HLA-B*07:02 and HLA-C*07:02 are associated with trimethoprim-sulfamethoxazole respiratory failure.

We have identified an underrecognized severe adverse drug reaction (ADR) of trimethoprim-sulfamethoxazole (TMP-SMX) associated respiratory failure in previously healthy children and young adults. We investigated potential genetic risk factors associated with TMP-SMX induced respiratory failure in a cohort of seven patients. We explored whole genome sequence among seven patients representing nearly half of all reported cases worldwide and 63 unrelated control individuals in two stages: (1) human leukocyte antigen (HLA) locus variation as several other ADRs have been associated HLA genetic variants and (2) coding variation to catalog and explore potential rare variants contributing to this devastating reaction. All cases were either heterozygous (carriers) or homozygous for the common HLA-B*07:02-HLA-C*07:02 haplotype. Despite the small sample size, this observation is statistically significant both in conservative comparison to maximum reported population frequencies (binomial P = 0.00017 for HLA-B and P = 0.00028 for HLA-C) and to our control population assessed by same HLA genotyping approach (binomial P = 0.000001 for HLA-B and P = 0.000018 for HLA-C). No gene elsewhere in the genome harnessed shared rare case enriched coding variation. Our results suggests that HLA-B*07:02 and HLA-C*07:02 are necessary for a patient to develop respiratory failure due to TMP-SMX.

Simulation-Based System Analysis: Testing Preparedness for Extracorporeal Membrane Oxygenation Cannulation in Pediatric COVID-19 Patients.

INTRODUCTION: Coronavirus Disease-2019 presents risk to both patients and medical teams. Staff-intensive, complex procedures such as extracorporeal membrane oxygenation (ECMO) or extracorporeal cardiopulmonary resuscitation (eCPR) may increase chances of exposure and spread. This investigation aimed to rapidly deploy an in situ Simulation-based Clinical Systems Testing (SbCST) framework to identify Latent Safety Threats (LSTs) related to ECMO/eCPR initiation during a pandemic. METHODS: The adapted SbCST framework tested systems related to ECMO/eCPR initiation in the Neonatal and Pediatric Intensive Care Units. Systems were evaluated in six domains (Resources, Processes/Systems, Facilities, Clinical Performance, Infection Control, and Communication). We conducted three high-fidelity simulations with members from the Neonatal Intensive Care Unit General Surgery, Pediatric Intensive Care Unit Cardiovascular Surgery (CV), and Pediatric Intensive Care Unit General Surgery teams. Content experts evaluated systems issues during simulation, and LSTs were identified during debriefing. Data were analyzed for frequency of LSTs and trends in process gaps. RESULTS: Sixty-six LSTs were identified across three scenarios. Resource issues comprised the largest category (26%), followed by Process/System issues (24%), Infection Control issues (24%), Communication issues (17%), and Facility and Clinical Performance issues (5% each). LSTs informed new team strategies such as the use of a "door/PPE monitor" and "inside/outside" team configuration. CONCLUSIONS: The adapted SbCST framework identified multiple LSTs related to ECMO/eCPR cannulation and infection control guidelines in the setting of Coronavirus Disease-2019. Through SbCSTs, we developed guidelines to conserve PPE and develop optimal workflows to reduce patient/staff exposure in a high-risk procedure. This project may guide other hospitals to adapt SbCSTs strategies to test/adjust rapidly changing guidelines.

Implementation and Maintenance of a Pediatric Severe Burn Guidelines Quality Improvement Project.

Introduction: Critically injured pediatric burn patients require specialized management, yet few verified pediatric burn centers exist in the United States. Many pediatric hospitals have resources to care for severely burned patients but lack standardized care guidelines, which improve outcomes. To improve the morbidity and mortality of severely burned pediatric patients admitted to the pediatric intensive care unit, we created a specialized burn team. We implemented Pediatric Severe Burn Guidelines, focusing on improving fluid resuscitation accuracy and providing timely nutritional support. Methods: This investigation is of a 9-year (2010-2019) retrospective preintervention and postintervention study of the effect of the formation of a multidisciplinary burn leadership committee and development and implementation of Pediatric Severe Burn Guidelines. The primary outcome measures are increasing the accuracy of fluid resuscitation and improving the timely administration of nutritional support. The process measure is the percentage of time the electronic health record power plan was used for burn admissions with burn leadership review of the cases. Balancing measures are pediatric intensive care unit and hospital length of stay. Results: Preprotocol patients received acceptable fluid resuscitation 25% (5/20) of the time compared to 61.5% (8/13) of the time in postprotocol patients (P = 0.04). In postprotocol patients, there is an improvement in the timely placement of postpyloric feeding tube and initiation of feeds 48 hours after admission. Conclusions: Extensive guidelines for standardized care require careful implementation and monitoring of adherence gaps. Creating a specialized burn team and implementing clinical guidelines standardize care leading to improvement in critical patient outcomes.

Extracorporeal Membrane Oxygenation as a Bridge to Chimeric Antigen Receptor T-cell Therapy for Severe Refractory Sepsis in the Setting of Relapsed Refractory Pediatric Acute Lymphoblastic Leukemia: A Case Report.

Pediatric oncology patients with sepsis are at higher risk of morbidity and mortality compared with pediatric patients without malignancy. Historically, patients with relapsed and/or refractory disease were not considered candidates for aggressive life support strategies including extracorporeal membrane oxygenation support. CASE SUMMARY: We report a 4-year-old female with relapsed refractory pre-B cell acute lymphoblastic leukemia preparing for chimeric antigen receptor T cell therapy with tisagenlecleucel who was admitted with fever and neutropenia. She progressed to refractory septic shock secondary to Escherichia coli bacteremia and required escalation of hemodynamic support to venoarterial extracorporeal membrane oxygenation cannulation. She cleared her E. coli bacteremia, was decannulated, subsequently received her chimeric antigen receptor T-cell therapy, and was declared disease free 1 month from her initial presentation. CONCLUSION: The ability to provide chimeric antigen receptor T-cell therapy at designated institutions can augment extracorporeal membrane oxygenation candidacy discussions in oncology patients with relapsed disease and may make extracorporeal membrane oxygenation candidacy for oncology patients with refractory sepsis more favorable.

Severe Acute Respiratory Failure in Healthy Adolescents Exposed to Trimethoprim-Sulfamethoxazole.

Pulmonary toxicity induced by trimethoprim-sulfamethoxazole (TMP-SMX) has been described, although the disease process is poorly understood. We report 5 previously healthy adolescent patients who developed acute respiratory failure while taking TMP-SMX. Four of the 5 adolescents required extracorporeal membrane oxygenation support, and 2 of the teenagers died. All children required a tracheostomy, and all cases were complicated by pneumothoraces and pneumomediastinum. The majority of children were prescribed TMP-SMX for the treatment of acne vulgaris.

Clinical Course of Enterovirus D68 in Hospitalized Children.

BACKGROUND: Enterovirus D68 (EV-D68) has been sporadically reported as a cause of respiratory tract infections. In 2014, an international outbreak of EV-D68 occurred and caused severe respiratory disease in the pediatric population. METHODS: A retrospective chart review was performed of children admitted to Children's Mercy Hospital from August 1, 2014, to September 15, 2014, with positive multiplex polymerase chain reaction testing for EV/rhinovirus (RV). Specimens were subsequently tested for EV-D68, and clinical data were obtained from the medical records. Patients with EV-D68 were compared with children presenting simultaneously with other EV/RV. RESULTS: Of 542 eligible specimens, children with EV-D68 were significantly older than children with other EV/RV (4.6 vs. 2.2 years, P < 0.001). Children with EV-D68 were more likely to have a history of asthma (38.6% vs. 30.0%, P = 0.04) or recurrent wheezing (22.1% vs. 14.8%, P = 0.04). EV-D68-positive children more commonly received supplemental oxygen (86.7% vs. 65.0%, P < 0.001), albuterol (91.2% vs. 65.5%, P < 0.001) and corticosteroids (82.9% vs. 58.6%, P < 0.001). Age ≥5 years was an independent risk factor for intensive care unit management in EV-D68-infected children. Children with a history of asthma or recurrent wheezing and EV-D68 received supplemental oxygen (92.7% vs. 82.4%, P = 0.007) and magnesium (42.7% vs. 29.7%, P = 0.03) at higher rates and more continuous albuterol (3 vs. 2 hours, P = 0.03) than those with other EV/RV. CONCLUSIONS: EV-D68 causes severe disease in the pediatric population, particularly in children with a history of asthma or recurrent wheezing. EV-D68-positive children are more likely to require therapy for refractory bronchospasm and may need intensive care unit- level care.

Continuing Medical Education for Air Medical Providers: The Successes and Challenges.

OBJECTIVE: Research has shown that patients transported by nonpediatric teams have higher rates of morbidity and mortality. There is currently a paucity of pediatric standardized ongoing medical education for emergency medical service providers, thus we aimed to develop a model curriculum to increase their knowledge regarding pediatric respiratory distress and failure. METHODS: The curriculum was based on the Kolb Learning Cycle to optimize learning. Target learners were flight nurses (registered nurse) and emergency medical technicians of a private helicopter emergency transport team. The topics included were pediatric stridor, wheezing, and respiratory failure. Online modules were developed for continued spaced education. Knowledge gained from the interventions was measured by precurricular and postcurricular testing and compared with paired t tests. A linear mixed regression model was used to investigate covariates of interest. RESULTS: Sixty-two learners attended the workshop. Fifty-nine learners completed both precurricular and postcurricular testing. The mean increase between pretest and posttest scores was 12.1% (95% confidence interval, 9.4, 14.8; P < 0.001). Type of licensure (private emergency medical technician vs registered nurse) and number of years experience had no association with the level of knowledge gained. Learners who had greater than 1 year of pediatric transport experience scored higher on their pretests. There was no significant retention shown by those who participated in spaced education. CONCLUSIONS: The curriculum was associated with a short term increased knowledge regarding pediatric respiratory distress and failure for emergency helicopter transport providers and could be used as an alternative model to develop standardized ongoing medical education in pediatrics. Further work is needed to achieve knowledge retention in this learner population.

Severe enterovirus 68 respiratory illness in children requiring intensive care management.

BACKGROUND: Enterovirus 68 (EV-D68) causes acute respiratory tract illness in epidemic cycles, most recently in Fall 2014, but clinical characteristics of severe disease are not well reported. OBJECTIVES: Children with EV-D68 severe respiratory disease requiring pediatric intensive care unit (PICU) management were compared with children with severe respiratory disease from other enteroviruses/rhinoviruses. STUDY DESIGN: A retrospective review was performed of all children admitted to Children's Mercy Hospital PICU from August 1-September 15, 2014 with positive PCR testing for enterovirus/rhinovirus. Specimens were subsequently tested for the presence of EV-D68. We evaluated baseline characteristics, symptomatology, lab values, therapeutics, and outcomes of children with EV-D68 viral infection compared with enterovirus/rhinovirus-positive, EV-D68-negative children. RESULTS: A total of 86 children with positive enterovirus/rhinovirus testing associated with respiratory symptoms were admitted to the PICU. Children with EV-D68 were older than their EV-D68-negative counterparts (7.1 vs. 3.5 years, P=0.01). They were more likely to have a history of asthma or recurrent wheeze (68% vs. 42%, P=0.03) and to present with cough (90% vs. 63%, P=0.009). EV-D68 children were significantly more likely to receive albuterol (95% vs. 79%, P=0.04), magnesium (75% vs. 42%, P=0.004), and aminophylline (25% vs. 4%, P=0.03). Other adjunctive medications used in EV-D68 children included corticosteroids, epinephrine, and heliox; 44% of EV-D68-positive children required non-invasive ventilatory support. CONCLUSIONS: EV-D68 causes severe disease in the pediatric population, particularly in children with asthma and recurrent wheeze; children may require multiple adjunctive respiratory therapies.