Heterologous ("nonspecific") and sex-differential effects of vaccines: epidemiology, clinical trials, and emerging immunologic mechanisms.

A growing body of evidence from epidemiologic, clinical, and immunologic studies indicates that vaccines can influence morbidity and mortality independent of vaccine-specific B-cell or T-cell immunity. For example, the live attenuated measles vaccine and BCG vaccine may reduce mortality from infections other than measles or tuberculosis, respectively. Immunologists call these heterologous effects and epidemiologists have called them nonspecific effects, indicating that they manifest against a broad range of pathogens/disease. These effects differ by sex, can be beneficial or detrimental, and appear to be mediated by mechanisms including innate immune memory (also known as "trained immunity") and cross-reacting lymphocytes. Herein we review recent studies in this emerging field based on a meeting of experts, the recent Optimmunize meeting, held in Copenhagen, Denmark, in August 2012. Further characterization of these effects is likely to expand the way vaccines are evaluated and alter the manner and sequence in which they are given.

Validation of the hospital outcome prediction equation (HOPE) model for monitoring clinical performance.

BACKGROUND: The aim of this study was to validate a risk-adjusted hospital outcome prediction equation (HOPE) using a statewide administrative dataset. METHODS: Retrospective observational study using multivariate logistic regression modelling. Calibration and discrimination were assessed by standardized mortality ratio (SMR), area under the receiver operating characteristic plot (ROC AUC), Hosmer-Lemeshow contingency tables and goodness-of-fit statistic in an independent dataset, and in all 23 important tertiary, metropolitan and regional hospitals. The dependent variable was in-hospital death. All consecutive adult hospital separations between 1 July 2004 and 30 June 2006, excluding obstetric and day-case only admissions, from all acute health services within the State of Victoria, Australia were included. RESULTS: A total of 379 676 consecutive records (1 July 2004 to 30 June 2005) was used to derive the HOPE model. Six variables (age, male sex, admission diagnosis, emergency admission, aged-care resident and inter-hospital transfer) were selected for inclusion in the final model. It was validated in the 384 489 consecutive records from the following year (1 July 2005 to 30 June 2006). The 95% confidence interval for the SMR was 0.98-1.02, and for the ROC AUC, 0.87-0.88. Discrimination and (one or more) calibration criteria were achieved in 22 (96%) of the 23 hospitals. CONCLUSION: The HOPE model is a simple risk-adjusted outcome prediction tool, based on six variables from data that are routinely collected for administrative purposes and appears to be a reliable predictor of hospital outcome.

WITHDRAWN: Antibiotics for preventing pneumonia in children with measles.

BACKGROUND: Measles causes more than a million deaths a year, of which most are children under five years of age who die from pneumonia. OBJECTIVES: The objective of this review was to assess the effects of antibiotics given to children with measles on reducing pneumonia or mortality, and to assess whether antibiotics should be given to all children with measles in communities with a high fatality rate. SEARCH STRATEGY: We searched MEDLINE (1966 - 1999), EMBASE (1980-1999) and the specialized trials register of the Acute Respiratory Infections Group in August 1999, and all relevant journals in the University of Melbourne medical library for the years 1935-46. SELECTION CRITERIA: Randomised or controlled trials of antibiotics for children with measles. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. MAIN RESULTS: Six trials with 1304 children were included. All but one of the trials were unblinded, and randomisation was either not described or was by alternate allocation. In four studies, the incidence of pneumonia in the control group was similar to that in the antibiotic prophylaxis group; in the other two studies, the incidence of pneumonia was unusually high in the control group so these children had a higher complication rate than the antibiotic group. Four of the 764 children given antibiotics died compared with one of the 637 controls. AUTHORS' CONCLUSIONS: The quality of the trials reviewed was poor, and they provide very weak evidence for giving antibiotics to all children with measles. Available evidence suggests that antibiotics should be given only if a child has clinical signs of pneumonia or other evidence of sepsis.

Outcome-based clinical indicators for intensive care medicine.

The clinical indicator is a tool used to monitor the quality of health care. Its use in the Intensive Care Unit (ICU) is desirable for many reasons: the maintenance of minimum standards, the development of best practice and the delivery of cost-effective health care. The utility of clinical indicators in ICU is limited by the lack of universal, robust, transparent, evidence-based and risk-adjusted measures of quality, and the difficulties in defining "quality care" and "good outcome". Monitoring of adverse events, system descriptors, and resource indicators is valuable but they have a limited relationship to the quality of care. ICU mortality prediction models provide a global measure of quality and, despite their inherent deficiencies, remain one of the most robust and useful clinical indicators.

A randomised, controlled trial of once daily and multi-dose daily gentamicin in young Kenyan infants.

AIMS: To test the suitability of a simple once daily (OD) gentamicin regimen for use in young infants where routine therapeutic drug monitoring is not possible. METHODS: In an open, randomised, controlled trial, infants with suspected severe sepsis admitted to a Kenyan, rural district hospital received a novel, OD gentamicin regimen or routine multi-dose (MD) regimens. RESULTS: A total of 297 infants (over 40% < or =7 days) were randomised per protocol; 292 contributed at least some data for analysis of pharmacological endpoints. One hour after the first dose, 5% (7/136) and 28% (35/123) of infants in OD and MD arms respectively had plasma gentamicin concentrations <4 microg/ml (a surrogate of treatment inadequacy). Geometric mean gentamicin concentrations at this time were 9.0 microg/ml (95% CI 8.3 to 9.9) and 4.7 microg/ml (95% CI 4.2 to 5.3) respectively. By the fourth day, pre-dose concentrations > or =2 microg/ml (a surrogate of potential treatment toxicity) were found in 6% (5/89) and 24% (21/86) of infants respectively. Mortality was similar in both groups and clinically insignificant, although potential gentamicin induced renal toxicity was observed in <2% infants. CONCLUSIONS: A "two, four, six, eight" OD gentamicin regime, appropriate for premature infants and those in the first days and weeks of life, seems a suitable, safe prescribing guide in resource poor settings.

Oxygen administration in infants.

The main methods of oxygen administration to infants are reviewed. Some methods are more economical and therefore more useful in developing countries. All the methods have potential complications and therefore need to be carefully supervised.

Prolonged per-laryngeal endotracheal intubation in children: 40 years on.

Because tracheostomy has a very high complication rate in small children, prolonged mechanical ventilation was not performed satisfactorily in infants until a technique was developed that allowed prolonged per-laryngeal endotracheal intubation in children. Plastic polyvinyl chloride endotracheal tubes were introduced in the 1950s; they soften at body temperature, and are much less likely to cause subglottic stenosis than endotracheal tubes made from metal or rubber. The first account of prolonged per-laryngeal intubation of infants using polyvinyl chloride tubes was written by Dr Bernard Brandstater, and this remarkable document is reproduced here. It sets out all the important principles of endotracheal intubation in children: the tube must fit easily through the cricoid ring, it must be firmly fixed in place with the tip in the mid trachea, meticulous humidification and suction are essential, and the tube should be changed only if there are signs of obstruction.

Systematic review of rheumatic heart disease prevalence in children in developing countries: the role of environmental factors.

OBJECTIVES: To consider the worldwide prevalence of rheumatic heart disease in children in developing countries using surveys with uniform methodologies, and to consider the effect of environmental factors including socio-economic status, overcrowding, urbanization, nutrition and access to medical services on the distribution of rheumatic heart disease in developing countries. METHODS: Sixty-one surveys of the prevalence of rheumatic heart disease in developing countries were found using a systematic review of MEDLINE from January 1976 to July 1999. Twenty-four studies were selected for comparison based on their uniform methodological and diagnostic techniques. RESULTS: There is a high prevalence of rheumatic heart disease in the Pacific region with a lower prevalence in the Indian subcontinent, Asian, sub-Saharan African, Mediterranean, Latin American and Caribbean regions. However, aside from the Indian subcontinent, these regions have not been well studied, and it may be that the true prevalence is actually higher. CONCLUSIONS: There is a lack of good quality prevalence surveys of rheumatic heart disease in developing countries. It appears that a threshold level where higher socio-economic status is associated with reduced prevalence of rheumatic heart disease is not reached in developing countries. Therefore, differences in prevalence between socio-economic groups in the one area cannot be detected. A similar case can be made for overcrowding. Many regions need well-designed studies of rheumatic heart disease that incorporate assessment of environmental factors as well as the study of the microbiological epidemiology of rheumatic heart disease and group A streptococci.

Nasopharyngeal oxygen therapy produces positive end-expiratory pressure in infants.

UNLABELLED: The World Health Organisation recommends nasopharyngeal catheters as a safe and efficient method of oxygen administration in infants. However, little is known about the mechanisms of the improvement in oxygenation. The aim of the present study was to determine whether nasopharyngeal oxygen therapy produces positive end-expiratory pressure (PEEP). Nine spontaneously breathing infants (median age 13 months, range 10 days to 20 months) after heart surgery were investigated. All patients had normal pulmonary blood flow at the time of the study (Qp:Qs=1:1). Oxygen (oxygen fraction 1.0) was delivered by an 8 F catheter inserted into the nasopharynx (tip just visible below the soft palate). The pulmonary mechanics were analysed using a single compartment model of the respiratory system. Oesophageal pressure (Pes) at end-expiration, dynamic lung compliance (C(L)) and resistance (R(L)), minute ventilation, PaCO2 and PaO2 were measured at baseline without a nasopharyngeal catheter or oxygen, and at oxygen flows of 0.5 l/min, 1.0 l/min and 2.0 l/min. All the flows generated significant increases in PEEP. Mean difference in PEEP (SD, paired t-test versus baseline): 1.6 cm H2O (1.4, P=0.008) with 0.5 l/min of oxygen; 2.8 cm H2O (2.7, P=0.014) with 1.0 l/min of oxygen; and 4.0 cm H2O (2.9, P = 0.004) with 2.0 l/min of oxygen. There was a significant correlation between all the nasopharyngeal flows (in ml/kg per min) and the generated PEEP (P<0.001) and between the C(L) values and the generated PEEP (P < 0.05). There was no significant difference in PaCO2 and R(L). Minute ventilation was significantly less with nasopharyngeal oxygen than at baseline. As expected, PaO2 increased significantly with increasing oxygen flows. CONCLUSION: Administration of oxygen through an 8 F nasopharyngeal catheter at flow rates recommended by the World Health Organisation (0.5 l/min in newborns, 1.0 l/min in infants) produces moderate amounts of positive end-expiratory pressure. The levels achieved may contribute to an improvement in oxygenation by altering the visco-elastic properties of the lung.

Effect of reusing suction catheters on the occurrence of pneumonia in children.

OBJECTIVE: The purpose of this study was to determine whether disposable suction catheters can be reused in the same patient for a 24-hour period without affecting the incidence of pneumonia. DESIGN: The study design was a randomized controlled trial. SETTING: The study was conducted in the pediatric intensive care unit of a tertiary pediatric center. SAMPLE: Subjects included 486 children with an endotracheal tube in place. OUTCOME MEASURES: The development of pneumonia, diagnosed with radiographic and clinical evidence, was the measure. Cost analysis was also undertaken. METHOD: Subjects in the study group (n = 241) were suctioned using the same catheter for a 24-hour period. Those in the control group (n = 245) had a new catheter for each episode of suctioning. RESULTS: Pneumonia developed in 14 members (5.71%) of the control group and in 12 members (4.98%) of the study group, a difference of 0.7% (95% CI, -3.3% to 4.7%). Cost analysis indicated a saving of Aust $4.14 per patient per day. CONCLUSION: Reusing suction catheters for up to 24 hours is both safe and cost-effective.

A randomized trial of very early decompressive craniectomy in children with traumatic brain injury and sustained intracranial hypertension.

OBJECT: The object of our study was to determine, in children with traumatic brain injury and sustained intracranial hypertension, whether very early decompressive craniectomy improves control of intracranial hypertension and longterm function and quality of life. METHODS: All children were managed from admission onward according to a standardized protocol for head injury management. Children with raised intracranial pressure (ICP) were randomized to standardized management alone or standardized management plus cerebral decompression. A decompressive bitemporal craniectomy was performed at a median of 19.2 h (range 7.3-29.3 h) from the time of injury. ICP was recorded hourly via an intraventricular catheter. Compared with the ICP before randomization, the mean ICP was 3.69 mmHg lower in the 48 h after randomization in the control group, and 8.98 mmHg lower in the 48 hours after craniectomy in the decompression group (P=0.057). Outcome was assessed 6 months after injury using a modification of the Glasgow Outcome Score (GOS) and the Health State Utility Index (Mark 1). Two (14%) of the 14 children in the control group were normal or had a mild disability after 6 months, compared with 7 (54%) of the 13 children in the decompression group. Our conclusion was that when children with traumatic brain injury and sustained intracranial hypertension are treated with a combination of very early decompressive craniectomy and conventional medical management, it is more likely that ICP will be reduced, fewer episodes of intracranial hypertension will occur, and functional outcome and quality of life may be better than in children treated with medical management alone (P=0.046; owing to multiple significance testing P <0.0221 is required for statistical significance). This pilot study suggests that very early decompressive craniectomy may be indicated in the treatment of traumatic brain injury.

Calibration of the paediatric index of mortality in UK paediatric intensive care units.

AIM: To test a paediatric intensive care mortality prediction model for UK use. METHOD: Prospective collection of data from consecutive admissions to five UK paediatric intensive care units (PICUs), representing a broad cross section of paediatric intensive care activity. A total of 7253 admissions were analysed using tests of the discrimination and calibration of the logistic regression equation. RESULTS: The model discriminated and calibrated well. The area under the ROC plot was 0.84 (95% CI 0.819 to 0.853). The standardised mortality ratio was 0.87 (95% CI 0.81 to 0.94). There was remarkable concordance in the performance of the paediatric index of mortality (PIM) within each PICU, and in the performance of the PICUs as assessed by PIM. Variation in the proportion of admissions that were ventilated or transported from another hospital did not affect the results. CONCLUSION: We recommend that UK PICUs use PIM for their routine audit needs. PIM is not affected by the standard of therapy after admission to PICU, the information needed to calculate PIM is easy to collect, and the model is free.

The immature-to-total neutrophil ratio (IT ratio) is a sensitive indicator of sepsis after paediatric cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) causes a systemic inflammatory response syndrome (SIRS) with activation of neutrophils (increased immature-to-total neutrophil ratio, IT ratio). Does an additional inflammatory response induced by sepsis further increase the IT ratio, so that it can still be used as an indicator of sepsis? In 160 children we analysed retrospectively the IT ratios from the day before CPB to the 10th day after the operation (controls). The 95% confidence limits of the controls were plotted against postoperative day and compared with the IT ratio courses in all children of a 4-year period who developed sepsis during the first 10 days after CPB. All septic children (n = 9) had IT ratios above the upper 95% confidence limits of the controls on the day of positive culture or on the following day. The IT ratio remains a sensitive indicator of sepsis even after CPB.

Antibiotics for preventing pneumonia in children with measles.

BACKGROUND: Measles causes more than a million deaths a year, of which most are children under five years of age who die from pneumonia. OBJECTIVES: The objective of this review was to assess the effects of antibiotics given to children with measles on reducing pneumonia or mortality, and to assess whether antibiotics should be given to all children with measles in communities with a high fatality rate. SEARCH STRATEGY: We searched MEDLINE (1966 - 1999), EMBASE (1980-1999) and the specialized trials register of the Acute Respiratory Infections Group in August 1999, and all relevant journals in the University of Melbourne medical library for the years 1935-46. SELECTION CRITERIA: Randomised or controlled trials of antibiotics for children with measles. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. MAIN RESULTS: Six trials with 1304 children were included. All but one of the trials were unblinded, and randomisation was either not described or was by alternate allocation. In four studies, the incidence of pneumonia in the control group was similar to that in the antibiotic prophylaxis group; in the other two studies, the incidence of pneumonia was unusually high in the control group so these children had a higher complication rate than the antibiotic group. Four of the 764 children given antibiotics died compared with one of the 637 controls. REVIEWER'S CONCLUSIONS: The quality of the trials reviewed was poor, and they provide very weak evidence for giving antibiotics to all children with measles. Available evidence suggests that antibiotics should be given only if a child has clinical signs of pneumonia or other evidence of sepsis.