Association between circulating exhausted CD4+ T cells with poor meningococcal C conjugate vaccine antibody response in HIV-infected children and adolescents

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.

Antibody persistence following meningococcal C conjugate vaccination in children and adolescents infected with human immunodeficiency virus / Persistência de anticorpos seguida de vacina conjugada meningocócica C em crianças e adolescentes infectados por vírus da imunodeficiência humana

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.

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.

Bonafide, type-specific human papillomavirus persistence among HIV-positive pregnant women: predictive value for cytological abnormalities, a longitudinal cohort study

This study investigated the rate of human papillomavirus (HPV) persistence, associated risk factors, and predictors of cytological alteration outcomes in a cohort of human immunodeficiency virus-infected pregnant women over an 18-month period. HPV was typed through L1 gene sequencing in cervical smears collected during gestation and at 12 months after delivery. Outcomes were defined as nonpersistence (clearance of the HPV in the 2nd sample), re-infection (detection of different types of HPV in the 2 samples), and type-specific HPV persistence (the same HPV type found in both samples). An unfavourable cytological outcome was considered when the second exam showed progression to squamous intraepithelial lesion or high squamous intraepithelial lesion. Ninety patients were studied. HPV DNA persistence occurred in 50% of the cases composed of type-specific persistence (30%) or re-infection (20%). A low CD4+T-cell count at entry was a risk factor for type-specific, re-infection, or HPV DNA persistence. The odds ratio (OR) was almost three times higher in the type-specific group when compared with the re-infection group (OR = 2.8; 95% confidence interval: 0.43-22.79). Our findings show that bonafide (type-specific) HPV persistence is a stronger predictor for the development of cytological abnormalities, highlighting the need for HPV typing as opposed to HPV DNA testing in the clinical setting.

Prevalence of lipodystrophy and risk factors for dyslipidemia in HIV-infected children in Brazil

The aim of present study was to describe the frequency of lipodystrophy syndrome associated with HIV (LSHIV) and factors associated with dyslipidemia in Brazilian HIV infected children. HIV infected children on antiretroviral treatment were evaluated (nutritional assessment, physical examination, and laboratory tests) in this cross-sectional study. Univariate analysis was performed using Mann-Whitney test or Fisher's exact test followed by logistic regression analysis. Presence of dyslipidemia (fasting cholesterol >200 mg/dl or triglycerides >130 mg/dl) was the dependent variable. 90 children were enrolled. The mean age was 10.6 years (3-16 years), and 52 (58%) were female. LSHIV was detected in 46 children (51%). Factors independently associated with dyslipidemia were: low intake of vegetables/fruits (OR = 3.47, 95%CI = 1.04-11.55), current use of lopinavir/ritonavir (OR = 2.91, 95%CI = 1.11-7.67). In conclusion, LSHIV was frequently observed; inadequate dietary intake of sugars and fats, as well as current use of lopinavir/ritonavir was associated with dyslipidemia.

Neonatal factors associated with HIV long term non-progressors in a cohort of vertically infected children in Rio de Janeiro, Brazil ("Peixe" Project)

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 percent (89/213) were classified as LTNP. Variables independently associated with LTNP were: baseline (at study entry) CD4+ cells (per percent) (OR= 1.06, 95 percentCI=1.01-1.12); age of initiating follow-up, per month (OR= 1.03, 95 percentCI=1.01-1.06); ZDV use duriing newborn period (OR= 3.31, 95 percentCI=0.86-12.71); use of antiretroviral (ART) before classification C or severe immunosuppression (OR= 5.89, 95 percentCI=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.

Assessment of a two-step nucleic acid amplification assay for detection of Neisseria meningitidis followed by capsular genogrouping

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 percent (95 percent confidence interval, CI, 96-100 percent) compared to a sensitivity of 46 percent for culture (95 percent CI 37-55 percent), 61 percent for latex agglutination test (95 percent CI 52-70 percent), and 68 percent for Gram stain (95 percent CI 59-76 percent); PCR specificity was 97 percent (95 percent CI 82-100 percent). PCR correctly identified the serogroups A, B, C, W135, Y, and X in CSF samples with a sensitivity of 88 percent (95 percent CI 80-93 percent); the primer sets were 100 percent specific. The introduction of PCR-based assays shall increase laboratory confirmed cases, consequently enhancing surveillance of meningococcal disease.

Diagnosis of Streptococcus pneumoniae meningitis by polymerase chain reaction amplification of the gene for pneumolysin

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 percent (95 percent confidence interval, CI, 90-99 percent) compared to a sensitivity of 59 percent for culture (95 percent CI 49-69 percent), 66 percent for Gram stain (95 percent CI 56-74 percent), and 78 percent for latex agglutination test (95 percent CI 69-86 percent); PCR specificity was 100 percent (95 percent CI 83-100 percent). 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.

Taxa de abandono do tratamento antituberculose / Non-adherence rate of anti-tuberculosis treatment

Introdução: São raros os estudos sobre os fatores associados à ocorrência do abandono do tratamento antituberculose (TB) em pacientes atendidos em hospitais nos países em desenvolvimento, aonde, usualmente, inexistem atividades de controle de TB. Objetivos: Identificar fatores associados à ocorrência de abandono do tratamento anti-TB em pacientes atendidos num hospital geral, referência para AIDS. Desenho: estudo caso-controle. Métodos: os pacientes que iniciaram tratamento anti-TB, no período de 01 de janeiro a 31 de dezembro de 1997, foram considerados ilegíveis. Paciente caso foi definido como o indivíduo que não retornou para receber medicação decorridos 60 dias depois de sua última consulta médica. Análise logística condicional foi utilizada para identificar as características que, independentemente, estavam associadas à ocorrência de abandono do tratamento. Resultados: 228 pacientes foram registrados como TB no período. Após a revisão dos prontuários médicos e visita em 189 domicílios, o abandono do tratamento, de 28,9%, baixou para 20,2%. Na análise multivariada, os fatores associados ao abandono foram: a) não fornecimento de cartão retorno (OR =0.099; IC 0.008-1.2; p = 0.07), b) não sentir-se a vontade na consulta médica (OR = 0,16; IC 0.33 - 0.015; p = 0.001) e, c) pressão arterial não foi medida (OR = 0.072; IC 0.036-0,79; p= 0.024). Comentários: Provavelmente, em hospitais gerais na cidade do Rio de Janeiro, torna-se necessária a implementação de programas de controle de TB. Tais programas devem utilizar estratégias específicas para o tipo de paciente atendido visando menores taxas de abandono e de morbi/mortalidade.