María Elena Santolaya

Immunogenicity and tolerability of a multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled study

BACKGROUND Effective glycoconjugate vaccines against Neisseria meningitidis serogroups A, C, W-135, and Y have been developed, but serogroup B remains a major cause of severe invasive disease in infants and adolescents worldwide. We assessed immunogenicity and tolerability of a four-component vaccine (4CMenB) in adolescents. METHODS We did a randomised, observer-blind, placebo-controlled, study at 12 sites in Santiago and Valparaíso, Chile. Adolescents aged 11-17 years received one, two, or three doses of 4CMenB at 1 month, 2 month, or 6 month intervals. Immunogenicity was assessed as serum bactericidal activity using human complement (hSBA) against three reference strains for individual vaccine antigens, and assessed by ELISA against the fourth strain. Local and systemic reactions were recorded 7 days after each vaccination, and adverse events were monitored throughout the study. Participants were initially randomised to five groups (3:3:3:3:1) during the primary phase to receive either one dose, two doses 1 or 2 months apart, or three doses of 4CMenB, or three doses of placebo, with an additional three groups generated for the booster phase. All subjects received at least one dose of 4CMenB. Geometric mean titres, proportions of participants with serum bactericidal antibody titres of 4 or more, and Clopper-Pearson 95% CIs were calculated. The study is registered with ClinicalTrials.gov, number NCT00661713. FINDINGS Overall, 1631 adolescents (mean age 13·8 [SD 1·9] years) received at least one dose of 4CMenB. After two or three doses, 99-100% of recipients had hSBA titres of 4 or more against test strains, compared with 92-97% after one dose (p<0·0145) and 29-50% after placebo. At 6 months 91-100% of participants still had titres of 4 or more for each strain after two or three doses, but only 73-76% after one dose; seroresponse rates reached 99-100% for each strain after second or third doses at 6 months. Local and systemic reaction rates were similar after each 4CMenB injection and did not increase with subsequent doses, but remained higher than placebo. No vaccine-related serious adverse events were reported and no significant safety signals were identified. INTERPRETATION On the basis of immunogenicity responses this study provides evidence for an adolescent 4CMenB vaccine schedule of two doses, 1-6 months apart, to provide protection against meningococcal B infection. The extent of this protection against meningococcus B variants circulating worldwide will be determined by national surveys. FUNDING Novartis Vaccines and Diagnostics.

Prospective, Multicenter Evaluation of Risk Factors Associated With Invasive Bacterial Infection in Children With Cancer, Neutropenia, and Fever

PURPOSE To identify clinical and laboratory parameters present at the time of a first evaluation that could help predict which children with cancer, fever, and neutropenia were at high risk or low risk for an invasive bacterial infection. PATIENTS AND METHODS Over a 17-month period, all children with cancer, fever, and neutropenia admitted to five hospitals in Santiago, Chile, were enrolled onto a prospective protocol. Associations between admission parameters and risk for invasive bacterial infection were assessed by univariate and logistic regression analyses. RESULTS A total of 447 febrile neutropenic episodes occurred in 257 children. Five parameters were statistically independent risk factors for an invasive bacterial infection. Ranked by order of significance, they were as follows: C-reactive protein levels of 90 mg/L or higher (relative risk [RR], 4.2; 95% confidence interval [CI], 3.6 to 4.8); presence of hypotension (RR, 2.7; 95% CI, 2.3 to 3.2); relapse of leukemia as cancer type (RR, 1.8, 95% CI, 1.7 to 2.3); platelet count less than or equal to 50,000/mm(3) (RR, 1.7; 95% CI, 1.4 to 2.2); and recent (< or = 7 days) chemotherapy (RR, 1.3; 95% CI, 1.1 to 1.6). Other previously postulated risk factors (magnitude of fever, monocyte count) were not independent risk factors in this study population. CONCLUSION In a large population of children, common clinical and laboratory admission parameters were identified that can help predict the risk for an invasive bacterial infection. These results encourage the possibility of a more selective management strategy for these children.

Epidemiology of Candidemia in Latin America: A Laboratory-Based Survey

Background The epidemiology of candidemia varies depending on the geographic region. Little is known about the epidemiology of candidemia in Latin America. Methods We conducted a 24-month laboratory-based survey of candidemia in 20 centers of seven Latin American countries. Incidence rates were calculated and the epidemiology of candidemia was characterized. Results Among 672 episodes of candidemia, 297 (44.2%) occurred in children (23.7% younger than 1 year), 36.2% in adults between 19 and 60 years old and 19.6% in elderly patients. The overall incidence was 1.18 cases per 1,000 admissions, and varied across countries, with the highest incidence in Colombia and the lowest in Chile. Candida albicans (37.6%), C. parapsilosis (26.5%) and C. tropicalis (17.6%) were the leading agents, with great variability in species distribution in the different countries. Most isolates were highly susceptible to fluconazole, voriconazole, amphotericin B and anidulafungin. Fluconazole was the most frequent agent used as primary treatment (65.8%), and the overall 30-day survival was 59.3%. Conclusions This first large epidemiologic study of candidemia in Latin America showed a high incidence of candidemia, high percentage of children, typical species distribution, with C. albicans, C. parapsilosis and C. tropicalis accounting for the majority of episodes, and low resistance rates.

Prospective Evaluation of a Model of Prediction of Invasive Bacterial Infection Risk among Children with Cancer, Fever, and Neutropenia

A risk prediction model for invasive bacterial infection (IBI) was prospectively evaluated among children presenting with cancer, fever, and neutropenia. The model incorporated assessment of 5 previously identified risk factors: serum level of C-reactive protein (CRP) >/=90 mg/L, hypotension, identification of relapse of leukemia as the cancer type, platelet count of </=50,000 platelets/mm(3), and recent receipt of chemotherapy [16]. Children were uniformly evaluated at enrollment and were classified as having high or low risk for IBI according to a model that considers the number and type of variables present. Of the 263 febrile episodes evaluated during a 17-month period, 140 (53%) were in IBI-positive children. The sensitivity, specificity, and positive and negative predictive values of the model were 92%, 76%, 82%, and 90%, respectively. Identification of these 5 risk factors during the first 24 h of hospitalization was helpful in discriminating between children with a high or low risk for IBI.

Early Hospital Discharge Followed by Outpatient Management Versus Continued Hospitalization of Children With Cancer, Fever, and Neutropenia at Low Risk for Invasive Bacterial Infection

PURPOSE To compare outcome and cost of ambulatory versus hospitalized management among febrile neutropenic children at low risk for invasive bacterial infection (IBI). PATIENTS AND METHODS Children presenting with febrile neutropenia at six hospitals in Santiago, Chile, were categorized as high or low risk for IBI. Low-risk children were randomly assigned after 24 to 36 hours of hospitalization to receive ambulatory or hospitalized treatment and monitored until episode resolution. Outcome and cost were determined for each episode and compared between both groups using predefined definitions and questionnaires. RESULTS A total of 161 (41%) of 390 febrile neutropenic episodes evaluated from June 2000 to February 2003 were classified as low risk, of which 149 were randomly assigned to ambulatory (n = 78) or hospital-based (n = 71) treatment. In both groups, mean age (ambulatory management, 55 months; hospital-based management, 66 months), sex, and type of cancer were similar. Outcome was favorable in 74 (95%) of 78 ambulatory-treated children and 67 (94%) of 71 hospital-treated children (P = NS). Mean cost of an episode was US 638 dollars (95% CI, 572 dollars to 703 dollars) and US 903 dollars (95% CI, 781 dollars to 1,025 dollars) for the ambulatory and hospital-based groups, respectively (P =.003). CONCLUSION For children with febrile neutropenia at low risk for IBI, ambulatory management is safe and significantly cost saving compared with standard hospitalized therapy.

Discontinuation of Antimicrobial Therapy for Febrile, Neutropenic Children with Cancer: A Prospective Study

During a 2-year period, all children with cancer, neutropenia, and fever who were admitted to Hospital de Niños Luis Calvo Mackenna (Santiago, Chile) were enrolled in a study of the safety of stopping antibiotic therapy on day 3 of treatment. Children who met predefined criteria for nonbacterial fever were randomized on day 3 to stop (group A) or continue (group B) antibiotic therapy. A total of 220 children with cancer had 238 episodes of fever and neutropenia; 68 children with 75 episodes met entry criteria for nonbacterial fever (group A, 36; group B, 39). Both groups were comparable in terms of age, gender, oncological disease, chemotherapy status, and initial neutrophil count. Resolution of symptoms occurred in 34 of 36 episodes in group A and 36 of 39 episodes in group B (P > .05). No deaths occurred, and bacterial superinfections were uncommon. For children with cancer as well as episodes of fever and neutropenia without an identifiable bacterial etiology at admission, stopping antibiotic therapy on day 3 was safe and not associated with a higher risk of bacterial superinfections.

Persistence of antibodies in adolescents 18−24 months after immunization with one, two, or three doses of 4CMenB meningococcal serogroup B vaccine

We previously demonstrated the immunogenicity and tolerability of the serogroup B meningococcal vaccine, 4CMenB (Bexsero®), in 11−17 y-olds randomized to receive 1, 2, or 3 doses at 1, 2, or 6 mo intervals. Participants in this extension study provided an additional blood sample 18−24 mo after last vaccine dose, to assess persistence of serum bactericidal activity with human complement (hSBA), and to compare with age-matched 4CMenB-naïve controls. In the original study, one month after one 4CMenB dose, 93% of subjects had seroprotective hSBA titers (≥4) against indicator serogroup B strains for individual vaccine antigens (fHbp, NadA and NZOMV), increasing to ~100% after two or three doses. After 18−24 mo, 62−73% of subjects given one dose had titers ≥4 against the three antigens, significantly lower rates than after two (77−94%) or three (86−97%) doses. Only proportions with titers ≥ 4 against NZOMV were significantly different between the two (77%) and three (90%, p < 0.0001) dose groups. These results confirm that two doses of 4CMenB, administered 1 to 6 mo apart, provide good levels of bactericidal activity against serogroup B meningococci, which were sustained at least 18−24 mo in over 64% of adolescents for all three tested vaccine-related antigens.

Bacterial and viral etiology of acute otitis media in Chilean children.

BACKGROUND Acute otitis media (AOM) is a main cause for antimicrobial prescription in Latin America. Pathogen diversity in different geographic regions underscores the need for updated knowledge on AOM microbiology. AIM To prospectively determine the role of bacteria and viruses in Chilean children with AOM. METHODS Between July, 1998, and June, 1999, children >3 months with a presumptive diagnosis of AOM were referred to the study ear, nose and throat physician. Middle ear fluid and nasopharyngeal aspirates were obtained from children with confirmed AOM and processed for common bacteria, Mycoplasma pneumoniae, Chlamydia pneumoniae and viruses. Antimicrobial susceptibility patterns and serotypes of Streptococcus pneumoniae strains were determined. RESULTS An ear, nose and throat physician confirmed diagnoses for 222 (42%) of 529 children referred with diagnosis of AOM, and 170 children met eligibility criteria for the study. One or more pathogens were detected in 140 of 170 (82%) children. Predominant bacteria were S. pneumoniae (37%), Haemophilus influenzae (24%) and Streptococcus pyogenes (13%). M. catarrhalis was detected in 2 children, C. pneumoniae was found in 1 and M. pneumoniae was not detected. Viruses were detected in 22 children (13%) from nasopharyngeal aspirates, and in 6 of them the same virus was detected in middle ear fluid. Penicillin-resistant (intermediate and high) S. pneumoniae represented 40% of isolates and 10% of H. influenzae were beta-lactamase producers. All 10 penicillin-resistant S. pneumoniae strains were resistant to cefuroxime. Eighteen S. pneumoniae serotypes were detected and 19F was associated with high level penicillin resistance. CONCLUSION This study can impact local management of AOM, and it should encourage continuous surveillance of AOM microbiology in Chile and other developing countries.

Predictors of severe sepsis not clinically apparent during the first twenty-four hours of hospitalization in children with cancer, neutropenia, and fever: a prospective, multicenter trial.

Background: Severe sepsis is not clinically apparent during the first 24 hours of hospitalization in most children with cancer and febrile neutropenia (FN), delaying targeted interventions that could impact mortality. The aim of this study was to prospectively evaluate biomarkers obtained within 24 hours of hospitalization as predictors of severe sepsis before it becomes clinically evident. Methods: Children with cancer, admitted with FN at high risk for an invasive bacterial infection in 6 public hospitals in Santiago, Chile, were monitored throughout their clinical course for occurrence of severe sepsis. Clinical, demographic and 6 biomarkers [eg, blood urea nitrogen, serum glucose, lactic dehydrogenase, serum C-reactive protein (CRP), interleukin (IL)-8, and procalcitonin] were obtained at the time of admission and after 24 hours. Biomarkers independently associated with severe sepsis diagnosed after the first 24 hours of hospitalization were identified by logistic regression analysis. Results: A total of 601 high risk FN episodes were enrolled between June 2004 and October 2006; 151 (25%) developed severe sepsis of which 116 (77%) were not clinically apparent during the first 24 hours of hospitalization. Risk factors for severe sepsis were age ≥12 years [odds ratio (OR): 3.85; 95% confidence interval (CI): 2.41–6.15], admission CRP ≥90 mg/L (OR: 2.03; 95% CI: 1.32–3.14), admission IL-8 ≥200 pg/mL (OR: 2.39; 95% CI: 1.51–3.78), 24-hour CRP ≥100 mg/L (OR: 3.06; 95% CI: 1.94–4.85), and 24-hour IL-8 ≥300 pg/mL (OR: 3.13; 95% CI 1.92–5.08). Conclusions: Age ≥12 years and admission or 24-hour values of CRP ≥90/100 mg/L and IL-8 ≥200/300 pg/mL are predictors of sepsis not clinically apparent during the first 24 hours of hospitalization.

Symptomatic and Asymptomatic Rotavirus and Norovirus Infections During Infancy in a Chilean Birth Cohort

Background: Rotavirus and more recently norovirus have been recognized as 2 of the most common causes of acute diarrhea in children. Comparative analysis of these infections in a birth cohort has not been performed and can provide relevant insight on clinical and viral behaviors. Methods: Mother-infant pairs from middle-low socioeconomic background living in the Metropolitan Region of Chile are being followed for 18 months in 2 outpatient clinics. Infants are evaluated monthly for asymptomatic excretion of rotavirus and norovirus and during acute diarrhea episodes (ADE) for rotavirus, norovirus, and bacterial enteropathogens. Severity of ADE is evaluated using the Vesikari score. Results: Between July 1, 2006 and September 1, 2008 a total of 198 children were followed for a mean of 15.7 months. Asymptomatic rotavirus and norovirus infections were detected in 1.3% and 8% of 2278 stool samples compromising 14% and 57% of infants, respectively. Incidence of ADE was approximately 0.8 for the first year of life and approximately 0.6 for the 13 to 18 month age group. Rotavirus and norovirus were detected in 15% and 18% of 145 ADE evaluated. Mean Vesikari score was 10.4 and 7.4 for rotavirus and norovirus respectively (P = 0.01) and severity was not associated with age of patients for either virus. Reinfections were more common for norovirus asymptomatic episodes: 44% versus 19% (P = 0.01) and borderline for symptomatic episodes: 40% versus 11% (P = 0.08). Rotavirus genotype G9P8 and norovirus genogroup II (GII) predominated although most asymptomatic episodes for both viruses were nontypable. None of 19 symptomatic GII norovirus infections had a previous documented GII infection compared with 10 of 31 asymptomatic GII infections (OR = 0. 95% CL = 0, 0.59; P = 0.008). Conclusions: Children had suffered a mean of approximately 1.4 ADE by 18 months of age of which 15% and 18% were caused by rotavirus and norovirus, respectively. In general rotavirus infections were more severe than norovirus infections and for both viruses severity was not related to age. Norovirus reinfections were significantly more common than rotavirus reinfections but for GII norovirus a primary infection seems to confer protection against clinically significant reinfections.