Heterologous versus homologous COVID-19 booster vaccination in previous recipients of two doses of CoronaVac COVID-19 vaccine in Brazil (RHH-001): a phase 4, non-inferiority, single blind, randomised study.

INTRODUCTION: The inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac, Sinovac) has been widely used in a two-dose schedule. We assessed whether a third dose of the homologous or a different vaccine could boost immune responses. METHODS: RHH-001 is a phase 4, participant masked, two centre, safety and immunogenicity study of Brazilian adults (18 years and older) in São Paulo or Salvador who had received two doses of CoronaVac 6 months previously. The third heterologous dose was of either a recombinant adenoviral vectored vaccine (Ad26.COV2-S, Janssen), an mRNA vaccine (BNT162b2, Pfizer-BioNTech), or a recombinant adenoviral-vectored ChAdOx1 nCoV-19 vaccine (AZD1222, AstraZeneca), compared with a third homologous dose of CoronaVac. Participants were randomly assigned (5:6:5:5) by a RedCAP computer randomisation system stratified by site, age group (18-60 years or 61 years and over), and day of randomisation, with a block size of 42. The primary outcome was non-inferiority of anti-spike IgG antibodies 28 days after the booster dose in the heterologous boost groups compared with homologous regimen, using a non-inferiority margin for the geometric mean ratio (heterologous vs homologous) of 0·67. Secondary outcomes included neutralising antibody titres at day 28, local and systemic reactogenicity profiles, adverse events, and serious adverse events. This study was registered with Registro Brasileiro de Ensaios Clínicos, number RBR-9nn3scw. FINDINGS: Between Aug 16, and Sept 1, 2021, 1240 participants were randomly assigned to one of the four groups, of whom 1239 were vaccinated and 1205 were eligible for inclusion in the primary analysis. Antibody concentrations were low before administration of a booster dose with detectable neutralising antibodies of 20·4% (95% CI 12·8-30·1) in adults aged 18-60 years and 8·9% (4·2-16·2) in adults 61 years or older. From baseline to day 28 after the booster vaccine, all groups had a substantial rise in IgG antibody concentrations: the geometric fold-rise was 77 (95% CI 67-88) for Ad26.COV2-S, 152 (134-173) for BNT162b2, 90 (77-104) for ChAdOx1 nCoV-19, and 12 (11-14) for CoronaVac. All heterologous regimens had anti-spike IgG responses at day 28 that were superior to homologous booster responses: geometric mean ratios (heterologous vs homologous) were 6·7 (95% CI 5·8-7·7) for Ad26.COV2-S, 13·4 (11·6-15·3) for BNT162b2, and 7·0 (6·1-8·1) for ChAdOx1 nCoV-19. All heterologous boost regimens induced high concentrations of pseudovirus neutralising antibodies. At day 28, all groups except for the homologous boost in the older adults reached 100% seropositivity: geometric mean ratios (heterologous vs homologous) were 8·7 (95% CI 5·9-12·9) for Ad26.COV2-S vaccine, 21·5 (14·5-31·9) for BNT162b2, and 10·6 (7·2-15·6) for ChAdOx1 nCoV-19. Live virus neutralising antibodies were also boosted against delta (B.1.617.2) and omicron variants (B.1.1.529). There were five serious adverse events. Three of which were considered possibly related to the vaccine received: one in the BNT162b2 group and two in the Ad26.COV2-S group. All participants recovered and were discharged home. INTERPRETATION: Antibody concentrations were low at 6 months after previous immunisation with two doses of CoronaVac. However, all four vaccines administered as a third dose induced a significant increase in binding and neutralising antibodies, which could improve protection against infection. Heterologous boosting resulted in more robust immune responses than homologous boosting and might enhance protection. FUNDING: Ministry of Health, Brazil.

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.

Cell activation, PD-1 expression and in vitro cytokine production in patients with juvenile systemic lupus erythematosus.

BACKGROUND: Juvenile systemic lupus erythematosus (jSLE) is known to be more severe and with a higher frequency of renal and central nervous system impairment when compared to systemic lupus erythematosus in adults. The study of immunological characteristics of jSLE patients might help to envisage better treatment strategies to reduce the burden of the disease. OBJECTIVE: To characterize peripheral lymphocytes, assessing activation markers, and PD-1 expression on T cells; to evaluate in vitro cytokine expression upon stimulation in jSLE patients and age-matched controls. METHODOLOGY: Eighteen jSLE patients on low disease activity and 25 matched healthy adolescents were evaluated for immune activation and PD-1 expression on peripheral blood lymphocytes by flow cytometry. Twenty-one cytokines were assessed by X-MAP technology after in vitro stimulation of peripheral blood with phytohemagglutinin. RESULTS: jSLE patients had lower numbers of CD4 T, CD8 T, B, and NK cells; higher central memory CD8 T cell percentages were noted in jSLE adolescents in comparison with controls (p = 0.014). B cells subsets showed a higher percentage of exhausted memory subset than controls (p = 0.014). The expression of PD-1 on CD4 T and CD8 T cells did not show relevant changes in jSLE adolescents. After stimulation of peripheral blood, cell supernatant of jSLE patients showed a trend to lower concentrations of IL-10 (p=0.080) and higher concentrations of IL-23 (p = 0.063) than controls. CONCLUSIONS: jSLE patients on low disease activity maintain lymphopenia of all subsets, with a B cell profile of exhaustion. Upon in vitro stimulation, peripheral blood cell supernatant showed a shift to IL-23, suggesting a role of inhibitors of this cytokine as another potential therapeutic target for those patients.

Candida spp bloodstream infections in a Latin American Pediatric Oncology Reference Center: Epidemiology and associated factors.

BACKGROUND: Invasive fungal disease is a significant cause of morbidity and mortality in immunosuppressed children. The recognition of patients at risk for candidaemia is paramount to a better prognosis. OBJECTIVES: To characterize Candida spp bloodstream infections (BSI) in a reference centre for paediatric oncology and to describe the most prevalent risk factors associated with candida infections. PATIENTS/METHODS: This is a retrospective cohort study carried out with paediatric patients followed up with at the Institute of Pediatric Oncology, Brazil, who presented positive blood culture for Candida spp from January 2004 to December 2016. RESULTS: Ninety episodes of candidaemia were analysed; patients had a median age of 4.5 years, and 57.8% were males, with a diagnosis of solid tumours in 54.5% of cases. The most common Candida species were C albicans (35.6%), C parapsilosis (30.0%) and C tropicalis (16.7%). C tropicalis BSI was associated with neutropenia and skin lesions. Therapy was successful in 67.1% of the episodes. Older age and thrombocytopenia were associated with therapeutic failure. Death within 30 days occurred in 24.4% of patients; predictive factors were older age and admission to an ICU C parapsilosis candidaemia was a protective factor for death when compared to C albicans. CONCLUSION: The main species isolated were C albicans, C parapsilosis and C tropicalis. C tropicalis BSI was associated with neutropenia and skin lesions. The death rate was significant, and a worse prognosis was associated with older age, thrombocytopenia and admission to an ICU C parapsilosis infection proved to be a protective factor against mortality.

Low Rates of Poliovirus Antibodies in Primary Immunodeficiency Patients on Regular Intravenous Immunoglobulin Treatment.

PURPOSE: Poliovirus has been nearly eliminated as part of a world-wide effort to immunize and contain circulating wild-type polio. Nevertheless, poliovirus has been detected in water supplies and represents a threat to patients with humoral immunodeficiencies where infection can be fatal. To define the risk, we analyzed antibodies to poliovirus 1, 2, and 3 in serum samples collected over a year from patients with primary immunodeficiency diseases (PID) on regular intravenous immunoglobulin (IVIG) replacement. METHODS: Twenty-one patients on regular IVIG replacement therapy were evaluated: Twelve patients with common variable immune deficiency (CVID), six with X-linked agammaglobulinemia (XLA), and three with hyper IgM syndrome (HIGM). Over 1 year, four blood samples were collected from each of these patients immediately before immunoglobulin infusion. One sample of IVIG administered to each patient in the month before blood collection was also evaluated. Poliovirus antibodies were quantified by seroneutralization assay. RESULTS: All IVIG samples had detectable antibodies to the three poliovirus serotypes. Despite that, only 52.4, 61.9, and 19.0% of patients showed protective antibody titers for poliovirus 1, 2, and 3, respectively. Only two patients (9.5%) had protective antibodies for the three poliovirus serotypes on all samples. Most patients were therefore susceptible to all three poliovirus serotypes. CONCLUSIONS: This study demonstrates the need for ongoing vigilance regarding exposure of patients with PID to poliovirus in the community.

Safe administration of rotavirus vaccine in a cohort of infants exposed to immunosuppressive drugs during gestation.

In utero exposure to immunosuppressive drugs might be a contraindication to rotavirus vaccine, but that may vary according to the immunosuppressive regimen. We evaluated 24 infants born to kidney transplanted mothers exposed to 3 immunosuppressants during pregnancy (prednisone, azathioprine, and tacrolimus or cyclosporine) and 31 control infants not exposed to these medications. No differences in adverse events were detected after rotavirus vaccination at 2 and 4 months.

Adherence and immune response to revaccination following hematopoietic stem cell transplantation at a pediatric onco-hematology reference center.

BACKGROUND: Revaccination after hematopoietic stem cell transplantation (HSCT) is necessary to compensate for the loss of immunological memory. The aims of this study were to evaluate the adherence to revaccination schedule and the humoral immune response to different vaccine antigens in HSCT pediatric and young adult patients. METHODS: Patients submitted to HSCT for over 3 years were recruited. After written informed consent, a questionnaire was filled in, the vaccination card was analyzed, a blood sample was collected and tested by ELISA for diphtheria, Haemophilus influenzae type b (Hib), hepatitis A, hepatitis B, tetanus, measles, rubella, and varicella antibodies. RESULTS: Sixty-three patients (mean age at HSCT, 10.7 years) were evaluated. Forty-one (65%) were male; 34 (54%) had allogeneic and 29 (46%), autologous HSCT. Complete adherence to diphtheria revaccination was found in 79.4% patients and seropositivity was found in 92% of those who completed the revaccination schedule; for Hib, 68.3% adherence and 95.3% seropositivity were observed; for hepatitis A, 63.5% adherence and 92.5% seropositivity; for 3 doses of hepatitis B, 86.8% adherence and 79.2% seropositivity; for tetanus, 79.4% adherence and 100% seropositivity; for measles and rubella, 17.5% adherence and 100% seropositivity; for varicella, 7.9% adherence and 100% seropositivity. The existence of a Vaccination Center for Special Immunobiologicals in patients' municipality was positively associated with completed vaccine schedule; on the other hand, chronic GVHD was negatively associated with revaccination adherence. CONCLUSION: Hematopoietic stem cell transplantation patients showed good seropositivity rates after complete vaccination schedule. However, a low coverage rate was observed for live attenuated antigens.

Serum anti-phenolic glycolipid-1 IgA correlates to IgM isotype in leprosy patients: a possible candidate for seroepidemiological surveys?

OBJECTIVE: The aim of this study was to compare serum anti-phenolic glycolipid-1 IgA, IgG, and IgM levels in leprosy patients and controls. METHOD: Analysis of anti-PGL-1 IgA, IgG, or IgM in serum samples from multibacillary (MB, n=32) and paucibacillary (PB, n=22) leprosy patients, and in non-endemic controls (n=17), using an indirect enzyme-linked immunosorbent assay. RESULTS: A strong correlation between serum IgM and IgA isotypes was found (r=.745, P<.0001) in MB patients. A moderate correlation was found in all analyses in PB patients. A moderate agreement was found between anti-PGL1 IgA and IgM tests. Based on the ROC curves, the cut-off values were selected and the parameters of validation were calculated. Considering the clinical forms altogether, the diagnostic sensitivities were 50.0% for IgA, 22.2% for IgG, and 74.1% for IgM. The positive (VPP) and negative (VPN) predictive values were estimated for each isotype. For IgA, the VPP and VPN were, respectively, 100.0% (87.0%-100.0%; 95% confidence interval) and 38.7% (24.4%-54.5%); for IgG, 100% (87.0%-100.0%) and 28.8% (17.8%-42.1%), respectively; and for IgM, 95.2% (83.8%-99.4%) and 51.7% (32.5%-70.6%), respectively. CONCLUSION: Despite the limiting factors, anti-PGL1 IgA correlates to IgM levels and it could be considered as a possible laboratorial tool to be also used, for instance, in serological follow-up studies.

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

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.

Pertussis antibodies and vaccination coverage among healthcare professionals in Brazil is inadequate: A cross-sectional serological study.

INTRODUCTION: Worldwide, tetanus-diphtheria-acellular pertussis (Tdap) vaccination coverage of healthcare professionals (HCPs) is below 40%, but this data is not available for Brazil. We hypothesize that a high number of HCPs are not immune to pertussis in Brazil. Main objective was to determine the seroprevalence of anti-pertussis toxin (anti-PT IgG) among HCPs. Secondary objectives were to evaluate Tdap vaccination coverage, to assess predictive factors associated with anti-PT IgG, and to estimate the decay of anti-PT IgG and time to Tdap vaccination. METHODS: Observational cross-sectional serological study in 352 HCPs who worked at São Paulo Hospital - Federal University of São Paulo (UNIFESP) in 2020, approved by UNIFESP Ethics Committee. Data collected included sociodemographics, knowledge about Tdap, and vaccination status. Anti-PT IgG were quantified by ELISA: <10 IU/mL seronegative and ≥ 10-1000 IU/mL seropositive. Titers ≥ 10-50 IU/mL were classified low positivity, indicating no recent B. pertussis infection or Tdap vaccination; >50 IU/mL high positivity, indicating recent B. pertussis infection or Tdap vaccination, and > 100 IU/mL as acute B. pertussis infection or Tdap vaccination in the previous year. Comparisons were done by Chi-square test, multivariable logistic regression, and Pearsons correlation, at 5% p-level. RESULTS: 331/352 HCPs were not aware the Brazilian National Immunization Program recommends Tdap for all HCPs and pregnant women. 68/339 HCPs received Tdap (mean 3.1 ± 2.0 years). 55/352 were seronegative for pertussis, all unvaccinated. 56/271 with no history of Tdap vaccination had high positivity. The probability of anti-PT IgG > 50 IU/mL was 11.5 times higher in Tdap vaccinated HCPs than in non-vaccinated (p < 0.001). There was a weak but significant correlation between anti-PT IgG and interval of Tdap vaccination (r = 0.404; p = 0.001). Anti-PT IgG dropped 5 IU/mL/year (p = 0.001). CONCLUSION: Better education of HCPs on needs and benefits of Tdap vaccination is critical. Goals must be to improve HCPs vaccination coverage.

Immune response and tolerability of varicella vaccine in children and adolescents with systemic lupus erythematosus previously exposed to varicella-zoster virus.

OBJECTIVES: The aim of the present paper is to evaluate the immune response and tolerability of varicella vaccine in children and adolescents with systemic lupus erythematosus previously exposed to varicella-zoster virus. METHODS: We performed a prospective and controlled study on a group of 54 SLE patients that were chosen at random to be or not to be vaccinated (28 were vaccinated and 26 were not). Twenty-eight healthy controls, of matching age and sex were also vaccinated. All were submitted to a questionnaire, physical evaluation and laboratory assays: lymphocyte immune-phenotyping by flow cytometry, plasma varicella zoster virus (VZV) serology by ELISA and in vitro interferon gamma (IFNγ) production by T-cells after stimulus with VZV antigen. They were evaluated before vaccination and at 30, 45, 180 and 360 days afterwards. RESULTS: We did not observe any differences in the frequency of adverse events in both vaccinated groups. At study entry, all individuals were seropositive for VZV antibodies. The serum VZV antibody titres similarly increased after vaccination. The frequency of flares and the SLEDAI score were also similar among the patients. Thirty days after vaccination the production of IFNγ specific to VZV was lower in the SLE group compared to healthy controls. In the follow-up we observed 4 cases of herpes zoster in the SLE unvaccinated group, but no zoster in the vaccinated group. CONCLUSIONS: The varicella vaccine was well tolerated in SLE group, who had pre-existing immunity to varicella. The varicella vaccine immunogenicity measurement by serum antibody titres was appropriate. The incidence of HZ was lower in the vaccinated lupus group.

Rubella antibodies in vertically and horizontally HIV-infected young adults vaccinated early in life and response to a booster dose in those with seronegative results.

BACKGROUND: Very limited data are available on the persistence of rubella antibodies in vertically HIV-infected individuals who were vaccinated early in life. METHODS: Prospective, cohort study on 4 groups of patients: 96 vertically HIV-1-infected individuals (v-HIV), 69 horizontally HIV-1-infected individuals (h-HIV), 93 healthy controls previously vaccinated for rubella (vac-CON) and 20 healthy controls with history of rubella disease (dis-CON). A blood sample was collected and rubella antibodies were analyzed by ELISA. Rubella antibodies above 10 IU/mL were considered protective. Individuals with seronegative results were offered an extra MMR vaccine dose and were tested at least 30 days afterwards. RESULTS: Time since previous rubella vaccination was similar in v-HIV, h-HIV and vac-CON (16, 11 and 11 years; p = 0.428). v-HIV and h-HIV were also comparable regarding median CD4 T cells (613 and 614 cells/mm3; p = 0.599) and percentage on ART (93.8% and 98.6%; p = 0.135) at study entry. v-HIV had less individuals on virological suppression (63.5%) compared to 85.5% in h-HIV (p < 0.001). Rubella seropositivity and antibodies were significantly lower in v-HIV compared to h-HIV (32.3% vs 65.5%, 4.3 IU/mL vs 21.1 IU/mL; p < 0.001). Time interval between the last rubella vaccine dose and study entry was associated with an increase of rubella seronegativity, with a 7% higher chance of seronegativity for each one-year increase. After an extra MMR dose, 40 out of 48 (83.3%) seronegative individuals responded, with no significant difference among groups considering rubella seropositivity and antibody levels. CONCLUSION: As vertically HIV-infected individuals reach adolescence and adulthood, assessment of vaccine antibodies can identify those who might benefit from an extra vaccine dose.

Factors Associated with Behavioral Disorders in Children with Congenital Zika Syndrome and Their Families-A Cross-Sectional Study.

The Zika virus was responsible for an outbreak between 2015 and 2016 in Brazil: an alarming public health problem of international relevance. The Congenital Zika Syndrome (CZS) is often associated with manifestations that are responsible for cognitive and motor development delays and behavioral disorders. Thus, we aimed to characterize the clinical-epidemiological and familial context of those children and to identify factors associated with the risk of behavioral disorders using the Survey of Well-Being of Young Children questionnaire (SWYC). In total, 52 children diagnosed with CZS were evaluated. Logistic regressions were employed to assess predictive variables for behavioral alteration. Eighteen (35%) of the children presented a risk of behavioral alteration. Children born normocephalic were 36-fold more likely to present behavioral alteration (95% CI: 3.82 to 337.92, p = 0.002). Children with hearing and visual impairments showed reduced risks. In total, 35% percent of families reported food insecurity and 21% were at risk for maternal depression. Our findings suggest better social interactions and conditions to externalize reactions for children with CZS born normocephalic. The continuous assessment of these children and families may identify conditions associated with behavioral alteration and psychosocial vulnerabilities that help in decision-making, therefore optimizing patient-family interactions.

Assessment of liver disease by non-invasive methods in perinatally infected Brazilian adolescents and young adults living with Human Immunodeficiency Virus (HIV).

INTRODUCTION: Effective and long-term combined antiretroviral therapy (cART) has decreased morbidity and mortality in HIV-infected individuals. Despite treatment advances, HIV-infected children continue to develop noninfectious conditions, including liver fibrosis. METHODS: Cross-sectional study designed to identify liver fibrosis in HIV-infected adolescents and young adults, in an outpatients clinic of Pediatric Infectious Diseases Division at Escola Paulista de Medicina/Universidade Federal de São Paulo (UNIFESP), diagnosed by noninvasive methods (liver elastography-FibroScan®, APRI and FIB4). Variables examined included demographics, clinical, laboratories, HIV treatment. All participants underwent FibroScan® to measure liver parenchyma elasticity. Values equal to above 7.0 kPa were interpreted as the presence of significant liver fibrosis. Two different biomarkers of liver fibrosis were employed: the AST-to-Platelet Ratio Index (APRI) and the Fibrosis-4 score (FIB-4). APRI values above 1.5 have been considered as levels of clinically significant liver fibrosis and FIB-4 values above 3.25 suggested the presence of advanced fibrosis. RESULTS: Between August 2014 and March 2017, the study enrolled 97 patients, age 10-27 years old, fourteen of 97 subjects (14.4%) presented liver stiffness (≥7 kPa) detected by the liver elastography. No patient had APRI> 1.5. No patient had FIB4 value > 3.25. The only isolated laboratory parameter that could be significantly associated with high liver stiffness was thrombocytopenia (p = 0.022, Fisher's exact test). CONCLUSION: Liver stiffness was identified in 14.4% (14/97) of this cohort by liver elastography. Liver disease in HIV-infected adolescents and young adults manifests itself silently, so should be routinely investigated.

Tdap booster to adolescents with juvenile idiopathic arthritis on and off anti-TNF agents is safe and immunogenic.

INTRODUCTION: The response to vaccines in juvenile idiopathic arthritis (JIA) patients on and off anti-tumor necrosis factor (anti-TNF) agents remains highly discussed. There are no published studies on the immune response following a Tdap booster dose in JIA patients so far. OBJECTIVE: To evaluate the immune response and safety after a Tdap booster in JIA patients and in healthy adolescents. METHODS: Nineteen adolescents with JIA according to the ILAR criteria on anti-TNF medication, 19 adolescents with JIA off anti-TNF medication, and 27 healthy adolescents (control group) were compared after a Tdap booster. Adverse events and disease activity were evaluated. Lymphocyte immunophenotyping was performed by flow cytometry. Tetanus, diphtheria and pertussis toxin antibodies were assessed by ELISA; whole blood was stimulated with whole-cell pertussis, and supernatants were assessed for cytokines by xMAP. RESULTS: The three groups showed a similar frequency of adverse events. There was no disease reactivation after the Tdap booster. Tetanus, diphtheria and pertussis antibodies showed a significant response when D0 and D14 concentrations were compared in both JIA groups and controls. Over time, a different pattern of response to the Tdap booster was observed among the groups for tetanus antibodies (p = 0.005) but not for diphtheria and pertussis antibodies. In contrast to the protection attained for tetanus and diphtheria, in the three groups, not all individuals showed pertussis seroconversion at either D14 or D28. In addition, the seroconversion of three subjects with JIA on anti-TNF medication was not maintained at D28. JIA patients off anti-TNF showed a higher percentage of naive CD8 + T cells (p = 0.007) and central memory CD8 + cells (p = 0.003) and a lower percentage of effector CD8 + T cells (p = 0.003) and NK cell numbers (p = 0.018) than the control group. The JIA group off anti-TNF medication had fewer B lymphocytes than both the JIA group on anti-TNF medication and the control group (p = 0.016). Cellular immunity to Bordetella pertussis showed that IFNγ levels were significantly lower in both JIA groups than in the control group (p = 0.003), IL10 levels were higher in the JIA off anti-TNF group (p = 0.009), IL17A and IL5 levels were lower in the JIA on anti-TNF group than in the control group (p = 0.018 and p = 0.016, respectively); however, an increase in IFNγ (p = 0.008), IL17A (p = 0.030) and TNFα (p = 0.041) levels was observed at D14 in both patient groups. Both JIA groups showed higher levels of IL21 than the control group (p = 0.023). CONCLUSION: We conclude that individuals with JIA on or off anti-TNF agents showed a good response to a booster dose for the three antigens studied in the absence of major adverse events and without the reactivation of the disease.

Humoral and cellular immune responses to measles and tetanus: the importance of elapsed time since last exposure and the nature of the antigen.

OBJECTIVE: This study aims to assess the cellular and humoral immune response pre- and post-vaccine rechallenge in healthy adults with previous exposure to measles (virus or vaccine) and different time intervals since last tetanus vaccine. METHODS: Humoral immunity was tested by ELISA, and cellular immunity was tested by intracellular interferon gamma detection after in vitro stimulation with antigens. RESULTS: While cellular immunity was comparable among vaccinated individuals and those who had measles, higher antibody levels were found in those who had the disease in the past. Both antibodies and CD4(+) T cell tetanus immune responses depended on elapsed time since last immunization. Following a vaccine booster, an increase in cellular immunity and antibodies was observed to both tetanus and measles. Measles humoral response was much more intense among individuals previously exposed to a wild virus. CONCLUSIONS: In an era when natural boosters are less frequent, an immune surveillance might be necessary to investigate waning immunity as occurs for tetanus.

Low CD4+ T-cell levels and B-cell apoptosis in vertically HIV-exposed noninfected children and adolescents.

Lymphocyte subsets, activation markers and apoptosis were assessed in 20 HIV-exposed noninfected (ENI) children born to HIV-infected women who were or not exposed to antiretroviral (ARV) drugs during pregnancy and early infancy. ENI children and adolescents were aged 6-18 years and they were compared to 25 age-matched healthy non-HIV-exposed children and adolescents (Control). ENI individuals presented lower CD4(+) T cells/mm(3) than Control group (control: 1120.3 vs. ENI: 876.3; t-test, p = 0.030). ENI individuals had higher B-cell apoptosis than Control group (Control: 36.6%, ARV exposed: 82.3%, ARV nonexposed: 68.5%; Kruskal-Wallis, p < 0.05), but no statistical difference was noticed between those exposed and not exposed to ARV. Immune activation in CD4(+) T, CD8(+) T and in B cells was comparable in ENI and in Control children and adolescents. Subtle long-term immune alterations might persist among ENI individuals, but the clinical consequences if any are unknown, and these children require continued monitoring.

Opportunistic infections in pediatrics: when to suspect and how to approach.

OBJECTIVES: To describe the characteristics of opportunistic infections in pediatrics regarding their clinical aspects, as well as the diagnostic strategy and treatment. SOURCE OF DATA: Non-systematic review of literature studies in the PubMed database. SYNTHESIS OF DATA: Opportunistic infections caused by non-tuberculous mycobacteria, fungi, Herpesvirae, and infections affecting individuals using immunobiological agents are analyzed. Because these are severe diseases with a rapid evolution, diagnostic suspicion should be early, associated with the patient's clinical assessment and history pointing to opportunistic infections. Whenever possible, samples of secretions, blood, and other fluids and tissues should be collected, with early therapy implementation. CONCLUSIONS: Despite the improved diagnosis of opportunistic infections in recent years, they remain a challenge for pediatricians who are not used to these infections. They should raise the suspicion and start treating the case, but should also resort to specialists in the management of these infections to provide a better outcome for these patients, who still have high mortality.