Clinical and Epidemiological Aspects of Diphtheria: A Systematic Review and Pooled Analysis.

BACKGROUND: Diphtheria, once a major cause of childhood morbidity and mortality, all but disappeared following introduction of diphtheria vaccine. Recent outbreaks highlight the risk diphtheria poses when civil unrest interrupts vaccination and healthcare access. Lack of interest over the last century resulted in knowledge gaps about diphtheria's epidemiology, transmission, and control. METHODS: We conducted 9 distinct systematic reviews on PubMed and Scopus (March-May 2018). We pooled and analyzed extracted data to fill in these key knowledge gaps. RESULTS: We identified 6934 articles, reviewed 781 full texts, and included 266. From this, we estimate that the median incubation period is 1.4 days. On average, untreated cases are colonized for 18.5 days (95% credible interval [CrI], 17.7-19.4 days), and 95% clear Corynebacterium diphtheriae within 48 days (95% CrI, 46-51 days). Asymptomatic carriers cause 76% (95% confidence interval, 59%-87%) fewer cases over the course of infection than symptomatic cases. The basic reproductive number is 1.7-4.3. Receipt of 3 doses of diphtheria toxoid vaccine is 87% (95% CrI, 68%-97%) effective against symptomatic disease and reduces transmission by 60% (95% CrI, 51%-68%). Vaccinated individuals can become colonized and transmit; consequently, vaccination alone can only interrupt transmission in 28% of outbreak settings, making isolation and antibiotics essential. While antibiotics reduce the duration of infection, they must be paired with diphtheria antitoxin to limit morbidity. CONCLUSIONS: Appropriate tools to confront diphtheria exist; however, accurate understanding of the unique characteristics is crucial and lifesaving treatments must be made widely available. This comprehensive update provides clinical and public health guidance for diphtheria-specific preparedness and response.

Which Variables Are Useful for Predicting Severe Infection in Children With Febrile Neutropenia?

To distinguish children with chemotherapy-induced febrile neutropenia (FN) at low risk of severe infection, the variables that are significant risk factors must be identified. Our objective was to identify them by applying evidence-based standards. This retrospective 2-center cohort study included all episodes of chemotherapy-induced FN in children in 2005 and 2006. The medical history, clinical, and laboratory data available at admission were collected. Severe infection was defined by bacteremia, a positive culture of a normally sterile body fluid, invasive fungal infection, or localized infection at high risk of extension. Univariate analysis identified potential predictive variables. A generalized mixed model was used to determine the adjusted variables that predict severe infection. We analyzed 372 FN episodes. Severe infections occurred in 16.1% of them. Variables predictive of severe infection at admission were: disease with high risk of prolonged neutropenia (adjusted odds ratio [aOR]=2.5), blood cancer (aOR=1.9), fever ≥38.5°C (aOR=3.7), and C-reactive protein level ≥90 mg/L (aOR=4.5). Now that we have identified these variables significantly associated with the risk of severe infection, they must be validated prospectively before combining the best predictive variables in a decision rule that can be used to distinguish children at low risk.

Which decision rules meet methodological standards in children with febrile neutropenia? Results of a systematic review and analysis.

BACKGROUND: Clinical decision rules (CDRs) have sought to identify the few children with chemotherapy-induced febrile neutropenia (FN) really at risk of severe infection to reduce the invasive procedures and costs for those at low risk. Several reports have shown that most rules do not perform well enough to be clinically useful. Our objective was to analyze the derivation methods and validation procedures of these CDRs. PROCEDURE: A systematic review using Medline, Ovid, Refdoc, and the Cochrane Library through December 2012 searched for all CDRs predicting the risk of severe infection and/or complications in children with chemotherapy-induced FN. Their methodological quality was analyzed by 17 criteria for deriving and validating a CDR identified in the literature. The criteria published by the Evidence Based Medicine Working Group were applied to the published validations of each CDR to assess their level of evidence. RESULTS: The systematic research identified 612 articles and retained 12 that derived CDRs. Overall, the CDRs met a median of 65% of the methodological criteria. The criteria met least often were that the rule made clinical sense, or described the course of action, or that the variables and the CDR were reproducible. Only one CDR, developed in South America, met all methodological criteria and provided the highest level of evidence; unfortunately it was not reproducible in Europe. CONCLUSION: Only one CDR developed for children with FN met all methodological standards and reached the highest level of evidence.

Predicting the risk of severe bacterial infection in children with chemotherapy-induced febrile neutropenia.

BACKGROUND: The prognosis of febrile neutropenia (FN) in childhood cancer has been considerably improved by the intensification of treatment, including systematic hospitalization and broad-spectrum antibiotics. As only few children present with a severe bacterial infection (SBI), clinical decision rules have been developed to distinguish those at risk for SBI. The aim of this study was to evaluate the reproducibility of six clinical decision rules proposed in the literature and to compare their performance. METHODS: This retrospective two-center cohort study included all episodes of chemotherapy-induced FN in children admitted between January 2005 and December 2006. Each rule was applied to our patients. Their sensitivity (Se) and specificity (Sp) were calculated and compared with the authors' results, to assess reproducibility. The most predictive rule was defined in advance as that yielding 100% Se, the highest Sp, and the greatest simplicity for bedside application. RESULTS: Three hundred seventy-seven episodes of FN in 167 patients were collected; 64 episodes were associated with SBI, including 36 with bacteremia. Four of the six rules were reproducible, but none were able to be validated. The most predictive rule for bacteremia had 96% Se (95% confidence interval (CI): 79-99%) and 25% Sp (95% CI: 19-33%), and the most predictive rule for SBI had 95% Se (95% CI: 87-98%), but no power of discrimination (Sp = 5%, 95% CI: 3-8%). CONCLUSION: This study emphasizes the difficulty in identifying standardized decision rules in the management of a condition with numerous clinical variables like FN.

Safety of a heat-stable rotavirus vaccine among children in Niger: Data from a phase 3, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Rotavirus remains a major cause of diarrhea among children under 5 years of age. The efficacy of RotaSIIL, a pentavalent rotavirus vaccine, was shown in an event-driven trial in Niger. We describe the two-year safety follow-up of this trial. METHODS: Follow-up of safety outcomes began upon administration of the first dose of RotaSIIL or placebo. Adverse events were followed until 28 days after the third dose, and serious adverse events were followed until 2 years of age. Suspected cases of intussusception were evaluated at first point of contact and then referred to hospital for surgical evaluation. Causes of death were obtained by chart review and verbal autopsy. Passive surveillance was carried out in health centers. Community health workers carried out active surveillance in villages. Between-group differences were evaluated using the chi-squared test and Fisher's exact test. RESULTS: A total of 4092 children were randomized, and 4086 received at least one dose of RotaSIIL or placebo, constituting the intention-to-treat population, who accrued a total of 7385 child-years of follow-up time. At two years of follow-up, 58 (2.8%) participants who received RotaSIIL and 49 (2.4%) participants who received placebo had died (p = 0.38). Most deaths were due to infectious causes common to the study area. One participant had confirmed intussusception, 542 days after receiving the third dose of RotaSIIL. A total of 395 (19.3%) participants receiving RotaSIIL and 419 (20.5%) participants receiving placebo experienced any serious adverse event (p = 0.36). Most serious adverse events were hospitalizations due to infection (malaria, lower respiratory tract infection and gastroenteritis) or marasmus. Overall, 1474 (72.1%) participants receiving RotaSIIL and 1456 (71.1%) participants receiving placebo had at least one adverse event (p = 0.49) in the follow-up period. CONCLUSIONS: At two years of follow-up, RotaSIIL was found to be safe. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02145000.