Neonatal BCG Vaccination for Prevention of Allergy in Infants: The MIS BAIR Randomised Controlled Trial.

BACKGROUND: The beneficial off-target effects of Bacille Calmette-Guérin (BCG) vaccination potentially include protection against allergy. OBJECTIVE: In the MIS BAIR trial, we aimed to determine whether neonatal BCG vaccination reduces atopic sensitisation and clinical food allergy in infants. METHODS: In this randomised controlled trial, 1272 neonates were allocated to BCG-Denmark vaccine (0.05 mL intradermal dose) or no BCG at birth. Randomisation was stratified by recruitment site, mode of delivery and plurality of birth. The primary outcome was the incidence of atopic sensitisation determined by skin prick test at 1 year of age. Food allergy was determined by 3-monthly online questionnaires and oral food challenges. Data were analysed by intention-to-treat using binary regression. CLINICALTRIALS: gov (NCT01906853). RESULTS: Atopic sensitisation during the first year of life was 22.9% among infants in the BCG group and 18.9% in the control group (adjusted risk difference (aRD) 3.8% (95% CI -1.5 to 9.1) after multiple imputation). Clinical food allergy was similar between infants in the BCG and control groups (9.8% vs. 9.6%; aRD 0.2, 95% CI -3.4 to 3.8). An interaction was observed between the primary outcome and maternal history of BCG vaccination. No interaction was observed for the additional prespecified potential effect modifiers tested (sex, delivery mode, family history of any allergy, season of birth, hepatitis B vaccination at randomisation, BCG scar and age at BCG administration). CONCLUSIONS AND CLINICAL RELEVANCE: Neonatal BCG-Denmark vaccination does not protect against atopic sensitisation or clinical food allergy in the first year of life.

Pragmatic Randomized Trial of Corticosteroids and Inhaled Epinephrine for Bronchiolitis in Children in Intensive Care.

OBJECTIVE: To determine whether the combination of systemic corticosteroids and nebulized epinephrine, compared with standard care, reduces the duration of positive pressure support in children with bronchiolitis admitted to intensive care. STUDY DESIGN: We performed a pragmatic, multicenter, open-label, randomized trial between July 2013 and November 2019 in children younger than 18 months old with a clinical diagnosis of bronchiolitis. The intervention group received the equivalent of 13 mg/kg prednisolone over 3 days, then 1 mg/kg daily for 3 days, plus 0.05 mL/kg of nebulized 1% epinephrine made up to 6 ml with 0.9% saline via jet nebulizer and mask using oxygen at 12 l/min every 30 minutes for 5 doses, then 1-4 hourly for 3 days, then as required for 3 days. The primary outcome was clinician-managed duration of positive pressure support in intensive care defined as high-flow nasal-prong oxygen, nasopharyngeal continuous positive airway pressure, or mechanical ventilation. RESULTS: In total, 210 children received positive pressure support. In the corticosteroid-epinephrine group, 107 children received positive pressure support for a geometric mean of 26 (95% CI, 22-32) hours compared with 40 (95% CI 34-47) hours in 103 controls, adjusted ratio 0.66 (95% CI 0.51-0.84), P = .001. In the intervention group, 41 (38%) children experienced at least 1 adverse event, compared with 39 (38%) in the control group. CONCLUSIONS: In children with severe bronchiolitis, the duration of clinician-managed pressure support was reduced by regular treatment with systemic corticosteroids and inhaled epinephrine compared with standard care. CLINICAL TRIAL REGISTRATION: Australian Clinical Trials Research Network: ACTRN12613000316707.

Prevention of infant eczema by neonatal Bacillus Calmette-Guérin vaccination: The MIS BAIR randomized controlled trial.

BACKGROUND: Bacille Calmette-Guérin (BCG) vaccine could play a role in counteracting the rising prevalence of atopic diseases, through its beneficial off-target effects. We aimed to determine whether neonatal BCG vaccination reduces the incidence of eczema in infants. METHODS: Randomized controlled trial with 1272 infants allocated to receive BCG-Denmark or no BCG at birth. The primary outcome was the 12-month incidence of eczema based on 3-monthly questionnaires. Eczema was also assessed at a 12-month clinic visit. ClinicalTrial.gov: NCT01906853. RESULTS: The 12-month eczema incidence was 32.2% in the BCG group compared with 36.6% in the control group (adjusted risk difference (aRD) -4.3%, 95% CI -9.9% to 1.3%, multiple imputation model). In addition, comparing infants in the BCG group with the control group, 15.7% vs. 19.2% had eczema lesions at the 12-month visit (aRD -3.5%, 95% CI -8.0% to 1.0%); 35.7% vs. 39.0% reported using topical steroids (aRD -3.3, 95% CI -9.2 to 2.7); and 7.3% vs. 10.2% had severe eczema scores (aRD -3.0%, 95% CI -8.8% to 2.7%). In 344 high-risk infants (two atopic parents), the 12-month eczema incidence was 35.3% in the BCG group compared with 46.8% in the control group (aRD -11.5%, 95% CI -21.9% to -1.2%; number needed to treat 8.7, 95% CI 4.6 to 83.3). CONCLUSION: There is insufficient evidence to recommend neonatal BCG vaccination in all infants for the prevention of eczema in the first year of life; however, a modest beneficial effect was observed among high-risk infants. A single dose of BCG-Denmark soon after birth could reduce the incidence of eczema in infants with two atopic parents.

Association Between Centralization and Outcome for Children Admitted to Intensive Care in Australia and New Zealand: A Population-Based Cohort Study.

OBJECTIVES: To describe regional differences and change over time in the degree of centralization of pediatric intensive care in Australia and New Zealand (ANZ) and to compare the characteristics and ICU mortality of children admitted to specialist PICUs and general ICUs (GICUs). DESIGN: A retrospective cohort study using registry data for two epochs of ICU admissions, 2003-2005 and 2016-2018. SETTING: Population-based study in ANZ. PATIENTS: A total of 43,256 admissions of children aged younger than 16 years admitted to an ICU in ANZ were included. Infants aged younger than 28 days without cardiac conditions were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was risk-adjusted ICU mortality. Logistic regression was used to investigate the association of mortality with the exposure to ICU type, epoch, and their interaction. Compared with children admitted to GICUs, children admitted to PICUs were younger (median 25 vs 47 mo; p < 0.01) and stayed longer in ICU (median 1.6 vs 1.0 d; p < 0.01). For the study overall, 93% of admissions in Australia were to PICUs whereas in New Zealand only 63% of admissions were to PICUs. The adjusted odds of death in epoch 2 relative to epoch 1 decreased (adjusted odds ratio [AOR], 0.50; 95% CI, 0.42-0.59). There was an interaction between unit type and epoch with increased odds of death associated with care in a GICU in epoch 2 (AOR, 1.63; 95% CI, 1.05-2.53 for all admissions; 1.73, CI, 1.002-3.00 for high-risk admissions). CONCLUSIONS: Risk-adjusted mortality of children admitted to specialist PICUs decreased over a study period of 14 years; however, a similar association between time and outcome was not observed in high-risk children admitted to GICUs. The results support the continued use of a centralized model of delivering intensive care for critically ill children.

Neonatal Bacille Calmette-Guérin Vaccination and Infections in the First Year of Life: The MIS BAIR Randomized Controlled Trial.

BACKGROUND: Bacille Calmette-Guérin (BCG) vaccination has beneficial off-target effects that may include protecting against non-mycobacterial infectious diseases. We aimed to determine whether neonatal BCG vaccination reduces lower respiratory tract infections (LRTI) in infants in the Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR) trial. METHODS: In this investigator-blinded trial, neonates in Australia were randomized to receive BCG-Denmark vaccination or no BCG at birth. Episodes of LRTI were determined by symptoms reported in parent-completed, 3-month questionnaires over the first year of life. Data were analyzed by intention-to-treat using binary regression. RESULTS: A total of 1272 neonates were randomized to the BCG vaccination (n = 637) or control (n = 635) group. The proportion of participants with an episode of LRTI in the first year of life among BCG-vaccinated infants was 54.8% compared to 58.0% in the control group, resulting in a risk difference of -3.2 (95% confidence interval, -9.0 to 2.6) after multiple imputation. There was no interaction observed between the primary outcome and sex, maternal BCG, or the other prespecified effect modifiers. CONCLUSIONS: Based on the findings of this trial, there is insufficient evidence to support the use of neonatal BCG vaccination to prevent LRTI in the first year of life in high-income settings.

Five-Year Survival of Children With Chronic Critical Illness in Australia and New Zealand.

OBJECTIVE: Outcomes for children with chronic critical illness are not defined. We examined the long-term survival of these children in Australia and New Zealand. DESIGN: All cases of PICU chronic critical illness with length of stay more than 28 days and age 16 years old or younger in Australia and New Zealand from 2000 to 2011 were studied. Five-year survival was analyzed using Kaplan-Meir estimates, and risk factors for mortality evaluated using Cox regression. SETTING: All PICUs in Australia and New Zealand. PATIENTS: Nine hundred twenty-four children with chronic critical illness. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Nine hundred twenty-four children were admitted to PICU for longer than 28 days on 1,056 occasions, accounting for 1.3% of total admissions and 23.5% of bed days. Survival was known for 883 of 924 patients (95.5%), with a median follow-up of 3.4 years. The proportion with primary cardiac diagnosis increased from 27% in 2000-2001 to 41% in 2010-2011. Survival was 81.4% (95% CI, 78.6-83.9) to PICU discharge, 70% (95% CI, 66.7-72.8) at 1 year, and 65.5% (95% CI, 62.1-68.6) at 5 years. Five-year survival was 64% (95% CI, 58.7-68.6) for children admitted in 2000-2005 and 66% (95% CI, 61.7-70) if admitted in 2006-2011 (log-rank test, p = 0.37). After adjusting for admission severity of illness using the Paediatric Index of Mortality 2 score, predictors for 5-year mortality included bone marrow transplant (hazard ratio, 3.66; 95% CI, 2.26-5.92) and single-ventricle physiology (hazard ratio, 1.98; 95% CI, 1.37-2.87). Five-year survival for single-ventricle physiology was 47.2% (95% CI, 34.3-59.1) and for bone marrow transplantation 22.8% (95% CI, 8.7-40.8). CONCLUSIONS: Two thirds of children with chronic critical illness survive for at-least 5 years, but there was no improvement between 2000 and 2011. Cardiac disease constitutes an increasing proportion of pediatric chronic critical illness. Bone marrow transplant recipients and single-ventricle physiology have the poorest outcomes.

Paediatric index of mortality 3: an updated model for predicting mortality in pediatric intensive care*.

OBJECTIVES: To provide an updated version of the Paediatric Index of Mortality 2 for assessing the risk of mortality among children admitted to an ICU. DESIGN: International, multicenter, prospective cohort study. SETTING: Sixty ICUs that accept pediatric admissions in Australia, New Zealand, Ireland, and the United Kingdom. PATIENTS: All children admitted in 2010 and 2011 younger than 18 years old at the time of admission and either died in ICU or were discharged. Patients who were transferred to another ICU were not included. Fifty-three thousand one hundred twelve patient admissions were included in the analysis. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: A revised prediction model was built using logistic regression. Variable selection was based on significance at the 95% level and overall improvement of the model's discriminatory performance and goodness of fit. The final model discriminated well (area under the curve, 0.88, 0.88-0.89); however, the model performed better in Australia and New Zealand than in the United Kingdom and Ireland (area under the curve was 0.91, 0.90-0.93 and 0.85, 0.84-0.86, respectively). CONCLUSIONS: Paediatric Index of Mortality 3 provides an international standard based on a large contemporary dataset for the comparison of risk-adjusted mortality among children admitted to intensive care.

Implications of Non-Specific Effects for Testing, Approving, and Regulating Vaccines.

The current framework for testing and regulating vaccines was established before the realization that vaccines, in addition to their effect against the vaccine-specific disease, may also have "non-specific effects" affecting the risk of unrelated diseases. Accumulating evidence from epidemiological studies shows that vaccines in some situations can affect all-cause mortality and morbidity in ways that are not explained by the prevention of the vaccine-targeted disease. Live attenuated vaccines have sometimes been associated with decreases in mortality and morbidity that are greater than anticipated. In contrast, some non-live vaccines have in certain contexts been associated with increases in all-cause mortality and morbidity. The non-specific effects are often greater for female than male individuals. Immunological studies have provided several mechanisms that explain how vaccines might modulate the immune response to unrelated pathogens, such as through trained innate immunity, emergency granulopoiesis, and heterologous T-cell immunity. These insights suggest that the framework for the testing, approving, and regulating vaccines needs to be updated to accommodate non-specific effects. Currently, non-specific effects are not routinely captured in phase I-III clinical trials or in the post-licensure safety surveillance. For instance, an infection with Streptococcus pneumoniae occurring months after a diphtheria-tetanus-pertussis vaccination would not be considered an effect of the vaccination, although evidence indicates it might well be for female individuals. Here, as a starting point for discussion, we propose a new framework that considers the non-specific effects of vaccines in both phase III trials and post-licensure.

Discordance Between Diagnosis Tools for Assessing Eczema in Infants: A Challenge for Intervention Trials.

BACKGROUND: There is no standardized definition for infant eczema, and various tools have been used across studies, precluding direct comparison. OBJECTIVE: The aim of the study was to assess and to compare the accuracy of diagnostic tools for infant eczema using the extensive data collected in Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR), an eczema prevention trial. METHODS: Eczema incidence was assessed by 3 questionnaire-based measures: modified UK diagnostic tool, parent-reported medically diagnosed eczema, and parent-reported use of topical corticosteroids. Agreement between the definitions was quantified using κ coefficient. Eczema severity was assessed by 3-monthly Patient-Oriented Eczema Measure (POEM) scores and a SCORing Atopic Dermatitis (SCORAD) clinical assessment at a 12-month visit (ClinicalTrial.gov: NCT01906853). RESULTS: Among the 538 participants fulfilling at least 1 of the 3 questionnaire-based eczema definitions, only 197 participants (37%) met all 3 definitions. Agreement between the definitions was poor with κ coefficients ranging from -0.11 to 0.62. The most frequently reported symptoms were generally dry skin (483/538, 90%) and pruritus (400/538, 74%). The face (352/538, 65%) and the trunk (306/538, 57%) were more frequently affected than the creases (257/538, 48%). Participants fulfilling all 3 questionnaire-based definitions of eczema were more likely to have higher severity scores and earlier onset of symptoms. CONCLUSIONS: There is poor agreement between currently available tools for assessing infant eczema.

Insulin infused at 0.05 versus 0.1 units/kg/hr in children admitted to intensive care with diabetic ketoacidosis.

OBJECTIVE: To compare the effects of infusing insulin at 0.05 units/kg/hr rather than 0.1 units/kg/hr in children admitted to the intensive care unit with diabetic ketoacidosis. DESIGN: A retrospective observational study. SETTING: A tertiary pediatric intensive care unit. PATIENTS: All children with diabetic ketoacidosis admitted during the 6-yr period from 2000 to 2005. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The effective plasma osmolality (plasma glucose concentration in mmol/L + twice the plasma sodium concentration in mmol/L), plasma glucose, plasma sodium, fluid intake, and acid-base status 12 hrs after the commencement of the insulin infusion. Compared to the 34 children who received 0.1 units/kg/hr of insulin, the 33 children who received 0.05 units/kg/hr of insulin were younger (median age, 25 mos vs. 62 mos, p = .024) and had a more gradual reduction in the effective plasma osmolality over the first 12 hrs (p < .0005); this was because plasma glucose decreased more slowly (p = .004) and plasma sodium increased faster (p < .0005). Both groups had a satisfactory improvement in acidosis and ketosis, and they had a similar length of stay in the intensive care unit. CONCLUSIONS: Further studies are needed to evaluate the role of using 0.05 units/kg/hr of insulin to treat children with diabetic ketoacidosis. The smaller dose of insulin may make it easier to lower the effective plasma osmolality gradually and might, therefore, reduce the risk of cerebral edema.

Rotating inotrope therapy in a pediatric population with decompensated heart failure.

OBJECTIVE: To describe the clinical course of a group of patients who received a rotating inotrope regimen, including levosimendan, for decompensated congestive heart failure. DESIGN: Case series. SETTING: Pediatric intensive care unit in a tertiary care children's hospital. PATIENTS: Nine pediatric patients with severe, decompensated heart failure. INTERVENTION: The study patients received a rotating inotrope regimen, including levosimendan, dobutamine, and, in some cases, milrinone. MEASUREMENTS AND MAIN RESULTS: Six patients were weaned from positive-pressure ventilation. Eight patients were discharged from the intensive care unit, and seven survived to hospital discharge. Two patients were successfully bridged to orthotopic cardiac transplantation. The therapies were generally well tolerated. CONCLUSIONS: Rotating inotropes were safe and seemed to be effective in this heterogeneous population of infants and children with decompensated heart failure. This therapeutic regimen warrants prospective comparative analysis.

Hospital-acquired complications in critically ill patients.

Background: The national hospital-acquired complications (HAC) system has been promoted as a method to identify health care errors that may be mitigated by clinical interventions. Objectives: To quantify the rate of HAC in multiday stay adults admitted to major hospitals. Design: Retrospective observational analysis of 5-year (July 2014 - June 2019) administrative dataset abstracted from medical records. Setting: All 47 hospitals with on-site intensive care units (ICUs) in the State of Victoria. Participants: All adults (aged ≥ 18 years) stratified into planned or unplanned, surgical or medical, ICU or other ward, and by hospital peer group (tertiary referral, metropolitan, regional). Main outcome measures: HAC rates in ICU compared with ward, and mixed-effects regression estimates of the association between HAC and i) risk of clinical deterioration, and ii) admission hospital site (intraclass correlation coefficient [ICC] > 0.3). Results: 211 120 adult ICU separations with mean hospital mortality of 7.3% (95% CI, 7.2-7.4%) reported 110 132 (42.6%) HAC events (commonly, delirium, infection, arrhythmia and respiratory failure) in 62 945 records (29.8%). Higher HAC rates were reported in elective (cardiac [50.3%] and non-cardiac [40.6%]) surgical subgroups compared with emergency medical subgroup (23.9%), and in tertiary (35.4%) compared with non-tertiary (22.7%) hospitals. HAC was strongly associated with on-admission patient characteristics (P < 0.001), but was weakly associated with hospital site (ICC, 0.08; 95% CI, 0.05-0.11). Conclusions: Critically ill patients have a high burden of HAC events, which appear to be associated with patient admission characteristics. HAC may an indicator of hospital admission complexity rather than hospital-acquired complications.

BCG vaccination to reduce the impact of COVID-19 in healthcare workers: Protocol for a randomised controlled trial (BRACE trial).

INTRODUCTION: BCG vaccination modulates immune responses to unrelated pathogens. This off-target effect could reduce the impact of emerging pathogens. As a readily available, inexpensive intervention that has a well-established safety profile, BCG is a good candidate for protecting healthcare workers (HCWs) and other vulnerable groups against COVID-19. METHODS AND ANALYSIS: This international multicentre phase III randomised controlled trial aims to determine if BCG vaccination reduces the incidence of symptomatic and severe COVID-19 at 6 months (co-primary outcomes) compared with no BCG vaccination. We plan to randomise 10 078 HCWs from Australia, The Netherlands, Spain, the UK and Brazil in a 1:1 ratio to BCG vaccination or no BCG (control group). The participants will be followed for 1 year with questionnaires and collection of blood samples. For any episode of illness, clinical details will be collected daily, and the participant will be tested for SARS-CoV-2 infection. The secondary objectives are to determine if BCG vaccination reduces the rate, incidence, and severity of any febrile or respiratory illness (including SARS-CoV-2), as well as work absenteeism. The safety of BCG vaccination in HCWs will also be evaluated. Immunological analyses will assess changes in the immune system following vaccination, and identify factors associated with susceptibility to or protection against SARS-CoV-2 and other infections. ETHICS AND DISSEMINATION: Ethical and governance approval will be obtained from participating sites. Results will be published in peer-reviewed open-access journals. The final cleaned and locked database will be deposited in a data sharing repository archiving system. TRIAL REGISTRATION: ClinicalTrials.gov NCT04327206.

The motor response to stimulation predicts outcome as well as the full Glasgow Coma Scale in children with severe head injury.

OBJECTIVES: To evaluate how well the full Glasgow Coma Scale and the motor response, which is a subscore of the Glasgow Coma Scale, predict the outcome in children who have sustained a traumatic brain injury. The best scores in the first 24 hrs were used. DESIGN: A retrospective observational study. SETTING: A pediatric intensive care unit. PATIENTS: Children admitted between January 1997 and December 1999. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Recovery with independent function (good outcome), or death, persistent coma, or dependent (bad outcome) at 6 months after the injury. Complete information was available for 130 patients. Both the full Glasgow Coma Scale and the motor response predicted outcome well: the area under the receiver operating characteristic plot was 0.88 (95% confidence interval, 0.82-0.95) for the full score and 0.89 (0.82-0.95) for the motor response. CONCLUSIONS: Both the full Glasgow Coma Scale score and the motor response provide a useful indication of long-term outcome, although neither score is sufficiently accurate to be used to limit treatment. The full Glasgow Coma Scale does not have a linear relationship with mortality, and there is poor interobserver agreement. The motor response should be used in children in preference to the full Glasgow Coma Scale; the predictive power is equivalent to the full Glasgow Coma Scale, there is a linear relationship to mortality, and it is easier to collect accurately.