Michael Peck

IL-13 R130Q, a common variant associated with allergy and asthma, enhances effector mechanisms essential for human allergic inflammation

Genetic factors are known to strongly influence susceptibility to allergic inflammation. The Th2 cytokine IL-13 is a central mediator of allergy and asthma, and common single-nucleotide polymorphisms in IL13 are associated with allergic phenotypes in several ethnically diverse populations. In particular, IL13+2044GA is expected to result in the nonconservative replacement of arginine 130 (R130) with glutamine (Q). We examined the impact of IL13+2044GA on the functional properties of IL-13 by directly comparing the activity of WT IL-13 and IL-13 R130Q on primary human cells involved in the effector mechanisms of allergic inflammation. Our results show that IL-13 R130Q was significantly more active than WT IL-13 in inducing STAT6 phosphorylation and CD23 expression in monocytes and hydrocortisone-dependent IgE switching in B cells. Notably, IL-13 R130Q was neutralized less effectively than WT IL-13 by an IL-13R2 decoy. Decreased neutralization of the minor variant could contribute to its enhanced in vivo activity. Neither IL-13 variant was able to engage T cells, which suggests that increased allergic inflammation in carriers of IL13+2044A depends on enhanced IL-13-mediated Th2 effector functions rather than increased Th2 differentiation. Collectively, our data indicate that natural variation in the coding region of IL13 may be an important genetic determinant of susceptibility to allergy.

Th1/Th2 Patterns and Balance in Cytokine Production in the Parents and Infants of a Large Birth Cohort

Regulation of human immune cell cytokine production in vivo is not well understood due in part to limitations on imposing experimental conditions. We proposed that life-imposed conditions (pregnancy, birth, age, gender), combined with large sample size, repeat sampling, and family-based recruitment would serve to reveal peripheral blood cell-derived cytokine patterns reflective of in vivo regulation regarding Th1/Th2 balance and familial correlation. Mononuclear cells were obtained from 483 trios in the Tucson Infant Immune Study: from mothers pre- and postpartum, infants at birth and at 3 mo, and fathers. Con A/PMA-stimulated supernatants were assayed by ELISA for IFN-γ, IL-4, IL-13, IL-5, and IL-10 and allergen-stimulated supernatants for IFN-γ, IL-4, and IL-13. Mitogen-stimulated prepartum samples were not globally Th2 biased, differing from postpartum only by a modestly reduced IFN-γ:IL-5 ratio. Prepartum samples actually produced less IL-10 and IL-13 although more IL-5 than paternal samples. Newborns were also not globally Th2 biased, with mitogen stimulation producing ∼10-fold less IL-4, IL-5, and IFN-γ than adults but only 2- to 3-fold less IL-13 and IL-10. Despite these group differences, all cytokines showed marked positive intraindividual correlations (all p < 0.001). Allergen stimulation gave results consistent with a lack of global Th2 bias. Mitogen stimulation revealed parent-child and parent-parent correlations. Thus, rather than a global Th2 bias, cytokine production in pregnant mothers and newborns appears regulated so as to maintain a relative balance among the cytokines, with the nature of the balance differing in mothers and infants and with production influenced by familial factors that include shared environment.

Benchmarks for multidimensional recovery after burn injury in young adults: The development, validation, and testing of the american burn association/shriners hospitals for children young adult burn outcome questionnaire

Although data exist on burn survival, there are little data on long-term burn recovery. Patient-centered health outcomes are useful in monitoring and predicting recovery and evaluating treatments. An outcome questionnaire for young adult burn survivors was developed and tested. This 5-year (2003–2008) prospective, controlled, multicenter study included burned and nonburned adults ages 19 to 30 years. The Young Adult Burn Outcome Questionnaires were completed at initial contact, 10 days, and 6 and 12 months. Factor analysis established construct validity. Reliability assessments used Cronbach &agr; and test-retest. Recovery patterns were investigated using generalized linear models, with generalized estimating equations using mixed models and random effects. Burned (n = 153) and nonburned subjects (n = 112) completed 620 questionnaires (47 items). Time from injury to first questionnaire administration was 157 ± 36 days (mean ± SEM). Factor analysis included 15 factors: Physical Function, Fine Motor Function, Pain, Itch, Social Function Limited by Physical Function, Perceived Appearance, Social Function Limited by Appearance, Sexual Function, Emotion, Family Function, Family Concern, Satisfaction With Symptom Relief, Satisfaction With Role, Work Reintegration, and Religion. Cronbach &agr; ranged from 0.72 to 0.92, with 11 scales >0.8. Test-retest reliability ranged from 0.29 to 0.94, suggesting changes in underlying health status after burns. Recovery curves in five domains, Itch, Perceived Appearance, Social Function Limited by Appearance, Family Concern, and Satisfaction with Symptom Relief, remained below the reference group at 24 months. The Young Adult Burn Outcome Questionnaire is a reliable and valid instrument for multidimensional functional outcomes assessment. Recovery in some domains was incomplete.

The correlation between burn mortality rates from fire and flame and economic status of countries

INTRODUCTION Over 95% of burn deaths occur in low- and middle-income countries globally. However, the association between burn mortality rates and economic health has not been evaluated for individual countries. This study seeks to answer the question, how strong is the correlation between burn mortality and national indices of economic strength? METHODS A retrospective review was performed for 189 countries during 2008-2010 using economic data from the World Bank as well as mortality data from the World Health Organization (WHO). Countries were categorized into four groups based on income level according to stratification by the World Bank: low income, lower middle income, upper middle income, and high income. The Pearson correlation coefficient was used to estimate presence and strength of association among death rates, Gini coefficient (measure of inequality of distribution of wealth), gross domestic product (GDP) per capita, and gross national index (GNI) per capita. RESULTS Statistically significant associations (p<0.05) were found between burn mortality and GDP per capita (r=-0.26), GNI per capita (r=-0.36), and Gini (r=+0.17). CONCLUSIONS A nations income level is negatively correlated with burn mortality; the lower the income level, the higher the burn mortality rates. The degree to which income within a country is equitably or inequitably distributed also correlates with burn mortality. SIGNIFICANCE Both governmental and non-governmental organizations need to focus on preventing burns in low-income countries, as well as in other countries in which there is marked disparity of income.

Assault by burning in Dhaka, Bangladesh

Assault by burning in Dhaka, Bangladesh, occurs in a variety of forms, resulting from various causes and motives. A total of 311 cases of intentional burns from the Burn Unit of Dhaka Medical College Hospital from April 2004 to May 2011 (6 years) were studied by retrospective and prospective observational review. The majority of victims (68%) were female. Concentrated sulphuric acid was the most commonly used chemical for attack. Disfigurement was the principal complication (mortality, 4%). Dowry-related issues, divorce and other marital quarrels were frequent backgrounds for assault by burning. Kerosene oil was used to ignite 78 girls or young women, most often related to conflicts over dowry (mortality 97%). A total of 102 victims (32%) in all burn groups were attacked because of dowry-related issues. Intentional contact burns were often inflicted on domestic servants. Although physical morbidity and mortality were not reported in contact and other types of burns, psychological disturbances were reported in all victims. A few victims had been assaulted prior to receiving burns, and fractures and deformities were also present on examination at the time of presentation for burn treatment. Ophthalmic injury, with frequent visual impairment, was very common in cases of chemical attack. Legal and social support for victims and their families are frequently inadequate to compensate for losses. Clearly, more attention in our community should be focussed on the prevention of burn assaults, adequate compensation and medical care for victims, as well as speedy retribution for perpetrators.

The design and evaluation of a system for improved surveillance and prevention programmes in resource-limited settings using a hospital-based burn injury questionnaire

Background Limited and fragmented data collection systems exist for burn injury. A global registry may lead to better injury estimates and identify risk factors. A collaborative effort involving the WHO, the Global Alliance for Clean Cookstoves, the CDC and the International Society for Burn Injuries was undertaken to simplify and standardise inpatient burn data collection. An expert panel of epidemiologists and burn care practitioners advised on the development of a new Global Burn Registry (GBR) form and online data entry system that can be expected to be used in resource-abundant or resource-limited settings. Methods International burn organisations, the CDC and the WHO solicited burn centre participation to pilot test the GBR system. The WHO and the CDC led a webinar tutorial for system implementation. Results During an 8-month period, 52 hospitals in 30 countries enrolled in the pilot and were provided the GBR instrument, guidance and a data visualisation tool. Evaluations were received from 29 hospitals (56%). Key findings Median time to upload completed forms was <10 min; physicians most commonly entered data (64%), followed by nurses (25%); layout, clarity, accuracy and relevance were all rated high; and a vast majority (85%) considered the GBR ‘highly valuable’ for prioritising, developing and monitoring burn prevention programmes. Conclusions The GBR was shown to be simple, flexible and acceptable to users. Enhanced regional and global understanding of burn epidemiology may help prioritise the selection, development and testing of primary prevention interventions for burns in resource-limited settings.

Transfusion Requirement in Burn Care Evaluation (TRIBE): A Multicenter Randomized Prospective Trial of Blood Transfusion in Major Burn Injury

Objective: Our objective was to compare outcomes of a restrictive to a liberal red cell transfusion strategy in 20% or more total body surface area (TBSA) burn patients. We hypothesized that the restrictive group would have less blood stream infection (BSI), organ dysfunction, and mortality. Background: Patients with major burns have major (>1 blood volume) transfusion requirements. Studies suggest that a restrictive blood transfusion strategy is equivalent to a liberal strategy. However, major burn injury is precluded from these studies. The optimal transfusion strategy in major burn injury is thus needed but remains unknown. Methods: This prospective randomized multicenter trial block randomized patients to a restrictive (hemoglobin 7–8 g/dL) or liberal (hemoglobin 10–11 g/dL) transfusion strategy throughout hospitalization. Data collected included demographics, infections, transfusions, and outcomes. Results: Eighteen burn centers enrolled 345 patients with 20% or more TBSA burn similar in age, TBSA burn, and inhalation injury. A total of 7054 units blood were transfused. The restrictive group received fewer blood transfusions: mean 20.3 ± 32.7 units, median = 8 (interquartile range: 3, 24) versus mean 31.8 ± 44.3 units, median = 16 (interquartile range: 7, 40) in the liberal group (P < 0.0001, Wilcoxon rank sum). BSI incidence, organ dysfunction, ventilator days, and time to wound healing (P > 0.05) were similar. In addition, there was no 30-day mortality difference: 9.5% restrictive versus 8.5% liberal (P = 0.892, &khgr;2 test). Conclusions: A restrictive transfusion strategy halved blood product utilization. Although the restrictive strategy did not decrease BSI, mortality, or organ dysfunction in major burn injury, these outcomes were no worse than the liberal strategy (Clinicaltrials.gov identifier NCT01079247).

Respiratory burn injuries: An overview

Respiratory burns are caused by the aspiration of heated gases or toxic products of incomplete combustion. The extent of damage is determined by the temperature of the inhaled gases, their composition and the duration of exposure. Along with age and size of full-thickness burn injury, the presence of respiratory burns is one of the most powerful predictors of poor outcome in patients admitted to burn centers. There are three types of respiratory burns: (a) Inhalation of systemic asphyxiants such as carbon monoxide. (b) Thermal damage to airway above vocal cords. (c) Injury to tracheobronchial tree and pulmonary parenchyma by inhaled toxicants. The goals of initial management of the airway and breathing are to protect the patency of the airway to prevent suffocation and to ensure adequate ventilation and oxygenation. High levels of inspired oxygen are necessary to treat carbon monoxide poisoning. Intubation and mechanical ventilator support with low tidal volumes is required to treat subglottic respiratory burns. Because there are no known antidotes to the poisonous effects of inhaled smoke, treatment of respiratory burns is protective and supportive.

Restrictive Transfusion Strategy Is More Effective in Massive Burns: Results of the TRIBE Multicenter Prospective Randomized Trial

OBJECTIVES Studies suggest that a restrictive transfusion strategy is safe in burns, yet the efficacy of a restrictive transfusion policy in massive burn injury is uncertain. Our objective: compare outcomes between massive burn (≥60% total body surface area (TBSA) burn) and major (20-59% TBSA) burn using a restrictive or a liberal blood transfusion strategy. METHODS Patients with burns ≥20% were block randomized by age and TBSA to a restrictive (transfuse hemoglobin <7 g/dL) or liberal (transfuse hemoglobin <10 g/dL) strategy throughout hospitalization. Data collected included demographics, infections, transfusions, and outcomes. RESULTS Three hundred and forty-five patients received 7,054 units blood, 2,886 in massive and 4,168 in restrictive. Patients were similar in age, TBSA, and inhalation injury. The restrictive group received less blood (45.57 ± 47.63 vs. 77.16 ± 55.0, p < 0.03 massive; 11.0 ± 16.70 vs. 16.78 ± 17.39, p < 0.001) major). In massive burn, the restrictive group had fewer ventilator days (p < 0.05). Median ICU days and LOS were lower in the restrictive group; wound healing, mortality, and infection did not differ. No significant outcome differences occurred in the major (20-59%) group (p > 0.05). CONCLUSIONS A restrictive transfusion strategy may be beneficial in massive burns in reducing ventilator days, ICU days and blood utilization, but does not decrease infection, mortality, hospital LOS or wound healing.

102 A system for improved burn injury surveillance in resource-limited settings

Background There are limited and fragmented data collection systems for burn injury. A global repository may lead to better burn injury estimates and help identify key risk factors. A collaborative effort involving the World Health Organisation (WHO), the Global Alliance for Clean Cookstoves, the U.S. Centres for Disease Control and Prevention (CDC), and the International Society for Burn Injuries was undertaken to simplify and standardise in-patient burn data collection. Utilising an expert panel of epidemiologists and burn care practitioners, a new form and online data entry system was developed which can be used in resource-abundant or resource-limited settings. The Global Burn Registry (GBR) form has three functions: 1) to determine the magnitude and risk factors for burns, 2) provide baseline and follow up data to test primary prevention interventions, and 3) be designed for use without modification around the world. Methods After development, international burn organisations, CDC and WHO solicited burn centre participation to pilot test the GBR system. WHO and CDC led a webinar to describe system implementation. Results During an 8 month period, 55 hospitals in 29 countries enrolled in the pilot and were provided the GBR instrument, guidance, and data visualisation tool. Evaluations were received from 29 hospitals (53%). Key findings were: median time to upload completed forms was less than 10 minutes; physicians most commonly entered data (64%), followed by nurses (25%); layout, clarity, accuracy, and relevance were all rated high; and a vast majority (85%) considered the GBR “highly valuable” for prioritising, developing, and monitoring burn prevention programs. Conclusions The GBR was shown to be simple, flexible, and acceptable to users. Enhanced regional and global understanding of burn epidemiology may help prioritise the selection, development, and testing of primary prevention interventions for burns in resource-limited settings.