ABSTRACT Immune exhaustion and senescence are scarcely studied in HIV-pediatric patients. We studied the circulatory CD8 T cells activation/exhaustion and senescent phenotype of children and adolescents vertically infected with HIV or uninfected controls based on the expression of human leukocyte antigen (HLA-DR), CD38, T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), programmed death 1 (PD-1) and CD57 by flow cytometry, during approximately one year. Eleven HIV-infected (HI) and nine HIV-uninfected (HU) children/adolescents who received two doses or one dose of meningococcal C conjugate vaccine (MenC), respectively, were involved in this study. Blood samples were collected before the immunization (T0), 1–2 months after the first dose (T1), and 1–2 months after the second dose (T2), which was administered approximately one year after the first one. HI patients not receiving combined antiretroviral therapy (cART) showed a higher frequency of CD8 T cells TIGIT+, PD-1+ or CD57+, as well as a higher frequency of CD8 T cells co-expressing CD38/HLA-DR/TIGIT or CD38/HLA-DR/PD-1 when compared to HI treated or HU individuals, at all times that they were assessed. CD8 T cells co-expressing CD38/DR/TIGIT were inversely correlated with the CD4/CD8 ratio but positively associated with viral load. The co-expression of CD38/DR/TIGIT or CD38/DR/PD-1 on CD8 T cells was also inversely associated with the CD4 T cells expressing co-stimulatory molecules CD127/CD28. The results showed a higher expression of exhaustion/senescence markers on CD8 T cells of untreated HI children/adolescents and its correlations with viral load.

OBJECTIVES: To investigate the expression levels of surface markers of activation (CD38 and HLA-DR), inhibition (PD-1, TIGIT and CD57) and co-stimulation (CD28 and CD127) on CD4+ T cells of children/adolescents with vertical HIV infection (HI patients) and HIV-uninfected (HU) controls vaccinated with the meningococcal C conjugate vaccine (MCC). METHODS: HI patients (n=12), aged 8-17 years, were immunized with two MCC injections, while HU controls (n=9), aged 5.3-10.7 years, received a single MCC dose (as per national recommendation at the time of this study, a single MCC vaccine dose should be given for healthy children and youth aged 1-18 years). The HI patients were categorized according to the combined antiretroviral therapy (cART) treatment. Blood samples were obtained before vaccination, after priming, and after the administration of a booster dose of vaccine to determine the serum bactericidal antibody (SBA) titers and the expression levels of surface markers on CD4+ T cells by flow cytometry. The levels of serum cytokines, IL-4 and CXCL-13 were also measured using Luminex kits. RESULTS: The co-expression of the TIGIT-HLA-DR-CD38 molecules increased in the CD4+ T cells of HI patients/no-cART who also showed a lower frequency of CD127+CD28+ CD4+ T cells than HI patients/cART and HU group subjects. There were significant negative correlations between the frequency of exhausted CD4+ T cells and the SBA response. IL-4 levels were higher in HI patients/cART and positively correlated with SBA titers but negatively associated with the expression of exhaustion markers. Moreover, the CXCL-13 levels were positively correlated with the exhausted CD4+ T cells. CONCLUSION: The results of our study suggest that the co-expression of exhaustion markers and/or loss of co-stimulatory molecules influence the SBA response in HI patients.

Resumo Objetivo: As pessoas infectadas pelo HIV (HIVI) estão sujeitas a infecção meningocócica e apresentam menor resposta a vacinas. São escassos os dados a respeito da persistência de longo prazo do anticorpo bactericida no soro humano (hSBA) após vacina conjugada meningocócica C (MCC) em HIVI jovens e visamos a descrever essa persistência em HIVI. Métodos: Foram recrutadas pessoas HIVI e pessoas não infectadas por HIV (HIVU), entre 2 e 18 anos, CD4 > 15%. A seroproteção (hSBA ≥ 1:4) basal aos 12–18 meses após a imunização foi avaliada e a associação dos diferentes fatores com a persistência de longo prazo foi calculada com a regressão logística. Resultados: Foram recrutados 145 HIVI e 50 HIVU e imunizados e sua idade média foi determinada em 11 anos (12 no grupo HIVI e 10 no grupo HIVU, valor de p = 0,02); 85 HIVI (44%) apresentaram carga viral indetectável (CVI). A taxa de seroproteção foi 27,2%: 24,1% no grupo HIVI e 36% no grupo HIVU 12-18 meses após imunização (p = 0,14). A imunidade basal [razão de chance (RC) = 7070, IC: 65,2–7666]; CVI no momento da participação (RC: 2,87, IC de 95%: 0,96-8,62) e renda familiar mais baixa (RC: 0,09, IC de 95%: 0,01-0,69) foram associadas a seroproteção entre as pessoas HIVI. Conclusão: A seroproteção aos 12-18 meses após única dose de MCC mostrou-se baixa em ambos os grupos e mais elevada entre as pessoas que apresentaram imunidade basal. Entre as pessoas HIVI, as vacinas devem ser administradas após a CVI ser atingida.

Abstract Objective: HIV-infected individuals (HIVI) are threatened by meningococcal infection and presented lower response to vaccines. Data are scarce on long-term persistence of human serum bactericidal antibody (hSBA) after a meningococcal C conjugate (MCC) vaccine in HIVI youth; the authors aimed to describe this persistence in HIVI. Methods: HIVI and HIV uninfected individuals (HIVU), aged 2–18 years, CD4 >15% were recruited. Seroprotection (hSBA ≥1:4) at baseline and at 12–18 months after immunization was evaluated and the association of the different factors with the long-term persistence was calculated using logistic regression. Results: A total of 145 HIVI, 50 HIVU were recruited and immunized, and their median age was 11 years (median age in HIVI group was 12 years, and 10 years in HIVU group, p-value = 0.02). 85 HIVI (44%) had undetectable viral load (UVL). Seroprotection rate was 27.2%: 24.1% in HIVI and 36% in HIVU 12–18 months after immunization (p = 0.14). Baseline immunity (odds ratio [OR] = 70.70, 95% CI: 65.2–766.6); UVL at entry (OR: 2.87, 95% CI: 0.96–8.62) and lower family income (OR: 0.09, 95% CI: 0.01–0.69) were associated with seroprotection among HIVI. Conclusion: Seroprotection at 12–18 months after single dose of MCC was low for both groups, and higher among individuals who presented baseline immunity. Among HIVI, vaccine should be administered after UVL is achieved.

There are only scarce data on HIV progression in vertically infected children in developing countries. The aim of this study is to describe factors from neonatal period associated with long term non-progression (LTNP), in a Brazilian cohort. A cohort study, with data systematically collected from the "Peixe" Cohort (cohort study of children conducted at the main HIV Pediatric Center in Rio de Janeiro, from 1996 to 2005). The study included children who were vertically infected and started follow up at 5 years of age or younger. LTNP, defined as not reaching category C or severe immunosuppression before 5 years of age. Neonatal and demographic factors were studied. Variables with p-value<0.15 were included in a logistic regression model. 213 patients were included, of whom 42% (89/213) were classified as LTNP. Variables independently associated with LTNP were: baseline (at study entry) CD4+ cells (per %) (OR= 1.06, 95%CI=1.01-1.12); age of initiating follow-up, per month (OR= 1.03, 95%CI=1.01-1.06); ZDV use duriing newborn period (OR= 3.31, 95%CI=0.86-12.71); use of antiretroviral (ART) before classification C or severe immunosuppression (OR= 5.89, 95%CI=2.03-17.10). Adjusting for age at the beginning of follow-up, antiretroviral that was unsuccessfully used to prevent maternal-to-child transmission (ZDV use in neonatal period) was associated with better prognosis. ARTs initiation before category C or severe immunosuppression was also associated with LTNP.

Immediate prevention of meningococcal disease relies in part on the prompt treatment with antibiotics of household and other close contacts of cases; however intervention with effective vaccination relies on identification of serogroup-causing strains. Parenteral antibiotic for patient with suspected meningococcal disease before hospital admission is currently recommended. Laboratory standard methods are hindered by failure to detect bacteria by this medical approach to improve patient prognosis. We assessed two polymerase chain reaction (PCR) assays to detect (crgA) and define the serogroups (siaD, orf-2, and ctrA) of Neisseria meningitidis in 120 cerebrospinal fluid (CSF) samples from positive cases (culture or antigen detection or direct smear). The PCR sensitivity for the identification of N. meningitidis was 100% (95% confidence interval, CI, 96-100%) compared to a sensitivity of 46% for culture (95% CI 37-55%), 61% for latex agglutination test (95% CI 52-70%), and 68% for Gram stain (95% CI 59-76%); PCR specificity was 97% (95% CI 82-100%). PCR correctly identified the serogroups A, B, C, W135, Y, and X in CSF samples with a sensitivity of 88% (95% CI 80-93%); the primer sets were 100% specific. The introduction of PCR-based assays shall increase laboratory confirmed cases, consequently enhancing surveillance of meningococcal disease.

Diagnosis of bacterial meningitis has long been based on classical methods of Gram stain, serological tests, and culture of cerebrospinal fluid (CSF). The performance of these methods, especially culture and direct smear, is thwarted by failure to detect bacteria following administration of antimicrobial agents and reluctance to performance lumbar punctures at admission. Indeed, patients with meningitis frequently receive antibiotics orally or by injection before the diagnosis is suspected or established. Thus an alternative method has become necessary to help clinicians and epidemiologists to management and control of bacterial meningitis. We evaluate the application of a polymerase chain reaction-based (PCR) assay for amplification of pneumolysin gene (ply) to diagnosis of Streptococcus pneumoniae meningitis. The PCR assay sensitivity for CSF was 96% (95% confidence interval, CI, 90-99%) compared to a sensitivity of 59% for culture (95% CI 49-69%), 66% for Gram stain (95% CI 56-74%), and 78% for latex agglutination test (95% CI 69-86%); PCR specificity was 100% (95% CI 83-100%). PCR results were available within 4 h of the start of the assay. This molecular approach proved to be reliable and useful to identify this bacterium compared with other classical laboratory methods for identification of bacterial meningitis pathogens.

The purpose of this study was to analyze the prevalence and risk factors for drug resistance among hospitalized patients in two tertiary care centers, an acquired immunodeficiency syndrome (AIDS) reference center and a sanatorium, in Rio de Janeiro, Brazil. From 1993-1994, 389 patients were diagnosed as having tuberculosis (TB). Isolates from 265 patients were tested for in vitro susceptibility to rifampin and isoniazid. Resistance to one or more drugs was detected in 44 patients (16.6%) and was significantly more common among recurrent cases in both hospitals (p=0.03 in the AIDS center and p=0.001 in the sanatorium). Twenty seven patients (10.2%) had isolates resistant to both isoniazid and rifampin. Multi-drug resistance was associated with human immunodeficiency virus (HIV) infection among patients who had never been treated for TB. In conclusion, drug-resistant TB is high in hospitalized patients in Rio de Janeiro, especially among HIV infected patients. Therefore, measures to control TB and prevent nosocomial transmission need urgently to be set up in the Brazilian hospitals.

Durante o período de um ano (maio de 1982 - abril de 1983) avaliou-se a circulação e manutenção de bactérias enteropatogênicas, em população de menor institucionalizada e funcionários adultos contactantes, na cidade do Rio de Janeiro, Brasil. Foram constituídos três grupos: A e B incluíram, respectivamente, 104 e 46 crianças, portadoras de quadro diarréico, diferenciando-se pelo período de ingresso na instituição, anterior (B) e durante (A) o período do estudo; o grupo C era composto de 82 adultos contactantes. Fontes de infecção parcialmente expressas pela positividade de coproculturas: 35,2% no grupo A, 39,1% no B e 19,7% nos adultos sadios, sugerem a potencialidade de outras vias de transmissão representadas pelo ambiente com 30% de contaminação fecal. Maior taxa de isolamento combinada a elevados títulos de anticorpos indicaram Escherichia coli (EPEC) como o agente prevalente, enquanto que na hemaglutinacão passiva, Shigella predominou. Admite-se que a instituição deve desempenhar um papel importante na epidemiologia e transmissão de infecções entéricas para a comunidade.

The circulation flow and maintenance of enteropathogenic bacteria were studied from May 1982 to april 1983 in a population of institutionalized children and adult staff contacts in the city of Rio de Janeiro, Brazil. Subjects were assigned to three groups; A and B, included, respectively, 105 and 46 children with diarrhea who were admitted in the institution in different periods, and group C with 82 adult contacts. Faecal cultures were positive in 35.2%, 39.1% and 19.7% of subjects of groups A, B and C, respectively. It suggests that the transmission was probably fostered by the environment because of as high as 30% of faecal contamination was found in environmental samples. Higher rate of isolation and elevated antibodies levels pointed out that Escherichia coli (EPEC) was the prevalent agent. Shigella predominated in the serological tests. These findings suggest that the institution itself may play an important role in the epidemiology and transmission of enteric infections in the community.