Publications by authors named "Beatriz Tavares Costa-Carvalho"

37 Publications

Latin American consensus on the supportive management of patients with severe combined immunodeficiency.

J Allergy Clin Immunol 2019 10 13;144(4):897-905. Epub 2019 Aug 13.

Fundación Mexicana para Niñas y Niños con Inmunodeficiencias Primarias (FUMENI), Mexico City, Mexico.

Severe combined immunodeficiency (SCID) represents the most lethal form of primary immunodeficiency, with mortality rates of greater than 90% within the first year of life without treatment. Hematopoietic stem cell transplantation and gene therapy are the only curative treatments available, and the best-known prognostic factors for success are age at diagnosis, age at hematopoietic stem cell transplantation, and the comorbidities that develop in between. There are no evidence-based guidelines for standardized clinical care for patients with SCID during the time between diagnosis and definitive treatment, and we aim to generate a consensus management strategy on the supportive care of patients with SCID. First, we gathered available information about SCID diagnostic and therapeutic guidelines, then we developed a document including diagnostic and therapeutic interventions, and finally we submitted the interventions for expert consensus through a modified Delphi technique. Interventions are grouped in 10 topic domains, including 123 "agreed" and 38 "nonagreed" statements. This document intends to standardize supportive clinical care of patients with SCID from diagnosis to definitive treatment, reduce disease burden, and ultimately improve prognosis, particularly in countries where newborn screening for SCID is not universally available and delayed diagnosis is the rule. Our work intends to provide a tool not only for immunologists but also for primary care physicians and other specialists involved in the care of patients with SCID.
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http://dx.doi.org/10.1016/j.jaci.2019.08.002DOI Listing
October 2019

Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common missense variant.

Sci Immunol 2018 12;3(30)

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA.

Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in less than 1/600,000 individuals. We show that homozygosity for the common P1104A allele, which is found in about 1/600 Europeans and between 1/1000 and 1/10,000 individuals in regions other than East Asia, is more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls ( = 8.37 × 10; odds ratio, 89.31; 95% CI, 14.7 to 1725). Moreover, the frequency of P1104A in Europeans has decreased, from about 9% to 4.2%, over the past 4000 years, consistent with purging of this variant by endemic tuberculosis. Surprisingly, we also show that TYK2 P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2. Moreover, TYK2 P1104A is properly docked on cytokine receptors and can be phosphorylated by the proximal JAK, but lacks catalytic activity. Last, we show that the catalytic activity of TYK2 is essential for IL-23, but not IL-12, responses in cells expressing wild-type JAK2. In contrast, the catalytic activity of JAK2 is redundant for both IL-12 and IL-23 responses, because the catalytically inactive P1057A JAK2, which is also docked and phosphorylated, rescues signaling in cells expressing wild-type TYK2. In conclusion, homozygosity for the catalytically inactive P1104A missense variant of selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.
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http://dx.doi.org/10.1126/sciimmunol.aau8714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341984PMC
December 2018

IN TIME: THE VALUE AND GLOBAL IMPLICATIONSOF NEWBORN SCREENING FORSEVERE COMBINED IMMUNODEFICIENCY.

Rev Paul Pediatr 2018 Oct-Dec;36(4):388-397

Divisão de Alergia e Imunologia, Children's Research Institute, University of South Florida, St. Petersburg, FL, Estados Unidos.

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http://dx.doi.org/10.1590/1984-0462/;2018;36;4;00020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322803PMC
July 2019

The heterogeneity of autoimmune polyendocrine syndrome type 1: Clinical features, new mutations and cytokine autoantibodies in a Brazilian cohort from tertiary care centers.

Clin Immunol 2018 12 1;197:231-238. Epub 2018 Oct 1.

Division of Endocrinology, Department of Medicine, Universidade Federal de Sao Paulo, Sao Paulo, Sao Paulo, Brazil.

Autoimmune polyendocrine syndrome type 1 (APS1) is characterized by multiorgan autoimmunity. We aim at characterizing a multi-center Brazilian cohort of APS1 patients by clinical evaluation, searching mutation in the AIRE gene, measuring serum autoantibodies, and investigating correlations between findings. We recruited patients based on the clinical criteria and tested them for AIRE mutations, antibodies against interferon type I and interleukins 17A, 17F and 22. We identified 12 unrelated families (13 patients) with typical signs of APS1 in the proband, and the screening of relatives recognized an asymptomatic child. Candidiasis was present in all cases, and 19 other manifestations were observed. All patients carried one of 10 different mutations in AIRE, being 3 new ones, and were positive for anti-interferon type I serum antibody. Anti-interleukin-17A levels inversely correlated with the number of manifestations in each patient. This negative correlation may suggest a protective effect of anti-interleukin-17A with a potential therapeutic application.
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http://dx.doi.org/10.1016/j.clim.2018.09.012DOI Listing
December 2018

Assessing cardiovascular risk in ATM heterozygotes.

Rev Assoc Med Bras (1992) 2018 Feb;64(2):148-153

Pediatrics Department, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.

Objective: To evaluate the carotid intima-media complex (CIMC) thickness and lipid metabolism biomarkers associated with cardiovascular risk (CR) in parents of patients with ataxia-telangiectasia and verify an association with gender.

Method: A cross-sectional and controlled study with 29 ATM heterozygotes and 14 healthy controls. Biochemical tests and CIMC thickness measurement were performed.

Results: The mean CIMC measurement in heterozygous ATM was 0.72 ± 0.1 mm (minimum: 0.5 mm and maximum: 1.0 mm). Noticed high percentage of amounts above 75 percentile compared to the population referential (16 [76.2%]), without any significant statistical differences between the female and the male gender (11/15 [73.3%] vs. 5/6 [83.3%]; p=0.550). The comparison between heterozygous and controls, stratified by gender, showed that in heterozygous ATMs, women had higher concentrations of HDL-c compared to men, as well as higher values of hs-CRP in relation to the control women. In heterozygous ATMs, stratified by gender, the correlation between HDL-c and hs-CRP was inversely proportional and stronger among women, with a tendency to statistical significance.

Conclusion: Heterozygous ATMs did not differ from controls in relation to the biomarkers studied related to CR. However, most of them presented increased CIMC, independent predictor of death, risk for myocardial infarction and stroke, compared to the referential for the same age group. This finding suggests CR in the heterozygous ATM and shows to the need to monitor CIMC thickness and nutritional orientations.
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http://dx.doi.org/10.1590/1806-9282.64.02.148DOI Listing
February 2018

CD40 ligand deficiency causes functional defects of peripheral neutrophils that are improved by exogenous IFN-γ.

J Allergy Clin Immunol 2018 11 5;142(5):1571-1588.e9. Epub 2018 Mar 5.

Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address:

Background: Patients with X-linked hyper-IgM syndrome caused by CD40 ligand (CD40L) deficiency often present with episodic, cyclic, or chronic neutropenia, suggesting abnormal neutrophil development in the absence of CD40L-CD40 interaction. However, even when not neutropenic and despite immunoglobulin replacement therapy, CD40L-deficient patients are susceptible to life-threatening infections caused by opportunistic pathogens, suggesting impaired phagocyte function and the need for novel therapeutic approaches.

Objectives: We sought to analyze whether peripheral neutrophils from CD40L-deficient patients display functional defects and to explore the in vitro effects of recombinant human IFN-γ (rhIFN-γ) on neutrophil function.

Methods: We investigated the microbicidal activity, respiratory burst, and transcriptome profile of neutrophils from CD40L-deficient patients. In addition, we evaluated whether the lack of CD40L in mice also affects neutrophil function.

Results: Neutrophils from CD40L-deficient patients exhibited defective respiratory burst and microbicidal activity, which were improved in vitro by rhIFN-γ but not soluble CD40L. Moreover, neutrophils from patients showed reduced CD16 protein expression and a dysregulated transcriptome suggestive of impaired differentiation. Similar to CD40L-deficient patients, CD40L knockout mice were found to have impaired neutrophil responses. In parallel, we demonstrated that soluble CD40L induces the promyelocytic cell line HL-60 to proliferate and mature by regulating the expression of genes of the same Gene Ontology categories (eg, cell differentiation) when compared with those dysregulated in peripheral blood neutrophils from CD40L-deficient patients.

Conclusion: Our data suggest a nonredundant role of CD40L-CD40 interaction in neutrophil development and function that could be improved in vitro by rhIFN-γ, indicating a potential novel therapeutic application for this cytokine.
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http://dx.doi.org/10.1016/j.jaci.2018.02.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123297PMC
November 2018

II Brazilian Consensus on the use of human immunoglobulin in patients with primary immunodeficiencies.

Einstein (Sao Paulo) 2017 ;15(1):1-16

Faculdade de Ciências Médicas, Santa Casa de São Paulo, São Paulo, SP, Brazil.

In the last few years, new primary immunodeficiencies and genetic defects have been described. Recently, immunoglobulin products with improved compositions and for subcutaneous use have become available in Brazil. In order to guide physicians on the use of human immunoglobulin to treat primary immunodeficiencies, based on a narrative literature review and their professional experience, the members of the Primary Immunodeficiency Group of the Brazilian Society of Allergy and Immunology prepared an updated document of the 1st Brazilian Consensus, published in 2010. The document presents new knowledge about the indications and efficacy of immunoglobulin therapy in primary immunodeficiencies, relevant production-related aspects, mode of use (routes of administration, pharmacokinetics, doses and intervals), adverse events (major, prevention, treatment and reporting), patient monitoring, presentations available and how to have access to this therapeutic resource in Brazil.
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http://dx.doi.org/10.1590/S1679-45082017AE3844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433300PMC
December 2017

CLINICAL MANAGEMENT OF LOCALIZED BCG ADVERSE EVENTS IN CHILDREN.

Rev Inst Med Trop Sao Paulo 2016 Nov 3;58:84. Epub 2016 Nov 3.

Reference Center for Special Immunobiologicals, Division of Pediatric Infectious Diseases, Federal University of São Paulo, São Paulo, SP, Brazil.

BCG adverse events (BCG-AE) are rare conditions with no well-established treatment. This study aims to describe clinical characteristics and outcome of localized BCG-AE. Children with BCG-AEs who were treated at the Reference Center for Special Immunobiologicals of the Federal University of São Paulo from 2009 to 2011 were included. Patients were followed monthly until 3 months after healing. One hundred and twenty-seven patients with localized BCG-AE were followed: 67 (52.7%) had suppurative lymphadenitis; 30 (23.6%) injection-site abscess; five (3.9%) had enlarged lymph node > 3 cm; four (3.1%) had ulcer > 1 cm; and one (0.8%) had a local bacterial infection. Five patients (3.9%) had more than one BCG-AE simultaneously. Fifteen patients (11.8%) had atypical manifestations: seven wart-like lesions; five BCG reactivations; two other dermatologic lesions and one with vasomotor phenomenon. Isoniazid was used in 96 patients with typical BCG-AE (85.7%) until lesion resolution which took place 3.1 months later (in median); the healing rate was 90.6%. Patients with atypical manifestations had an individual approach. Regarding the outcome, 105/112 patients with typical AE and 13/15 patients with atypical AE had resolution of BCG-AE. Localized BCG-AE caused by BCG Moreau RJ had positive outcome when treated with a short course of isoniazid. Atypical BCG-AE are not infrequent.
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http://dx.doi.org/10.1590/S1678-9946201658084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5096638PMC
November 2016

Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation.

J Allergy Clin Immunol 2017 Apr 30;139(4):1282-1292. Epub 2016 Sep 30.

Hospital for Sick Children, Toronto, Ontario, Canada.

Background: X-linked hyper-IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared with those seen in healthy subjects. Hematopoietic cell transplantation (HCT) has been considered a curative therapy, but the procedure has inherent complications and might not be available for all patients.

Objectives: We sought to collect data on the clinical presentation, treatment, and follow-up of a large sample of patients with XHIGM to (1) compare long-term overall survival and general well-being of patients treated with or without HCT along with clinical factors associated with mortality and (2) summarize clinical practice and risk factors in the subgroup of patients treated with HCT.

Methods: Physicians caring for patients with primary immunodeficiency diseases were identified through the Jeffrey Modell Foundation, United States Immunodeficiency Network, Latin American Society for Immunodeficiency, and Primary Immune Deficiency Treatment Consortium. Data were collected with a Research Electronic Data Capture Web application. Survival from time of diagnosis or transplantation was estimated by using the Kaplan-Meier method compared with log-rank tests and modeled by using proportional hazards regression.

Results: Twenty-eight clinical sites provided data on 189 patients given a diagnosis of XHIGM between 1964 and 2013; 176 had valid follow-up and vital status information. Sixty-seven (38%) patients received HCT. The average follow-up time was 8.5 ± 7.2 years (range, 0.1-36.2 years). No difference in overall survival was observed between patients treated with or without HCT (P = .671). However, risk associated with HCT decreased for diagnosis years 1987-1995; the hazard ratio was significantly less than 1 for diagnosis years 1995-1999. Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2-10.8; P < .001). Among survivors, those treated with HCT had higher median Karnofsky/Lansky scores than those treated without HCT (P < .001). Among patients receiving HCT, 27 (40%) had graft-versus-host disease, and most deaths occurred within 1 year of transplantation.

Conclusion: No difference in survival was observed between patients treated with or without HCT across all diagnosis years (1964-2013). However, survivors treated with HCT experienced somewhat greater well-being, and hazards associated with HCT decreased, reaching levels of significantly less risk in the late 1990s. Among patients treated with HCT, treatment at an early age is associated with improved survival. Optimism remains guarded as additional evidence accumulates.
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http://dx.doi.org/10.1016/j.jaci.2016.07.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374029PMC
April 2017

Human CD40 ligand deficiency dysregulates the macrophage transcriptome causing functional defects that are improved by exogenous IFN-γ.

J Allergy Clin Immunol 2017 Mar 20;139(3):900-912.e7. Epub 2016 Aug 20.

Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address:

Background: CD40 ligand (CD40L) deficiency predisposes to opportunistic infections, including those caused by fungi and intracellular bacteria. Studies of CD40L-deficient patients reveal the critical role of CD40L-CD40 interaction for the function of T, B, and dendritic cells. However, the consequences of CD40L deficiency on macrophage function remain to be investigated.

Objectives: We sought to determine the effect of CD40L absence on monocyte-derived macrophage responses.

Methods: After observing the improvement of refractory disseminated mycobacterial infection in a CD40L-deficient patient by recombinant human IFN-γ (rhIFN-γ) adjuvant therapy, we investigated macrophage functions from CD40L-deficient patients. We analyzed the killing activity, oxidative burst, cytokine production, and in vitro effects of rhIFN-γ and soluble CD40 ligand (sCD40L) treatment on macrophages. In addition, the effect of CD40L absence on the macrophage transcriptome before and after rhIFN-γ treatment was studied.

Results: Macrophages from CD40L-deficient patients exhibited defective fungicidal activity and reduced oxidative burst, both of which improved in the presence of rhIFN-γ but not sCD40L. In contrast, rhIFN-γ and sCD40L ameliorate impaired production of inflammatory cytokines. Furthermore, rhIFN-γ reversed defective control of Mycobacterium tuberculosis proliferation by patients' macrophages. The absence of CD40L dysregulated the macrophage transcriptome, which was improved by rhIFN-γ. Additionally, rhIFN-γ increased expression levels of pattern recognition receptors, such as Toll-like receptors 1 and 2, dectin 1, and dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin in macrophages from both control subjects and patients.

Conclusion: Absence of CD40L impairs macrophage development and function. In addition, the improvement of macrophage immune responses by IFN-γ suggests this cytokine as a potential therapeutic option for patients with CD40L deficiency.
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http://dx.doi.org/10.1016/j.jaci.2016.07.018DOI Listing
March 2017

Unrelated Hematopoietic Cell Transplantation in a Patient with Combined Immunodeficiency with Granulomatous Disease and Autoimmunity Secondary to RAG Deficiency.

J Clin Immunol 2016 10 18;36(7):725-32. Epub 2016 Aug 18.

Division of Hematology, CHOC Children's Hospital, 1201 W. La Veta Avenue, Orange, CA, 92868, USA.

The use of HLA-identical hematopoietic stem cell transplantation (HSCT) demonstrates overall survival rates greater than 75 % for T-B-NK+ severe combined immunodeficiency secondary to pathogenic mutation of recombinase activating genes 1 and 2 (RAG1/2). Limited data exist regarding the use of HSCT in patients with hypomorphic RAG variants marked by greater preservation of RAG activity and associated phenotypes such as granulomatous disease in combination with autoimmunity. We describe a 17-year-old with combined immunodeficiency and immune dysregulation characterized by granulomatous lung disease and autoimmunity secondary to compound heterozygous RAG mutations. A myeloablative reduced toxicity HSCT was completed using an unrelated bone marrow donor. With the increasing cases of immune dysregulation being discovered with hypomorphic RAG variants, the use of HSCT may advance to the forefront of treatment. This case serves to discuss indications of HSCT, approaches to preparative therapy, and the potential complications in this growing cohort of patients with immune dysregulation and RAG deficiency.
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http://dx.doi.org/10.1007/s10875-016-0326-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5286911PMC
October 2016

Interferon-gamma reduces the proliferation of M. tuberculosis within macrophages from a patient with a novel hypomorphic NEMO mutation.

Pediatr Blood Cancer 2016 10 8;63(10):1863-6. Epub 2016 Jul 8.

Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.

X-linked ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is caused by mutations in the nuclear factor-kappa B essential modulator (NEMO) gene. Here, we report the clinical and genetic features of a XL-EDA-ID patient who developed bacillus Calmette-Guérin infection. Patient lymphocytes failed to degrade IκB-α, and sequencing of NEMO identified the novel mutation c.1238A>C/p.H413P. Furthermore, patient monocyte-derived macrophages ingested Mycobacterium tuberculosis normally, but failed to control the intracellular proliferation of bacilli, a defect which was improved in the presence of interferon-gamma (IFN-γ). This work expands the genetic spectrum of XL-EDA-ID and demonstrates improvement in macrophage function in a NEMO-deficient patient by IFN-γ.
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http://dx.doi.org/10.1002/pbc.26098DOI Listing
October 2016

Neonatal screening for severe combined immunodeficiency in Brazil.

J Pediatr (Rio J) 2016 Jul-Aug;92(4):374-80. Epub 2016 May 18.

Department of Immunology, Instituto de Ciências Biomédicas, Universidade de São Paulo (USP), São Paulo, SP, Brazil. Electronic address:

Objective: To apply, in Brazil, the T-cell receptor excision circles (TRECs) quantification technique using real-time polymerase chain reaction in newborn screening for severe combined immunodeficiency and assess the feasibility of implementing it on a large scale in Brazil.

Methods: 8715 newborn blood samples were collected on filter paper and, after DNA elution, TRECs were quantified by real-time polymerase chain reaction. The cutoff value to determine whether a sample was abnormal was determined by ROC curve analysis, using SSPS.

Results: The concentration of TRECs in 8,682 samples ranged from 2 to 2,181TRECs/μL of blood, with mean and median of 324 and 259TRECs/μL, respectively. Forty-nine (0.56%) samples were below the cutoff (30TRECs/μL) and were reanalyzed. Four (0.05%) samples had abnormal results (between 16 and 29TRECs/μL). Samples from patients previously identified as having severe combined immunodeficiency or DiGeorge syndrome were used to validate the assay and all of them showed TRECs below the cutoff. Preterm infants had lower levels of TRECs than full-term neonates. The ROC curve showed a cutoff of 26TRECs/μL, with 100% sensitivity for detecting severe combined immunodeficiency. Using this value, retest and referral rates were 0.43% (37 samples) and 0.03% (3 samples), respectively.

Conclusion: The technique is reliable and can be applied on a large scale after the training of technical teams throughout Brazil.
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http://dx.doi.org/10.1016/j.jped.2015.10.006DOI Listing
April 2017

Health-Related Quality of Life and Health Resource Utilization in Patients with Primary Immunodeficiency Disease Prior to and Following 12 Months of Immunoglobulin G Treatment.

J Clin Immunol 2016 07 18;36(5):450-61. Epub 2016 Apr 18.

Baxalta US, Inc, Cambridge, MA, USA.

Purpose: Health-related quality of life (HRQOL) has not been examined in patients with predominant antibody deficiency both pre- and post-immunoglobulin G (IgG) treatment initiation. HRQOL and health resource utilization (HRU) were assessed in newly diagnosed patients with primary immunodeficiency disease (PIDD) pre- and 12 months post-IgG treatment initiation.

Methods: Adults (age ≥18 years) completed the 36-item Short Form Health Survey, version 2; pediatric patients (PP)/caregivers completed the Pediatric Quality of Life Inventory (PedsQL). Scores were compared with normative data from the US general population (GP) and patients with other chronic conditions (OCC).

Results: Seventeen adult patients (APs), 8 PPs, and 8 caregivers completed baseline assessments. APs had significantly lower baseline mean physical component summary scores versus GP (37.4 vs 50.5, p < 0.01) adults with chronic back pain (44.1, p < 0.05) or cancer (44.4, p < 0.05) and lower mental component summary scores versus GP (41.6 vs 49.2, p < 0.05). PPs had lower PedsQL total (63.1 vs 82.7), physical summary (64.5 vs 84.5), and psychosocial summary (62.5 vs 81.7) scores versus GP. Post-IgG treatment, 14 APs, 6 PPs, and 8 caregivers completed assessments. Hospital admissions (0.2 versus 1.8, p < 0.01), serious infections (3.3 versus 10.9, p < 0.01) and antibiotic prescriptions (3.0 versus 7.1; p < 0.01) decreased significantly overall. While APs reported significant improvement in role-physical (p = 0.01), general health (p < 0.01), and social functioning (p = 0.02) and caregivers in vitality (p < 0.01), PPs did not.

Conclusions: Pre-IgG treatment, patients with PIDD experienced diminished HRQOL versus GP and patients with OCC; post-treatment, HRU decreased and certain HRQOL aspects improved for APs and caregivers.
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http://dx.doi.org/10.1007/s10875-016-0279-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896988PMC
July 2016

22q11.2 Deletion Syndrome due to a Translocation t(6;22) in a Patient Conceived via in vitro Fertilization.

Mol Syndromol 2016 Feb 14;6(5):242-7. Epub 2015 Nov 14.

Genetics Division, Department of Morphology and Genetics, Universidade Federal de São Paulo, Brazil.

We report on a patient conceived via in vitro fertilization (IVF) with a 22q11.2 deletion due to an unusual unbalanced translocation involving chromosomes 6 and 22 in a karyotype with 45 chromosomes. Cytogenomic studies showed that the patient has a 3.3-Mb deletion of chromosome 22q and a 0.4-Mb deletion of chromosome 6p, which resulted in haploinsufficiency of the genes responsible for the 22q11.2 deletion syndrome and also of the IRF4 gene, a member of the interferon regulatory factor family of transcription factors, which is expressed in the immune system cells. The rearrangement could be due to the manipulation of the embryo or as a sporadic event unrelated to IVF. Translocation involving chromosome 22 in a karyotype with 45 chromosomes is a rare event, with no previous reports involving chromosomes 6p and 22q.
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http://dx.doi.org/10.1159/000441243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772615PMC
February 2016

PROTECTIVE LEVELS OF VARICELLA-ZOSTER ANTIBODY DID NOT EFFECTIVELY PREVENT CHICKENPOX IN AN X-LINKED AGAMMAGLOBULINEMIA PATIENT.

Rev Inst Med Trop Sao Paulo 2015 Sep-Oct;57(5):455-7

Departmento de Pediatria, Universidade Federal de São Paulo, São Paulo, SP, Brasil,

We describe the case of an eight-year-old boy with X-linked agammaglobulinemia who developed mild varicella despite regular intravenous immunoglobulin (IVIG) therapy. He maintained protective antibody levels against varicella and the previous batches of IVIG that he received had adequate varicella-specific IgG levels. The case illustrates that IVIG may not prevent VZV infection.
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http://dx.doi.org/10.1590/S0036-46652015000500017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4660460PMC
April 2016

Neutrophil oxidative burst activates ATM to regulate cytokine production and apoptosis.

Blood 2015 Dec 21;126(26):2842-51. Epub 2015 Oct 21.

Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Berlin, Germany;

Neutrophils play an essential role in the initial stages of inflammation by balancing pro- and antiinflammatory signals. Among these signals are the production of proinflammatory cytokines and the timely initiation of antiinflammatory cell death via constitutive apoptosis. Here we identify ataxia-telangiectasia mutated (ATM) kinase as a modulator of these neutrophil functions. Ataxia-telangiectasia (AT) is a pleiotropic multisystem disorder caused by mutations in the gene-encoding ATM, a master regulator of the DNA damage response. In addition to progressive neurodegeneration and high rates of cancer, AT patients have numerous symptoms that can be linked to chronic inflammation. We report that neutrophils isolated from patients with AT overproduce proinflammatory cytokines and have a prolonged lifespan compared with healthy controls. This effect is partly mediated by increases in activation of p38 MAP kinase. Furthermore, we show that the oxidative burst, catalyzed by nicotinamide adenine dinucleotide phosphate oxidase, can activate ATM in neutrophils. Finally, activation of ATM and DNA damage signaling suppress cytokine production and can abrogate the overproduction of IL-8 in ROS-deficient cells. This reveals a novel mechanism for the regulation of cytokine production and apoptosis, establishing DNA damage as a downstream mediator of immune regulation by reactive oxygen species. We propose that deficiencies in the DNA damage response, like deficiencies in the oxidative burst seen in chronic granulomatous disease, could lead to pathologic inflammation.
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http://dx.doi.org/10.1182/blood-2015-05-645424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692144PMC
December 2015

Clinical and Genotypic Spectrum of Chronic Granulomatous Disease in 71 Latin American Patients: First Report from the LASID Registry.

Pediatr Blood Cancer 2015 Dec 15;62(12):2101-7. Epub 2015 Jul 15.

Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.

Aim: We analyzed data from 71 patients with chronic granulomatous disease (CGD) with a confirmed genetic diagnosis, registered in the online Latin American Society of Primary Immunodeficiencies (LASID) database.

Results: Latin American CGD patients presented with recurrent and severe infections caused by several organisms. The mean age at disease onset was 23.9 months, and the mean age at CGD diagnosis was 52.7 months. Recurrent pneumonia was the most frequent clinical condition (76.8%), followed by lymphadenopathy (59.4%), granulomata (49.3%), skin infections (42%), chronic diarrhea (41.9%), otitis (29%), sepsis (23.2%), abscesses (21.7%), recurrent urinary tract infection (20.3%), and osteomyelitis (15.9%). Adverse reactions to bacillus Calmette-Guérin (BCG) vaccination were identified in 30% of the studied Latin American CGD cases. The genetic diagnoses of the 71 patients revealed 53 patients from 47 families with heterogeneous mutations in the CYBB gene (five novel mutations: p.W361G, p.C282X, p.W483R, p.R226X, and p.Q93X), 16 patients with the common deletion c.75_76 del.GT in exon 2 of NCF1 gene, and two patients with mutations in the CYBA gene.

Conclusion: The majority of Latin American CGD patients carry a hemizygous mutation in the CYBB gene. They also presented a wide range of clinical manifestations most frequently bacterial and fungal infections of the respiratory tract, skin, and lymph nodes. Thirty percent of the Latin American CGD patients presented adverse reactions to BCG, indicating that this vaccine should be avoided in these patients.
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http://dx.doi.org/10.1002/pbc.25674DOI Listing
December 2015

Higher Cardiovascular Risk in Common Variable Immunodeficiency and X-Linked Agammaglobulinaemia Patients.

Ann Nutr Metab 2015 14;66(4):237-41. Epub 2015 Jul 14.

Federal University of Sao Paulo, Sao Paulo, Sao Paulo, Brazil.

Introduction: Common variable immunodeficiency and X-linked agammaglobulinaemia are primary immunodeficiencies classified as antibody deficiencies, and they both result in hypogammaglobulinaemia.

Objective: Evaluate the lipid profile and other cardiovascular risk biomarkers in CVID and XLA patients.

Methods: In total, 24 patients and 12 healthy controls matched by age and gender were included in the study. We evaluated anthropometric measurements, and seric total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), triglycerides (TG), apo A-I, small dense LDL (sdLDL), C-reactive protein (CRP), and tumour necrosis factor alpha (TNF-alpha), myeloperoxidase (MPO), cholesteryl ester transfer protein (CETP), and lecithin cholesterol acyltransferase (LCAT) were assessed.

Results: CRP (p = 0.008) and TNF-alpha (p < 0.001) concentrations were significantly higher, whereas HDL-c (p = 0.025) and apo A-I (p = 0.013) levels were significantly lower in patients than in the controls. In the patient group, a negative and significant correlation was observed between HDL-c and TNF-alpha (r = -0.406; p = 0.049) and between HDL-c and TG (r = -0.641; p = 0.001).

Conclusion: Common variable immunodeficiency and X-linked agammaglobulinaemia patients presented themselves with increased inflammatory markers associated with a decreased HDL-c and apo A-I levels, which can predispose to a high cardiovascular risk.
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http://dx.doi.org/10.1159/000435818DOI Listing
November 2016

Risk of Atherosclerosis in Patients with Ataxia Telangiectasia.

Ann Nutr Metab 2015 4;66(4):196-201. Epub 2015 Jun 4.

Pediatric Department, Universidade Federal de São Paulo, São Paulo, S.P., Brazil.

Background And Aims: Evaluate the nutritional status, plasma concentration of vitamin E and markers of cardiovascular risk in ataxia telangiectasia (AT) patients.

Methods: Cross-sectional study with 13 patients with AT and 22 healthy controls, evaluating the following factors: nutritional status, food intake, lipid profile, plasma concentration of vitamin E, malondialdehyde and high sensitivity C-reactive protein, linking them with atherosclerosis risk in AT patients.

Results: Average age was 14.6 in the AT group, 30.8% were malnourished and 23.1% had stunting. A greater impairment of lean body mass was found in these patients. Concentrations of triglycerides (TG), total cholesterol (CT), LDL-c, non-HDL cholesterol (NHDL-c) were significantly higher in patients and HDL-c, lower. Vitamin E/total lipids and vitamin E/TG ratios were lower in the AT group, and significant inverse correlation between these ratios and NHDL-c, CT/HDL-c, and LDL-c/HDL-c, log TG/HDL-c was observed in the AT group. Alanine aminotransferase correlated directly and significantly with NHDL-c, CT/HDL-c and LDL-c/HDL-c, in patients.

Conclusion: The alterations of lipid metabolism biomarkers suggestive of atherosclerotic risk of male AT patients coupled with lower vitamin E/total lipids ratio and low lean body mass may complicate the clinical course of the disease and emphasizes the importance of multidisciplinary care, routine monitoring of cardiovascular biomarkers and appropriate nutritional guidance.
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http://dx.doi.org/10.1159/000430790DOI Listing
November 2016

Maternally acquired IgG immunity in neonates born to renal transplanted women.

Vaccine 2015 Jun 15;33(27):3104-9. Epub 2015 May 15.

Department of Pediatrics, Federal University of São Paulo, São Paulo, SP, Brazil. Electronic address:

Neonates born to renal transplanted women are exposed in utero to immunosuppressors and to antenatal conditions that may predispose the neonate to a high risk of prematurity and intrauterine growth retardation. These factors might interfere with the transfer of maternal IgG immunity. Total IgG levels and specific antibodies to measles, varicella, tetanus, Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae (serotypes 4,6B,9V,14,18C,19F and 23F) were evaluated on maternal and cord blood samples of 23 sets of renal transplanted women and their newborns and 32 sets of healthy women-newborns at term. Total IgG levels were measured by nephelometry and specific antibodies, by ELISA. Renal transplanted mothers had lower median tetanus antibodies (0.67IU/mL) than controls (1.53IU/mL; p=0.017). Neonates from renal transplanted mothers had lower median tetanus antibodies (0.95IU/mL) than controls (1.97IU/mL, p=0.008). Antibodies to measles, varicella, Hib and the 7 serotypes of S. pneumoniae were similar between groups. Maternal antibodies were associated with an increase in neonatal antibodies for all antigens; gestational age was associated with an increase in Hib neonatal antibodies. Preeclampsia was associated with a decrease in neonatal total IgG and serotype 4 S. pneumoniae antibodies; chronic hypertension was associated with a decrease in neonatal serotype 6B S. pneumoniae antibodies. As neonates from transplanted women may be born with lower tetanus antibodies than controls, efforts should be made to keep maternal vaccines up-to-date. Clinical antenatal care with control of preeclampsia, chronic hypertension and prevention of premature delivery might also contribute to neonatal antibody levels to specific antigens at birth.
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http://dx.doi.org/10.1016/j.vaccine.2015.04.104DOI Listing
June 2015

Antibody levels to tetanus, diphtheria, measles and varicella in patients with primary immunodeficiency undergoing intravenous immunoglobulin therapy: a prospective study.

BMC Immunol 2014 Jun 21;15:26. Epub 2014 Jun 21.

Federal University of Sao Paulo, Rua dos Otonis, 731, CEP: 04025-002 São Paulo, Brazil.

Background: Patients with antibody deficiencies depend on the presence of a variety of antibody specificities in intravenous immunoglobulin (IVIG) to ensure continued protection against pathogens. Few studies have examined levels of antibodies to specific pathogens in IVIG preparations and little is known about the specific antibody levels in patients under regular IVIG treatment. The current study determined the range of antibodies to tetanus, diphtheria, measles and varicella in IVIG products and the levels of these antibodies in patients undergoing IVIG treatment.

Methods: We selected 21 patients with primary antibody deficiencies who were receiving regular therapy with IVIG. Over a period of one year, we collected four blood samples from each patient (every 3 months), immediately before immunoglobulin infusion. We also collected samples from the IVIG preparation the patients received the month prior to blood collection. Antibody levels to tetanus, diphtheria, measles and varicella virus were measured in plasma and IVIG samples. Total IgG levels were determined in plasma samples.

Results: Antibody levels to tetanus, diphtheria, varicella virus and measles showed considerable variation in different IVIG lots, but they were similar when compared between commercial preparations. All patients presented with protective levels of antibodies specific for tetanus, measles and varicella. Some patients had suboptimal diphtheria antibody levels. There was a significant correlation between serum and IVIG antibodies to all pathogens, except tetanus. There was a significant correlation between diphtheria and varicella antibodies with total IgG levels, but there was no significant correlation with antibodies to tetanus or measles.

Conclusions: The study confirmed the variation in specific antibody levels between batches of the same brand of IVIG. Apart from the most common infections to which these patients are susceptible, health care providers must be aware of other vaccine preventable diseases, which still exist globally.
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http://dx.doi.org/10.1186/1471-2172-15-26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074853PMC
June 2014

Medical awareness concerning primary immunodeficiency diseases in the city of São Paulo, Brazil.

Einstein (Sao Paulo) 2013 Dec;11(4):479-85

Objective: To evaluate medical knowledge of primary immunodeficiency in the city of São Paulo (SP).

Methods: A 14-item questionnaire about primary immunodeficiency was applied to physicians who worked at general hospitals. One of the questions presented 25 clinical situations that could be associated or not with primary immunodeficiency, and the percentage of appropriate answers generated a knowledge indicator.

Results: Seven hundred and forty-six participated in the study, among them 215 pediatricians (28.8%), 244 surgeons (32.7%), and 287 clinicians (38.5%). About 70% of the physicians responded that they had learned about primary immunodeficiency in graduate school or in residency training. Treatment of patients that use antibiotics frequently was reported by 75% dos physicians, but only 34.1% had already investigated a patient and 77.8% said they did not know the ten warning signs for primary immunodeficiency. The knowledge indicator obtained showed a mean of 45.72% (±17.87). Only 26.6% if the pediatricians and 6.6% of clinicians and surgeons showed a knowledge indicator of at least 67% (equivalent to an appropriate answer in two thirds of the clinical situations).

Conclusion: There is a deficit in medical knowledge of primary immunodeficiency in the city of São Paulo, even among pediatricians, despite having greater contact with the theme over the last few years. The improvement of information on primary immunodeficiency in the medical community is an important step towards the diagnosis and treatment process of these diseases.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880386PMC
http://dx.doi.org/10.1590/s1679-45082013000400013DOI Listing
December 2013

First report of the Hyper-IgM syndrome Registry of the Latin American Society for Immunodeficiencies: novel mutations, unique infections, and outcomes.

J Clin Immunol 2014 Feb 9;34(2):146-56. Epub 2014 Jan 9.

Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, 1730 Lineu Prestes Avenue, São Paulo, SP, ZIP 05508-000, Brazil.

Hyper-IgM (HIGM) syndrome is a heterogeneous group of disorders characterized by normal or elevated serum IgM levels associated with absent or decreased IgG, IgA and IgE. Here we summarize data from the HIGM syndrome Registry of the Latin American Society for Immunodeficiencies (LASID). Of the 58 patients from 51 families reported to the registry with the clinical phenotype of HIGM syndrome, molecular defects were identified in 37 patients thus far. We retrospectively analyzed the clinical, immunological and molecular data from these 37 patients. CD40 ligand (CD40L) deficiency was found in 35 patients from 25 families and activation-induced cytidine deaminase (AID) deficiency in 2 unrelated patients. Five previously unreported mutations were identified in the CD40L gene (CD40LG). Respiratory tract infections, mainly pneumonia, were the most frequent clinical manifestation. Previously undescribed fungal and opportunistic infections were observed in CD40L-deficient patients but not in the two patients with AID deficiency. These include the first cases of pneumonia caused by Mycoplasma pneumoniae, Serratia marcescens or Aspergillus sp. and diarrhea caused by Microsporidium sp. or Isospora belli. Except for four CD40L-deficient patients who died from complications of presumptive central nervous system infections or sepsis, all patients reported in this study are alive. Four CD40L-deficient patients underwent successful bone marrow transplantation. This report characterizes the clinical and genetic spectrum of HIGM syndrome in Latin America and expands the understanding of the genotype and phenotype of this syndrome in tropical areas.
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http://dx.doi.org/10.1007/s10875-013-9980-4DOI Listing
February 2014

Attending to warning signs of primary immunodeficiency diseases across the range of clinical practice.

J Clin Immunol 2014 Jan 16;34(1):10-22. Epub 2013 Nov 16.

Division of Allergy, Clinical Immunology and Rheumatology, Department of Pediatrics, Federal University of São Paulo (UNIFESP-EPM), 725 Otonis Street, São Paulo, SP, 04025-002, Brazil,

Purpose: Patients with primary immunodeficiency diseases (PIDD) may present with recurrent infections affecting different organs, organ-specific inflammation/autoimmunity, and also increased cancer risk, particularly hematopoietic malignancies. The diversity of PIDD and the wide age range over which these clinical occurrences become apparent often make the identification of patients difficult for physicians other than immunologists. The aim of this report is to develop a tool for educative programs targeted to specialists and applied by clinical immunologists.

Methods: Considering the data from national surveys and clinical reports of experiences with specific PIDD patients, an evidence-based list of symptoms, signs, and corresponding laboratory tests were elaborated to help physicians other than immunologists look for PIDD.

Results: Tables including main clinical manifestations, restricted immunological evaluation, and possible related diagnosis were organized for general practitioners and 5 specialties. Tables include information on specific warning signs of PIDD for pulmonologists, gastroenterologists, dermatologists, hematologists, and infectious disease specialists.

Conclusions: This report provides clinical immunologists with an instrument they can use to introduce specialists in other areas of medicine to the warning signs of PIDD and increase early diagnosis. Educational programs should be developed attending the needs of each specialty.
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http://dx.doi.org/10.1007/s10875-013-9954-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930833PMC
January 2014

Effects of inspiratory muscle training on lung volumes, respiratory muscle strength, and quality of life in patients with ataxia telangiectasia.

Pediatr Pulmonol 2014 Mar 19;49(3):238-44. Epub 2013 Aug 19.

Department of Pediatrics, School of Medicine, Federal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil.

Background: Ataxia telangiectasia (AT) is a genetic syndrome caused by a mutation of chromosome 11. The clinical features are cerebellar ataxia, telangiectasia, and progressive loss of muscular coordination, including an inefficient cough secondary to progression of neurological disease.

Objective: To evaluate the effects of inspiratory muscle training (IMT) on ventilation, lung volume, dyspnoea, respiratory muscle strength, and quality of life in patients with AT.

Methods: A longitudinal study was conducted with 11 AT patients and nine healthy volunteers. Ventilometry, subjective sensation of dyspnoea, maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and quality of life were assessed before and after a 24-week IMT program. The IMT load used was set at 60% of the MIP, and the training was performed for 20 min daily.

Results: Patients with AT had lower height and weight and also had lower respiratory muscle strength and lung volume compared with healthy volunteers. Furthermore, patients with AT showed a significant improvement when pre- and post-IMT were compared for ventilatory pattern: Vt (476.5 ± 135 ml vs. 583.3 ± 66 ml, P = 0.015) and f (23.3 ± 6 rpm vs. 20.4 ± 4 rpm, P = 0.018), and VC (1,664 ± 463 ml/kg vs. 2,145 ± 750 ml/kg, P = 0.002). IMT also significantly improved the sensation of dyspnoea (median 0.5; minimum 0; maximum 1.0; P = 0.022) and respiratory muscle strength: MIP (-22.2 ± 2 cmH2O vs. -38 ± 9 cmH2O, P < 0.001) and MEP (29 ± 7 cmH2O vs. 40 ± 8 cmH2O, P = 0.001). The health and vitality domains of the SF-36 also showed significant improvement (P = 0.009 and P = 0.014, respectively) post-IMT.

Conclusion: IMT was effective in improving ventilatory pattern, lung volume, respiratory muscle strength, and the health and vitality domains for quality of life in patients with AT. IMT may be an effective adjunct therapy to drug treatment for patients with AT.
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http://dx.doi.org/10.1002/ppul.22828DOI Listing
March 2014

Expanding the clinical and genetic spectrum of human CD40L deficiency: the occurrence of paracoccidioidomycosis and other unusual infections in Brazilian patients.

J Clin Immunol 2012 Apr 23;32(2):212-20. Epub 2011 Dec 23.

Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, São Paulo ZIP 05508-000, Brazil.

CD40 ligand (CD40L) deficiency or X-linked hyper-IgM syndrome (X-HIGM) is a well-described primary immunodeficiency in which Pneumocystis jiroveci pneumonia is a common clinical feature. We have identified an unusual high incidence of fungal infections and other not yet described infections in a cohort of 11 X-HIGM patients from nine unrelated Brazilian families. Among these, we describe the first case of paracoccidioidomycosis (PCM) in X-HIGM. The molecular genetic analysis of CD40L was performed by gene sequencing and evaluation of CD40L protein expression. Nine of these 11 patients (82%) had fungal infections. These included fungal species common to CD40L deficiency (P. jiroveci and Candida albicans) as well as Paracoccidioides brasiliensis. One patient presented with PCM at age 11 years and is now doing well at 18 years of age. Additionally, one patient presented with a simultaneous infection with Klebsiella and Acinetobacter, and one with condyloma caused by human papilloma virus. Molecular analysis revealed four previously described CD40L mutations, two novel missense mutations (c.433 T > G and c.476 G > C) resulting in the absence of CD40L protein expression by activated CD4(+) cells and one novel insertion (c.484_485insAA) within the TNFH domain leading to a frame shift and premature stop codon. These observations demonstrated that the susceptibility to fungal infections in X-HIGM extends beyond those typically associated with X-HIGM (P. jiroveci and C. albicans) and that these patients need to be monitored for those pathogens.
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http://dx.doi.org/10.1007/s10875-011-9623-6DOI Listing
April 2012