Juliana Themudo Lessa Mazzucchelli

Immediate infusion-related adverse reactions to intravenous immunoglobulin in a prospective cohort of 1765 infusions

Intravenous immunoglobulin (IVIG) is increasingly recommended for many diseases apart from primary immunodeficiency diseases (PID). Although effective and safe, adverse reactions may occur. We conducted a 2-year prospective observational study in 117 patients with PID who received regular IVIG replacement therapy at a median dose of 600 mg/kg every 3 to 4 weeks to examine IVIGs adverse effects; 1765 infusions were performed (mean=15/patient) in 75 males and 42 females (aged 3 months to 77 years) in 3 groups: ≤ 9 years (34.2%), 10-19 years (26.5%), and ≥ 20 years (39.3%). Fifty patients had common variable immunodeficiency (CVID), 11 had X-linked agammaglobulinemia (XLA), and 55 had other immune system disorders. The drugs administered were Octagam® (49.1%), Tegeline® (17.3%), Imunoglobulin® (18.6%), Flebogama® (12.9%), Vigam® (1.2%), and Kiovig® (0.4%). Immediate infusion-related adverse reactions occurred in the cases of 38 out 1765 infusions (2.15%, IC95% 1.53%-2.94%), which were classified as mild (81.6%), moderate (10.5%), or severe (7.9%). Time until reaction ranged from 10 to 240 min (mean = 85.7, median = 60). Reaction rates were similar across age groups. The most common reactions were malaise, headache, and abdominal pain. Reported severe events were tightness of the throat and seizure. All symptoms improved with temporary or complete IVIG interruption and symptomatic medications. Sixteen of 38 reactions to infusions occurred in the presence of an acute infection (p=0.09). Tegeline® represented a greater reaction risk factor than Octagam® (p < 0.001). These results indicate that IVIG infusion can be considered a safe procedure. Low reaction incidence and few severe immediate infusion-related adverse reactions were observed.

Neonatal screening for severe combined immunodeficiency in Brazil

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.

Conhecimento médico sobre as imunodeficiências primárias na cidade de São Paulo, Brasil

OBJECTIVE: To evaluate medical knowledge of primary immunodeficiency in the city of Sao 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 Sao 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.ABSTRACT Objective: To evaluate medical knowledge of primary immunodeficiency in the city of Sao 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 Sao 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.

TRIAGEM NEONATAL DE IMUNODEFICIÊNCIAS GRAVES COMBINADAS POR MEIO DE TRECS E KRECS: SEGUNDO ESTUDO PILOTO NO BRASIL

ABSTRACT Objective: To validate the quantification of T-cell receptor excision circles (TRECs) and kappa-deleting recombination excision circles (KRECs) by real-time polymerase chain reaction (qRT-PCR) for newborn screening of primary immunodeficiencies with defects in T and/or B cells in Brazil. Methods: Blood samples from newborns and controls were collected on filter paper. DNA was extracted and TRECs, and KRECs were quantified by a duplex real-time PCR. The cutoff values were determined by receiver operating characteristic curve analysis using SPSS software (IBM®, Armonk, NY, USA). Results: Around 6,881 samples from newborns were collected and TRECs and KRECs were quantified. The TRECs values ranged between 1 and 1,006 TRECs/µL, with mean and median of 160 and 139 TRECs/µL, respectively. Three samples from patients with severe combined immunodeficiency (SCID) showed TRECs below 4/µL and a patient with DiGeorge syndrome showed undetectable TRECs. KRECs values ranged from 10 to 1,097 KRECs/µL, with mean and median of 130 and 108 KRECs/µL. Four patients with agammaglobulinemia had results below 4 KRECs/µL. The cutoff values were 15 TRECs/µL and 14 KRECs/µL and were established according to the receiver operating characteristic curve analysis, with 100% sensitivity for SCID and agammaglobulinemia detection, respectively. Conclusions: Quantification of TRECs and KRECs was able to diagnose children with T- and/or B-cell lymphopenia in our study, which validated the technique in Brazil and enabled us to implement the newborn screening program for SCID and agammaglobulinemia.Objetivo: Validar a quantificacao de T-cell receptor excision circles (TRECs) e kappa-deleting recombination circles (KRECs) por reacao em cadeia de polimerase (polymerase chain reaction, PCR) em tempo real (qRT-PCR), para triagem neonatal de imunodeficiencias primarias que cursam com defeitos nas celulas T e/ou B no Brasil. Metodos: Amostras de sangue de recem-nascidos (RN) e controles foram coletadas em papel-filtro. O DNA foi extraido e os TRECs e KRECs foram quantificados por reacao duplex de qRT-PCR. O valor de corte foi determinado pela analise de Receiver Operating Characteristics Curve, utilizando-se o programa Statistical Package for the Social Sciences (SSPS) (IBM®, Armonk, NY, EUA). Resultados: 6.881 amostras de RN foram analisadas quanto a concentracao de TRECs e KRECs. Os valores de TRECs variaram entre 1 e 1.006 TRECs/µL, com media e mediana de 160 e 139 TRECs/µL, respectivamente. Tres amostras de pacientes diagnosticados com imunodeficiencia grave combinada (severe combined immunodeficiency, SCID) apresentaram valores de TRECs abaixo de 4/µL e um paciente com Sindrome de DiGeorge apresentou TRECs indetectaveis. Os valores de KRECs encontraram-se entre 10 e 1.097 KRECs/µL, com media e mediana de 130 e 108 KRECs/µL, e quatro pacientes com diagnostico de agamaglobulinemia tiveram resultados abaixo de 4 KRECs/µL. Os valores de corte encontrados foram 15 TRECs/µL e 14 KRECs/µL, e foram estabelecidos de acordo com a analise da Receiver Operating Characteristics Curve, com sensibilidade de 100% para deteccao de SCID e agamaglobulinemia, respectivamente. Conclusoes: A quantificacao de TRECs e KRECs foi capaz de diagnosticar criancas com linfopenias T e/ou B em nosso estudo, validando a tecnica e dando o primeiro passo para a implementacao da triagem neonatal em grande escala no Brasil.

Doctors' awareness concerning primary immunodeficiencies in Brazil

BACKGROUND PIDs are a heterogeneous group of genetic illnesses, and delay in their diagnosis is thought to be caused by a lack of awareness among physicians concerning PIDs. The latter is what we aimed to evaluate in Brazil. METHODS Physicians working at general hospitals all over the country were asked to complete a 14-item questionnaire. One of the questions described 25 clinical situations that could be associated with PIDs and a score was created based on percentages of appropriate answers. RESULTS A total of 4026 physicians participated in the study: 1628 paediatricians (40.4%), 1436 clinicians (35.7%), and 962 surgeons (23.9%). About 67% of the physicians had learned about PIDs in medical school or residency training, 84.6% evaluated patients who frequently took antibiotics, but only 40.3% of them participated in the immunological evaluation of these patients. Seventy-seven percent of the participating physicians were not familiar with the warning signs for PIDs. The mean score of correct answers for the 25 clinical situations was 48.08% (±16.06). Only 18.3% of the paediatricians, 7.4% of the clinicians, and 5.8% of the surgeons answered at least 2/3 of these situations appropriately. CONCLUSIONS There is a lack of medical awareness concerning PIDs, even among paediatricians, who have been targeted with PID educational programmes in recent years in Brazil. An increase in awareness with regard to these disorders within the medical community is an important step towards improving recognition and treatment of PIDs.

Early-onset thrombocytopenia, severe polyarthritis, and severe Β cell impairment in a Down syndrome patient

Background Down syndrome is the most common genetic disease and is associated with an increased frequency of congenital cardiac and gastrointestinal defects, hematological disorders, autoimmune diseases and immunodeficiency. Decreased numbers of T and B lymphocytes, particularly naive B cells, have been reported in these patients, although a significant association between lymphocyte subpopulation counts and the frequency of infections or the presence of autoimmunity was not found.

IgG serum levels in CVID patients during pregnancy

Background Common Variable Immunodeficiency (CVID) is characterized by reduced serum levels of immunoglobulins (Ig) and its treatment requires regular infusion of intravenous immunoglobulin (IVIG). Eventually CVID female patients will reach reproductive age and it is known that maternofetal transplacental transport of antibodies is important to protect the child in the first months of life. The IgG present in fetal circulation comes from the mother after being actively transfered across the placenta. Although the required receptors for the transfer are expressed early on, most of it occurs in the third trimester of pregnancy and therefore this is the most important period for newborn protection. Transplacental transport of IgG is similar in pregnant women with and without CVID(Costa-Carvalho et al.).To this date, it is not established how the IVIG infusion should be conducted in order to maintain adequate IgG levels for the pregnant woman with CVID and her newborn.