions: 80% immediate, 11% mixed, and 9% delayed. There was an association between positive skin test results with YFV and the severity of the reaction (OR:7.64; 95%CI:1.61-36.32; p = 0,011). Only the presence of sIgE to ovomucoid was associated with clinical symptoms (p = 0,025). Thirty patients underwent the YFV desensitization protocol. CONCLUSION: There is a relationship between the positivity of the egg's components and the severity of the clinical reaction. Furthermore, the relationship between the positivity of the tests with the YFV and egg's components may show a tendency to look at ovomucoid and conalbumin, but it is not a certainty. Therefore, further studies are needed to confirm these associations, and for now, the authors still recommend using the vaccine for testing when necessary.

Egg allergy and yellow fever vaccination

Abstract Objective Evaluate biomarkers capable of safely guiding Yellow fever vaccine (YFV) vaccination among individuals suspicious of hen's egg allergy, and identify factors associated with a higher risk for adverse events after immunization (AEAI). Methods Patients underwent skin prick test (SPT) for standardized allergens: whole egg, egg white, egg yolk; YFV (1:10 dilution; Biomanguinhos-Fiocruz), and intradermal test (IDT; YFV 0.02 mL, 1:100 dilution) and positive and negative controls. Serum levels of specific IgE (sIgE) for a whole egg, egg white, egg yolk, egg albumin, ovomucoid, lysozyme, and conalbumin (ImmunoCap®; ThermoFisher®) were obtained. Patients sensitized to YFV were submitted to YFV desensitization, and those negatives received YFV (0.5mL) and remained under surveillance for at least one hour. Results 103 patients were enrolled, 95% under 12 years old. 71% (81/103) of patients had reactions: 80% immediate, 11% mixed, and 9% delayed. There was an association between positive skin test results with YFV and the severity of the reaction (OR:7.64; 95%CI:1.61-36.32; p =0,011). Only the presence of sIgE to ovomucoid was associated with clinical symptoms (p =0,025). Thirty patients underwent the YFV desensitization protocol. Conclusion There is a relationship between the positivity of the egg's components and the severity of the clinical reaction. Furthermore, the relationship between the positivity of the tests with the YFV and egg's components may show a tendency to look at ovomucoid and conalbumin, but it is not a certainty. Therefore, further studies are needed to confirm these associations, and for now, the authors still recommend using the vaccine for testing when necessary.

Screening for Antibody Deficiencies in Adults by Serum Electrophoresis and Calculated Globin.

PURPOSE: This study aimed to investigate the correlation between calculated globulin (CG, total protein level minus albumin level) and the gamma globulin fraction (Gamma), obtained from serum protein electrophoresis with serum IgG levels in adults (≥ 18 years). METHODS: Using linear regression models, analyses of CG and Gamma levels correlation with IgG levels in adults were performed. Receiver-operator curves were created to determine cutoff values and the respective sensitivity and specificity measures. RESULTS: A total of 886 samples were analyzed. CG and Gamma were positively and statistically correlated with IgG levels (r2 = 0.4628 for CG, and = 0.7941 for Gamma, p < 0.0001 for both analyses). For the detection of hypogammaglobulinemia, i.e., IgG level below the reference value (6 g/L), a CG cutoff value of 24 g/L showed a sensitivity of 86.2% (95% CI 69.4-94.5) and a specificity of 92% (90.0-93.6). A Gamma cutoff value of 7.15 g/L yielded a sensitivity of 100% (88.3-100) and a specificity of 96.8 (95.3-97.8). CONCLUSION: Both CG and Gamma levels determined by protein electrophoresis analysis may be used to screen for antibody deficiencies in adults, enabling earlier diagnosis of antibody deficiencies in a routine clinical setting.

Hepatic fibrosis: a manifestation of the liver disease evolution in patients with Ataxia-telangiectasia.

BACKGROUND: Ataxia-telangiectasia (A-T) is a DNA repair disorder characterized by changes in several organs and systems. Advances in clinical protocols have resulted in increased survival of A-T patients, however disease progression is evident, mainly through metabolic and liver changes. OBJECTIVE: To identify the frequency of significant hepatic fibrosis in A-T patients and to verify the association with metabolic alterations and degree of ataxia. METHODS: This is a cross-sectional study that included 25 A-T patients aged 5 to 31 years. Anthropometric data, liver, inflammatory, lipid metabolism and glucose biomarkers (oral glucose tolerance test with insulin curve-OGTT) were collected. The Cooperative Ataxia Rating Scale was applied to assess the degree of ataxia. The following were calculated: Homeostasis Model Assessment-Insulin Resistance, Homeostasis Model Assessment-Adiponectin (HOMA-AD), Matsuda index, aspartate aminotransferase (AST): platelet ratio index, nonalcoholic fatty liver disease fibrosis score and BARD score. Liver ultrasonography and transient liver elastography by FibroScan® were performed. RESULTS: Significant hepatic fibrosis was observed in 5/25 (20%). Patients in the group with significant hepatic fibrosis were older (p < 0.001), had lower platelet count values (p = 0.027), serum albumin (p = 0.019), HDL-c (p = 0.013) and Matsuda index (p = 0.044); and high values of LDL-c (p = 0.049), AST (p = 0.001), alanine aminotransferase (p = 0.002), gamma-glutamyl transferase (p = 0.001), ferritin (p = 0.001), 120-min glycemia by OGTT (p = 0.049), HOMA-AD (p = 0.016) and degree of ataxia (p = 0.009). CONCLUSIONS: A non-invasive diagnosis of significant hepatic fibrosis was observed in 20% of A-T patients associated with changes in liver enzymes, ferritin, increased HOMA-AD, and the severity of ataxia in comparison with patients without hepatic fibrosis.

Vaccination strategies for people living with inborn errors of metabolism in Brazil

Abstract Objective: Through a literature review, make recommendations regarding immunizations in people living with Inborn Error of Metabolism (IEM) in Brazil, assess the possible impact on metabolic decompensations after immunization, and if this specific population may have an impaired immune response to vaccines. Source of data: The MeSH Terms vaccination OR vaccine OR immunization associated with the term inborn error of metabolism AND recommendation were used in combination with search databases. Only articles published after 1990, in the languages English, Spanish, French or Portuguese, human-related were included. Synthesis of data: A total of 44 articles were included to make the following recommendations. Individuals with IEMs need to be up to date with their immunizations. Regarding which vaccines should be offered, children and adults should follow the routine immunization schedules locally available, including the COVID-19 vaccines. The only exception is the rotavirus vaccine for hereditary fructose intolerance. The benefit of immunization outweighs the very low risk of metabolic decompensation. Since not all patients will have an adequate immune response, measuring antibody conversion and titers is recommended Conclusions: All patients should receive age-appropriate immunizations in their respective schedules without delays. The only situation when vaccination may be contraindicated is with oral rotavirus vaccine in hereditary fructose intolerance. Monitoring the levels of antibodies should be done to detect any immune dysfunction or the necessity for boosters. A personalized immunization schedule is ideal for patients with IEMs. The reference organizations could improve their recommendations to address all IEMs, not only some of them.

Implications of the non-specific effect induced by Bacillus Calmette-Guerin (BCG) vaccine on vaccine recommendations

Abstract Objectives: Since the beginning of its use for the prevention of tuberculosis (TB) in 1921, other uses of BCG (Bacillus Calmette-Guérin) have been proposed, particularly in the treatment of malignant solid tumors, multiple sclerosis, and other autoimmune diseases. Its beneficial impact on other infections, by nontuberculous mycobacteria, and by viruses, has been more often studied in recent years, especially after the introduction of the concept of trained immunity. The present study's objective was to review the possible indications of BCG and the immunological rationale for these indications. Data source: Non-systematic review carried out in the PubMed, SciELO and Google Scholar databases, using the following search terms: "BCG" and "history", "efficacy", "use", "cancer", "trained immunity", "other infections", "autoimmune diseases". Data synthesis: There is epidemiological evidence that BCG can reduce overall child morbidity/mortality beyond what would be expected from TB control. BCG is able to promote cross-immunity with nontuberculous mycobacteria and other bacteria. BCG promotes in vitro changes that increase innate immune response to other infections, mainly viral ones, through mechanisms known as trained immunity. Effects on cancer, except bladder cancer, and on autoimmune and allergic diseases are debatable. Conclusions: Despite evidence obtained from in vitro studies, and some epidemiological and clinical evidence, more robust evidence of in vivo efficacy is still needed to justify the use of BCG in clinical practice, in addition to what is recommended by the National Immunization Program for TB prevention and bladder cancer treatment.

Vaccination strategies for people living with inborn errors of metabolism in Brazil.

OBJECTIVE: Through a literature review, make recommendations regarding immunizations in people living with Inborn Error of Metabolism (IEM) in Brazil, assess the possible impact on metabolic decompensations after immunization, and if this specific population may have an impaired immune response to vaccines. SOURCE OF DATA: The MeSH Terms vaccination OR vaccine OR immunization associated with the term inborn error of metabolism AND recommendation were used in combination with search databases. Only articles published after 1990, in the languages English, Spanish, French or Portuguese, human-related were included. SYNTHESIS OF DATA: A total of 44 articles were included to make the following recommendations. Individuals with IEMs need to be up to date with their immunizations. Regarding which vaccines should be offered, children and adults should follow the routine immunization schedules locally available, including the COVID-19 vaccines. The only exception is the rotavirus vaccine for hereditary fructose intolerance. The benefit of immunization outweighs the very low risk of metabolic decompensation. Since not all patients will have an adequate immune response, measuring antibody conversion and titers is recommended CONCLUSIONS: All patients should receive age-appropriate immunizations in their respective schedules without delays. The only situation when vaccination may be contraindicated is with oral rotavirus vaccine in hereditary fructose intolerance. Monitoring the levels of antibodies should be done to detect any immune dysfunction or the necessity for boosters. A personalized immunization schedule is ideal for patients with IEMs. The reference organizations could improve their recommendations to address all IEMs, not only some of them.

Implications of the non-specific effect induced by Bacillus Calmette-Guerin (BCG) vaccine on vaccine recommendations.

OBJECTIVES: Since the beginning of its use for the prevention of tuberculosis (TB) in 1921, other uses of BCG (Bacillus Calmette-Guérin) have been proposed, particularly in the treatment of malignant solid tumors, multiple sclerosis, and other autoimmune diseases. Its beneficial impact on other infections, by nontuberculous mycobacteria, and by viruses, has been more often studied in recent years, especially after the introduction of the concept of trained immunity. The present study's objective was to review the possible indications of BCG and the immunological rationale for these indications. DATA SOURCE: Non-systematic review carried out in the PubMed, SciELO and Google Scholar databases, using the following search terms: "BCG" and "history", "efficacy", "use", "cancer", "trained immunity", "other infections", "autoimmune diseases". DATA SYNTHESIS: There is epidemiological evidence that BCG can reduce overall child morbidity/mortality beyond what would be expected from TB control. BCG is able to promote cross-immunity with nontuberculous mycobacteria and other bacteria. BCG promotes in vitro changes that increase innate immune response to other infections, mainly viral ones, through mechanisms known as trained immunity. Effects on cancer, except bladder cancer, and on autoimmune and allergic diseases are debatable. CONCLUSIONS: Despite evidence obtained from in vitro studies, and some epidemiological and clinical evidence, more robust evidence of in vivo efficacy is still needed to justify the use of BCG in clinical practice, in addition to what is recommended by the National Immunization Program for TB prevention and bladder cancer treatment.

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.

CD40 Ligand Deficiency in Latin America: Clinical, Immunological, and Genetic Characteristics.

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.

Successful Elosulfase Alfa Desensitization Protocol in a Patient With Morquio A Syndrome.

Patients with lysosomal storage diseases may require modifications to standard drug desensitization protocols; personalized medicine as well as development of new treatment options are needed.

Mucopolysaccharidosis patients have reduced functional capacity.

INTRODUCTION: Mucopolysaccharidoses (MPSs) are a group of rare diseases caused by an intralysosomal accumulation of glycosaminoglycans, resulting in a multisystemic clinical condition characterized by variable degrees of physical-functional impairment. OBJECTIVE: To evaluate the functional capacity (FC) of MPS patients and compare with a healthy control group. METHODS: This is a cross-sectional study of 6- to 39-year-old patients followed at a medical reference center and compared with their control peers, matched by age and sex. FC was assessed using the Sit-to-Stand Test (SST) and Incremental Shuttle Walk Test (ISWT). Heart rate (HR) and Borg rating of perceived exertion were measured before and after ISWT. HR recovery (HRR) was defined as the HR at the end of the test minus the HR in the second minute after ISWT. RESULTS: Nineteen (19) MPS patients, 69% with type II MPS and mean age 17 ± 11 years were evaluated. Every patient was under enzyme replacement therapy. The time to perform the SST was longer in the MPS group (10.6 ± 2.5 s vs. 6.7 ± 1.2 s; p < .01). The MPS group achieved lower values of distance covered on the ISWT (407.6 ± 329.8 m vs. 1131.9 ± 183.3 m; p < .01), with a significantly higher Borg (6 [5-8] vs. 2 [1-4]; p = .02). The MPS group's HRR was slower than the controls (32.9 ± 20.2 beats per minute [bpm] vs. 69.1 ± 25.9 bpm; p < .001). DISCUSSION: We observed a pronounced reduction in the MPS group's FC compared to their healthy peers and a worse HRR after completing the test.