The clinical and economic impact of cytomegalovirus infection in recipients of hematopoietic stem cell transplantation.

BACKGROUND: CMV infection (CMV-I) remains an important complication of hematopoietic stem cell transplantation (HSCT). METHODS: This was a retrospective, single-center cohort study in HSCT recipients. Primary outcomes were adjusted cost and all-cause mortality. Secondary analyses investigated CMV risk factors and the effect of serostatus. RESULTS: Overall, 690 transplant episodes were included (allogeneic [n = 310]; autologous [n = 380]). All received preemptive CMV antiviral therapy at first detectable DNAemia. CMV-I occurred in 34.8% of allogeneic and 2.1% of autologous transplants; median time to onset was 45 days. In allogeneic HSCT recipients, the primary risk factor for CMV-I was CMV donor/recipient (D/R) serostatus. In a Markov multi-state model for allogeneic HSCT recipients, the hazard ratio for CMV-I and relapse was 1.5 (95% CI 0.8-2.8) and for CMV-I and mortality 2.4 (95% CI 0.9-6.5). In a multivariable model for all patients, CMV-I was associated with increased total cost (coefficient = 0.21, estimated incremental daily cost USD $500; P = 0.02). Cost was attenuated in allogeneic HSCT recipients (coefficient = 0.13, USD $699 vs $613, or $24 892 per transplant episode; P = 0.23). CMV disease (CMV-D) complicated 29.6% of CMV-I events in allogeneic HSCT recipients, but was not associated with an incrementally increased adjusted risk of mortality compared with CMV-I alone. CMV-I (56.4%) and CMV-D (19.8%) were significantly overrepresented in D-/R+ serostatus HSCT recipients, and mortality was higher in R+ HSCT recipients. CONCLUSIONS: Despite early preemptive antiviral treatment, CMV-I impacts clinical outcomes and cost after HSCT, but the impact on cost is less pronounced in allogeneic HSCT recipients compared with autologous HSCT recipients.

Multidimensional biomarker predicts disease control in response to immunotherapy in recurrent or metastatic head and neck squamous-cell carcinoma.

PURPOSE: Anti-PD-1 therapy provides clinical benefit in 40-50% of patients with relapsed and/or metastatic head and neck squamous cell carcinoma (RM-HNSCC). Selection of anti- PD-1 therapy is typically based on patient PD-L1 immunohistochemistry (IHC) which has low specificity for predicting disease control. Therefore, there is a critical need for a clinical biomarker that will predict clinical benefit to anti-PD-1 treatment with high specificity. METHODS: Clinical treatment and outcomes data for 103 RM-HNSCC patients were paired with RNA-sequencing data from formalin-fixed patient samples. Using logistic regression methods, we developed a novel biomarker classifier based on expression patterns in the tumor immune microenvironment to predict disease control with monotherapy PD-1 inhibitors (pembrolizumab and nivolumab). The performance of the biomarker was internally validated using out-of-bag methods. RESULTS: The biomarker significantly predicted disease control (65% in predicted non-progressors vs. 17% in predicted progressors, p < 0.001) and was significantly correlated with overall survival (OS; p = 0.004). In addition, the biomarker outperformed PD-L1 IHC across numerous metrics including sensitivity (0.79 vs 0.64, respectively; p = 0.005) and specificity (0.70 vs 0.61, respectively; p = 0.009). CONCLUSION: This novel assay uses tumor immune microenvironment expression data to predict disease control and OS with high sensitivity and specificity in patients with RM-HNSCC treated with anti-PD-1 monotherapy.

Somnolence effects of antipsychotic medications and the risk of unintentional injury.

PURPOSE: This study examined the relationship between antipsychotic medications, categorized by published somnolence effects, and unintentional injury (UI). METHODS: The study population included patients of 18-64 years of age in a healthcare insurance database with claims from 2001 to 2004 and diagnoses of schizophrenia or affective disorder. A nested case-control design was used with cases defined by an E-code claim (a specified external cause of injury) for selected UIs. For cases, the index date referred to the first injury. For controls, the "control index date" was the date of claim if there was only a single medical claim; for patients with > or =2 claims, one was selected at random as the "control index date." Both groups had a prescription for a first-generation antipsychotic (FGA) or second-generation antipsychotic (SGA) overlapping the index date. Potential somnolence effects were defined as: low (referent)--aripiprazole/ziprasidone; medium--risperidone; high--olanzapine/quetiapine: or any single FGA. Logistic regression models were used to estimate odds ratio (OR) and 95% confidence interval (CI) for UI, adjusted for gender, age, concomitant drug, and psychiatric diagnosis. RESULTS: Among 648 cases and 5214 controls, high-somnolence SGAs were associated with an OR of 1.41 95%CI (1.03-1.93) for risk of UI, while medium-somnolence SGAs, and FGAs had ORs of 1.17 95%CI (0.83-1.64) and 1.17 95%CI (0.79-1.74), respectively. When quetiapine and olanzapine were disaggregated, ORs were 1.61 95%CI (1.15-2.25) and 1.25 95%CI (0.89-1.74), respectively. CONCLUSIONS: High-somnolence SGAs may lead to UI among patients. When prescribing antipsychotics, clinicians should consider potential somnolence.

Correlation of duodenal histology with tissue transglutaminase and endomysial antibody levels in pediatric celiac disease.

BACKGROUND & AIMS: IgA antibodies against tissue transglutaminase (TTGA) and endomysium (EMA) are sensitive and specific markers for celiac disease (CD). Data correlating TTGA and EMA levels with degree of villous atrophy are limited. We compared duodenal histopathology in pediatric CD patients with TTGA and EMA serologies, symptoms, height, and weight. METHODS: We identified 117 pediatric patients retrospectively who had serologic testing for IgA TTGA and IgA EMA and duodenal biopsies graded by modified Marsh criteria as 0-3c. Data were analyzed with Spearman rank correlation and multinomial logistic regression. RESULTS: IgA TTGA (r = .704, P < .001) and IgA EMA (r = 0.740, P < .001) correlated with intestinal villous atrophy in pediatric CD patients by Spearman rank correlation. Similar correlations were found in a subset of 23 patients younger than 3 years of age. Multinomial logistic regression revealed increased probability of Marsh 3a or greater changes with increasing TTGA or EMA levels. Strongly positive antibody levels (TTGA >100 units or EMA titer >1:1280) were highly specific (>98%) for Marsh 3a or greater lesions. Among symptoms, abdominal distention and diarrhea were associated with abnormal histology. CONCLUSIONS: IgA TTGA and EMA levels correlate with duodenal villous atrophy in pediatric CD patients. IgA TTGA >100 or EMA >1:1280 were nearly always associated with CD histopathology. With further validation of this observation, strongly positive titers might be considered sufficient for diagnosis of pediatric patients at risk for CD. Symptoms, height, and weight are not reliable predictors of CD.

Rheumatic chorea: relationship to systemic manifestations and response to corticosteroids.

OBJECTIVE: To describe Sydenham chorea among children in a cohort of patients with rheumatic fever (RF). STUDY DESIGN: An existing database was used to identify demographic characteristics, clinical manifestations, and therapy in persons with RF identified in Salt Lake City, Utah, from 1985 through January 2002. RESULTS: Of 584 cases in the database, 537 (91%) were new-onset RF (median age of 10 years) and 177 (33%) had chorea. Patients with chorea were more often female (OR = 0.37, 95% CI = 0.25-0.55, P < .0001) and were less likely to have carditis or arthritis. Prednisone treatment may lead to a shortened course of chorea (4.0 weeks in prednisone-treated [n = 32] vs 9.0 weeks in untreated [n = 14]; P < .0001). Among 33 patients seen at a median of 10.3 years (range 6.3-14.9 years) after their initial bout of chorea, 20% reported residual tremor or mood swings. Ten of the 33 (30%) had one or more recurrences of chorea. CONCLUSIONS: Chorea affected one-third of the children with RF. Patients with chorea were less likely to have severe cardiac or rheumatologic complications of RF. Therapy with prednisone shortened the duration of rheumatic chorea; some reported recurrences of chorea and had minor neurologic sequelae.

Unanswered questions prompted during pediatric primary care visits.

OBJECTIVES: To identify the frequency, types, and perceived importance of questions prompted during primary care visits for which pediatricians have no ready answer; to characterize pediatricians' responses to them; and to determine how questions prompted while caring for children with special health care needs (CSHCN) and children without special needs (Cw/oSN) differ. METHODS: Patient visits with 35 general pediatricians were observed. Parents completed a CSHCN screener. Physicians provided details about their unanswered questions and their pursuit of answers. RESULTS: Of 890 observed visits, 170 (19.1%) prompted unanswered questions, of which 60.1% were deemed important or very important. Physicians intended to pursue answers to 49.7% of the questions but actually pursued answers for only 27.5%, citing lack of time and inadequate information resources as barriers. One hundred sixty-seven (18.8%) visits were with CSHCN. Unanswered questions arose more often with CSHCN than with Cw/oSN (28.7% vs 16.9%; odds ratio 1.98; 95% confidence interval, 1.32-2.97), particularly during well visits (34.6% vs 14.9%; odds ratio 3.24; 95% confidence interval, 1.59-6.39). CSHCN prompted more diagnosis and treatment questions than Cw/oSN. Questions prompted by CSHCN were ranked as more important but were no more likely to be pursued than those prompted by Cw/oSN. CONCLUSIONS: Unanswered questions arise during nearly 20% of pediatric primary care visits. Visits with CSHCN, particularly well visits, generate more questions than those with Cw/oSN. Answers are pursued for few unanswered questions, both overall and for CSHCN. Potential strategies to overcome barriers to answering questions include scheduling more time or more visits for CSHCN.

Prehospital intranasal midazolam for the treatment of pediatric seizures.

BACKGROUND: The local emergency medical services (EMS) council implemented a new pediatric treatment protocol using a Mucosal Atomization Device (MAD) to deliver intranasal (IN) midazolam for seizure activity. METHODS: We sought to compare outcomes in seizing pediatric patients treated with IN midazolam using a MAD (IN-MAD midazolam) to those treated with rectal (PR) diazepam, 18 months before and after the implementation of the protocol. RESULTS: Of 857 seizure patients brought by EMS to our emergency department (ED), 124 patients (14%) had seizure activity in the presence of EMS and were eligible for inclusion in this study. Of the 124 patients eligible for this study, 67 patients (54%) received no medications in the prehospital setting, 39 patients (32%) were treated with IN-MAD midazolam, and 18 patients (15%) were treated with PR diazepam. Median seizure time noted by EMS was 19 minutes longer for PR diazepam (30 minutes) when compared with IN-MAD midazolam (11 minutes, P = 0.003). Patients treated with PR diazepam in the prehospital setting were significantly more likely to have a seizure in the ED (odds ratio [OR], 8.4; confidence interval [CI], 1.6-43.7), ED intubation (OR, 12.2; CI, 2.0-75.4), seizure medications in the ED to treat ongoing seizure activity (OR, 12.1; CI, 2.2-67.8), admission to the hospital (OR, 29.3; CI, 3.0-288.6), and admission to the pediatric intensive care unit (OR, 53.5; CI, 2.7-1046.8). CONCLUSIONS: The IN-MAD midazolam controlled seizures better than PR diazepam in the prehospital setting and resulted in fewer respiratory complications and fewer admissions.

Pediatric closed head injuries treated in an observation unit.

BACKGROUND: Closed head injury (CHI) is common in childhood and frequently results in hospital admission for observation and treatment. Observation units (OUs) have shown significant benefits for patients and physicians. At our institution, a level 1 pediatric trauma center, patients with CHI are often admitted to an OU for up to 24 hours of observation and treatment. STUDY OBJECTIVES: To describe characteristics of patients with a CHI admitted to a pediatric OU and to identify demographic, historical, clinical, and radiographic factors associated with the need for unplanned inpatient admission (UIA) after OU management. METHODS: Retrospective cohort review of all OU admissions for CHI at Primary Children's Medical Center (PCMC) from August 1999 through July 2001. Data collected included age, gender, mechanism of injury, presenting symptoms, physical examination findings, head computed tomography (CT) results, diagnosis, length of stay, outcome of the injury, and need for UIA. RESULTS: During the study period, 827 patients were seen in the ED for CHI. Two hundred eighty-five patients (34%) were admitted to the OU, 273 (33%) were admitted to an inpatient service, and 269 (33%) were discharged home. OU patients had a median age of 5.2 years, ranging from 2 weeks to 17 years. Sixty-one percent were male. The median admission length of stay was 13 hours. Common mechanisms of injury included: falls (60%), motor vehicle accidents (12%), bicycle accidents (10%), impacts from objects (9%), auto-pedestrian accidents (4.6%), and snow-related accidents (4.6%). Presenting symptoms in the ED included vomiting (39%), loss of consciousness (26%), amnesia to event (19%), persistent amnesia (5%), and seizures (4%). Physical examination findings noted in the ED included altered mental status (45%), facial abnormalities (43%), scalp abnormalities (38%), and neurologic deficits (9%). Two hundred eighty patients (98%) admitted to the OU had a head CT performed. Skull fractures were present in 109 patients (39%) and intracranial pathology (ie, epidural hematoma, subdural hematoma, or intraparenchymal contusion) was present in 38 patients (13%). Only 13 patients (5%) required admission to an inpatient service from the OU for the following reasons: continued need for intravenous (IV) fluids (n = 5), venous thrombosis (n = 2), persistent CSF leakage (n = 3), decreased level of consciousness (n = 1), pain management (n = 1), and clearing of the patient's cervical spine (n = 1). No patient deteriorated or required neurosurgery. Patients with basilar skull fractures, a head laceration (scalp or facial), and patients that needed IV fluids in the ED were more likely to need inpatient admission after a 24-hour observation stay. Logistic regression analysis identified basilar skull fractures (OR 11.61), face/scalp lacerations (OR 7.52), and the need for ED IV fluid administration (OR 4.26) to be associated with UIA. Most children with these findings were successfully discharged within 24 hours, however. Age, sex, loss of consciousness, seizure, vomiting, amnesia, altered mental status, neurologic deficits, intracranial pathology, and skull fractures (aside from basilar skull fractures) were not related to UIA. CONCLUSION: The vast majority (96%) of pediatric OU patients with CHI such as small intracranial hematomas, skull fractures, and concussions were discharged safely within 24 hours without serious complications. The presence of a basilar skull fracture, head laceration, and the need for ED IV fluids were associated with increased risk of UIA. OU admission is an efficient and effective management setting for children with stable intracranial pathology, skull fractures, and concussions.

Children with asthma admitted to a pediatric observation unit.

OBJECTIVE: Observation units (OUs) serve patients who require more evaluation or treatment than possible during an emergency department visit and who are anticipated to stay in the hospital for a short defined period. Asthma is a common admission diagnosis in a pediatric OU. Our main objective was to identify clinical factors associated with failure to discharge a child with asthma from our OU within 24 hours. METHODS: Retrospective chart review at a tertiary care children's hospital. Participants were children 2 years or older with asthma admitted from the emergency department to the OU during August 1999 to August 2001. The OU-discharged group comprised those successfully discharged from the OU within 24 hours. The unplanned inpatient admission group comprised those subsequently admitted from the OU to a traditional inpatient ward or those readmitted to the hospital within 48 hours of OU discharge. RESULTS: One hundred sixty-one children aged 2 to 20 years (median 4.0; 63% boys) met inclusion criteria; 40 patients (25%) required unplanned inpatient admission. In a multiple logistic regression model, 3 factors were associated with need for unplanned inpatient admission: female sex (adjusted odds ratio, 2.6; 95% confidence interval, 1.1-6.4; P = 0.03), temperature 38.5 degrees C or higher (adjusted odds ratio, 6.1; 95% confidence interval, 1.6-23.5; P < 0.01), and need for supplemental oxygen at the end of emergency department management (adjusted odds ratio, 5; 95% confidence interval, 1.7-15.1; P < 0.01). CONCLUSIONS: Many children with asthma can be admitted to a pediatric OU and discharged safely within 24 hours. Prospective studies are needed to confirm our findings and to identify other factors predictive of unplanned inpatient admission.

Molecular characterization of Streptococcus pyogenes isolates collected during periods of increased acute rheumatic fever activity in Utah.

BACKGROUND: Salt Lake City, Utah has seen a continuing resurgence of rheumatic fever (RF) since 1985. METHODS: emm genotyping and multilocus sequence typing of streptococcal isolates from periods of increased RF activity were performed. RESULTS: Multiple genotypes were present during 1985 and 1998, two peak years of RF activity, and in 1992, a year with reduced RF activity. emm3 and emm18.1 were present in 1985 and 1998, but not in 1992. Two other emm types, 12 and L28, were significantly elevated in 1998 (a peak RF year) over 1992 (a non-peak RF year). Allelic profiles for the emm3 and emm18.1 isolates exhibited clonality. CONCLUSIONS: During years of increased RF activity multiple emm types, including emm18.1 and emm3, were circulating in the community. During a year of decreased RF activity, emm3 and emm18.1 genotypes were absent. The clonality of the emm3 and emm18.1 types suggests that specific clones of both types are important in the resurgence of RF during these peak years. Two other genotypes, emm12 and emmL28, may also be associated with the persistence of RF in the Salt Lake City, UT area.

Evidence of increased bone resorption in neurofibromatosis type 1 using urinary pyridinium crosslink analysis.

Although neurofibromatosis type 1 (NF1) is a neurocutaneous disorder, skeletal abnormalities such as long-bone dysplasia, scoliosis, sphenoid wing dysplasia, and osteopenia are observed. To investigate the role of bone resorption as a mechanism for the bony abnormalities, we selected urinary pyridinium crosslinks (collagen degradation products excreted in urine) as a measure of bone resorption in NF1. Bone resorption was evaluated by quantitative assessment of the urinary excretion of pyridinium crosslinks [pyridinoline (Pyd) and deoxypyridinoline (Dpd)]. Total (free plus peptide-bound) pyridinium crosslinks from the first morning urines from 59 NF1 children (ages 5-19) were extracted and analyzed (17 children with a localized skeletal dysplasia, and 42 without). The data were compared with a healthy reference population without NF1 (n = 99). Multivariate analyses, controlling for age showed statistically significant increases for Dpd (p < 0.001) and the Dpd/Pyd ratio (p < 0.001) in NF1 individuals with and without a skeletal dysplasia. NF1 children have an increase in the urinary excretion of pyridinium crosslinks, reflecting increased bone resorption. The effects of NF1 haploinsufficiency likely contribute to abnormal bone remodeling, either directly or indirectly by aberrant Ras signaling, potentially predisposing NF1 individuals to localized skeletal defects.

Evaluation of an innovative pediatric clerkship structure using multiple outcome variables including career choice.

BACKGROUND: Few studies have examined alternative structures for inpatient clerkships. OBJECTIVE: Compare 2 inpatient clerkship structures using multiple outcome variables. DESIGN: Prospective, randomized controlled trial. SETTING: Tertiary-care, freestanding children's hospital. SUBJECTS: All medical students enrolled in the third-year pediatric clerkship in the 2001-2003 academic years. INTERVENTION: A clerkship structure consisting of an academic attending, a third-year pediatric resident, and 4 third-year medical students, but no interns. MEASUREMENTS: Student end-of-rotation examinations, evaluations, a questionnaire, and career choices were used to evaluate the intervention. Patient logs and resource utilization were also assessed. Statistical analysis included evaluating differences between groups and measuring effect size. RESULTS: Two hundred and three students were randomized. Compared with those on the traditional services, students on the intervention service encountered more key diagnoses in the patients they cared for (4.4 vs. 3.6, P < .01). These students also gave higher ratings to their overall attitude (4.48 vs. 4.26, P = .02) and input into patient care decisions (4.45 vs. 3.98, P < .01). More than twice as many students on the intervention service matched in pediatrics (OR 2.52, 95% confidence interval 0.99-6.38). Multivariate analysis of length of stay and total charges for selected patients revealed similar outcomes. CONCLUSIONS: A third-year pediatric clerkship that focuses on students is associated with increased satisfaction, higher interest in pediatrics, and consistent resource utilization. The intervention, therefore, merits continuation, whereas further research is required to identify which aspects of the intervention are responsible for its positive effects.

The prevalence of driveway back-over injuries in the era of sports utility vehicles.

BACKGROUND: Small children are vulnerable to serious accidents when a motor vehicle is placed in motion in a driveway. We describe a series of such accidents, consider the predisposing factors, and analyze the outcomes. METHODS: We conducted a retrospective review of the trauma database of a large, level I, freestanding children's hospital with specific attention to driveway auto-pedestrian accidents. RESULTS: During an 8-year period, 495 children were treated for injuries sustained in auto-pedestrian accidents, with 128 occurring in the driveway. The children's median age was 2.9 years, with 54% of the injuries sustained by boys. These often serious accidents carried an overall mortality rate of 6%. The most common injuries were abrasions, blunt head injury, and fractures. Chest trauma was associated with the highest mortality (11%), and both chest and abdominal trauma had the highest median Injury Severity Score of 13. Orthopedic injuries were the most common reason for operative intervention. Thirty-one percent of the children required intensive care unit monitoring, with their average unit stay being 3.9 days. Cars, trucks, and sports utility vehicles comprised 55%, 25%, and 12% of the accidents, respectively. Truck accidents carried the highest mortality rate (19%). Accidents were more likely to occur between 3:00 and 8:00 pm, between Thursday and Saturday, and between May and October. An increasing number of accidents occurred during the last 4 years of the study. CONCLUSIONS: Driveway injuries are an underrecognized often severe form of auto-pedestrian accidents. To prevent these family tragedies, drivers of large vehicles with children younger than 12 years old should be extremely attentive and account for children outside the vehicle before moving.

CT scan and the pediatric trauma patient--are we overdoing it?

BACKGROUND: Recent literature expresses concern for an increased risk of cancer in children exposed to low-dose radiation during computed tomography (CT). In response, children's hospitals have implemented the ALARA (as low as reasonably achievable) concept, but this is not true at most adult referring institutions. The purpose of this study was to assess the diagnostic necessity of CT in the evaluation of pediatric trauma patients. METHODS: A retrospective review was conducted of the trauma database at a large, level I, freestanding children's hospital with specific attention to the pattern of CT evaluations. RESULTS: From January 1999 to October 2003, 1,653 children with traumatic injuries were evaluated by the trauma team, with 1,422 patients undergoing 2,361 CT scans. Overall, 54% of obtained scans were interpreted as normal. Fifty percent of treated patients were transferred from referring hospitals. Approximately half arrived with previous CT scans with 9% of these requiring further imaging. Of the 897 patients that underwent abdominal CT imaging, only 2% were taken to the operating room for an exploratory laparotomy. In addition, of those patients who had abnormal findings on an abdominal CT scan, only 5% underwent surgical exploration. CONCLUSIONS: CT scans are used with regularity in the initial evaluation of the pediatric trauma patient, and perhaps abdominal CT imaging is being used too frequently. A substantial number of these scans come from referral institutions that may not comply with ALARA. The purported risk of CT radiation questions whether a more selective approach to CT evaluation of the trauma patient should be considered.