RESUMO
We previously reported 10-valent pneumococcal non-typeable Haemophilus influenzae (NTHi) protein D conjugate vaccine (PHiD-CV) efficacy in a double-blind randomized trial (ClinicalTrials.gov: NCT00466947) against various diseases, including acute otitis media (AOM). Here, we provide further analyses. In the Panamanian subset, 7,359 children were randomized (1:1) to receive PHiD-CV or control vaccine at age 2/4/6 and 15-18 months. Of these, 2,000 had nasopharyngeal swabs collected. AOM cases were captured when parents sought medical attention for children with AOM symptoms; surveillance was enhanced approximately 2 y into the study through regular telephone calls or home visits by study personnel, who advised parents to visit the clinic if their child had AOM symptoms. Mean follow-up was 31.4 months. Clinical AOM (C-AOM) cases were assessed by physicians and confirmed by otorhinolaryngologists. Middle ear fluid samples, taken from children with C-AOM after specific informed consent, and nasopharyngeal samples were cultured for pathogen identification. For 7,359 children, 2,574 suspected AOM cases were assessed by a primary healthcare physician; 649 cases were C-AOM cases as per protocol definition. From the 503 MEF samples collected, 158 resulted in a positive culture. In the intent-to-treat cohort (7,214 children), PHiD-CV showed VE against first C-AOM (24.0% [95% CI: 8.7, 36.7]) and bacterial (B-AOM) episodes (48.0% [20.3, 66.1]) in children <24 months, which declined thereafter with age. Pre-booster VE against C-AOM was 30.7% [12.9, 44.9]; post-booster, -6.7% [-36.4, 16.6]. PHiD-CV VE was 17.7% [-6.1, 36.2] against moderate and 32.7% [-20.5, 62.4] against severe C-AOM. VE against vaccine-serotype pneumococcal NPC was 31.2% [5.3, 50.3] 3 months post-booster, and 25.6% [12.7, 36.7] across all visits. NTHi colonization rates were low and no significant reduction was observed. PHiD-CV showed efficacy against C-AOM and B-AOM in children younger than 24 months, and reduced vaccine-serotype NPC.
Assuntos
Proteínas de Bactérias/imunologia , Proteínas de Transporte/imunologia , Portador Sadio/prevenção & controle , Infecções por Haemophilus/prevenção & controle , Vacinas Anti-Haemophilus/imunologia , Imunoglobulina D/imunologia , Lipoproteínas/imunologia , Otite Média/prevenção & controle , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/imunologia , Método Duplo-Cego , Orelha Média/microbiologia , Exsudatos e Transudatos/microbiologia , Feminino , Seguimentos , Vacinas Anti-Haemophilus/administração & dosagem , Humanos , Lactente , Masculino , Nasofaringe/microbiologia , Panamá , Vacinas Pneumocócicas/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: The relationship between pneumococcal conjugate vaccine-induced antibody responses and protection against community-acquired pneumonia (CAP) and acute otitis media (AOM) is unclear. This study assessed the impact of the ten-valent pneumococcal nontypable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) on these end points. The primary objective was to demonstrate vaccine efficacy (VE) in a per-protocol analysis against likely bacterial CAP (B-CAP: radiologically confirmed CAP with alveolar consolidation/pleural effusion on chest X-ray, or non-alveolar infiltrates and C-reactive protein ≥ 40 µg/ml); other protocol-specified outcomes were also assessed. METHODS AND FINDINGS: This phase III double-blind randomized controlled study was conducted between 28 June 2007 and 28 July 2011 in Argentine, Panamanian, and Colombian populations with good access to health care. Approximately 24,000 infants received PHiD-CV or hepatitis control vaccine (hepatitis B for primary vaccination, hepatitis A at booster) at 2, 4, 6, and 15-18 mo of age. Interim analysis of the primary end point was planned when 535 first B-CAP episodes, occurring ≥2 wk after dose 3, were identified in the per-protocol cohort. After a mean follow-up of 23 mo (PHiD-CV, n = 10,295; control, n = 10,201), per-protocol VE was 22.0% (95% CI: 7.7, 34.2; one-sided p = 0.002) against B-CAP (conclusive for primary objective) and 25.7% (95% CI: 8.4%, 39.6%) against World Health Organization-defined consolidated CAP. Intent-to-treat VE was 18.2% (95% CI: 5.5%, 29.1%) against B-CAP and 23.4% (95% CI: 8.8%, 35.7%) against consolidated CAP. End-of-study per-protocol analyses were performed after a mean follow-up of 28-30 mo for CAP and invasive pneumococcal disease (IPD) (PHiD-CV, n = 10,211; control, n = 10,140) and AOM (n = 3,010 and 2,979, respectively). Per-protocol VE was 16.1% (95% CI: -1.1%, 30.4%; one-sided p = 0.032) against clinically confirmed AOM, 67.1% (95% CI: 17.0%, 86.9%) against vaccine serotype clinically confirmed AOM, 100% (95% CI: 74.3%, 100%) against vaccine serotype IPD, and 65.0% (95% CI: 11.1%, 86.2%) against any IPD. Results were consistent between intent-to-treat and per-protocol analyses. Serious adverse events were reported for 21.5% (95% CI: 20.7%, 22.2%) and 22.6% (95% CI: 21.9%, 23.4%) of PHiD-CV and control recipients, respectively. There were 19 deaths (n = 11,798; 0.16%) in the PHiD-CV group and 26 deaths (n = 11,799; 0.22%) in the control group. A significant study limitation was the lower than expected number of captured AOM cases. CONCLUSIONS: Efficacy was demonstrated against a broad range of pneumococcal diseases commonly encountered in young children in clinical practice. TRIAL REGISTRATION: www.ClinicalTrials.gov NCT00466947.
Assuntos
Proteínas de Bactérias/imunologia , Proteínas de Transporte/imunologia , Haemophilus influenzae/imunologia , Imunoglobulina D/imunologia , Lipoproteínas/imunologia , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Vacinação , Vacinas Conjugadas/imunologia , Anticorpos Antibacterianos/sangue , Pré-Escolar , Método Duplo-Cego , Infecções por Haemophilus/microbiologia , Humanos , Imunização Secundária , Lactente , Análise de Intenção de Tratamento , América Latina , Otite Média/imunologia , Otite Média/microbiologia , Otite Média/prevenção & controle , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/microbiologia , Resultado do TratamentoRESUMO
BACKGROUND: Many studies have succeeded in identifying a subset of children with febrile neutropenia (FN) who are at lower risk of infectious complications and eventual death. Conversely, to the authors' knowledge, no scoring system has been published to date with which to assess the risk of mortality for the whole group of children with neutropenia and fever. METHODS: Between March 2000 and July 2004, 1520 episodes of FN in 981 children were included in a multicentric prospective study to evaluate a scoring system that was designed to identify high mortality risk at the onset of an FN episode in children with cancer. RESULTS: In the derivation set (714 episodes), 18 patients died (2.5%). A multivariate analysis yielded the following significant mortality-related risk factors: advanced stage of underlying malignant disease (odds ratio [OR], 3122.1; 95% confidence interval [95% CI], 0.0001-5.2), associated comorbidity (OR, 25.3; 95% CI, 7.7-83.2), and bacteremia (OR, 7.2; 95% CI, 2.4-22.0). A mortality score could be built with 3 points scored for the presence of advanced-stage underlying malignant disease, 2 points scored for the presence of associated comorbidity, and 1 point scored for bacteremia. If patients collected 4 points of the risk score at onset, then their risk of mortality was 5.8%; if patients had a score of 5 points, then their risk of mortality was 15.4%; and, if they reached the maximum score of 6 points, then their risk of mortality was raised to 40%. The sensitivity of the scoring system was 100%, and it had a specificity of 84.2%. In the validation set (806 episodes), 19 children died (2.3%). For children with scores >3, the scoring system had a sensitivity of 84.2%, a specificity of 83.2%, and a negative predictive value of 99.54% for predicting mortality. CONCLUSIONS: The use of a mortality score for high-risk patients was validated statistically by the current results. This is a major prognostic approach to categorize patients with high-risk FN at onset. A better initial predictive approach may allow better therapeutic decisions for these children, with an eventual impact on reducing mortality.