Kelly B. Flett

Hand, foot, and mouth disease caused by coxsackievirus a6.

To the Editor: Coxsackievirus A6 (CVA6) is a human enterovirus associated with herpangina in infants. In the winter of 2012, we evaluated a cluster of 8 patients, 4 months–3 years of age, who were brought for treatment at Boston Children’s Hospital (Boston, MA, USA) with a variant of hand, foot, and mouth disease (HFMD) that has now been linked to CVA6 (Table). During this same period, the Boston Public Health Commission’s syndromic surveillance system detected a 3.3-fold increase in emergency department discharge diagnoses of HFMD. In the United States, HFMD typically occurs in the summer and early autumn and is characterized by a febrile enanthem of oral ulcers and macular or vesicular lesions on the palms and soles; the etiologic agents are most often CVA16 and enterovirus 71. Table Demographic and clinical characteristics of patients with CVA6-associated HFMD, Boston, Massachusetts, USA, 2012* In contrast to the typical manifestation, the patients in the Boston cluster exhibited symptoms in late winter (Table) and had perioral (Figure, panel A) and perirectal (Figure, panel B) papules and vesicles on the dorsal aspects of the hands and feet (Figure, panel C). Patients experienced a prodrome lasting 1–3 days, consisting of fever (8 patients), upper respiratory tract symptoms (4 patients), and irritability (7 patients). This prodrome was followed by the development of a perioral papular rash (8 patients), which was often impetiginized with secondary crusting; a prominent papulovesicular rash on the dorsum of the hands and feet (6 patients); and a perirectal eruption (7 patients). Half of the patients had intraoral lesions. Fever abated in most of the patients within a day after onset of the exanthem. The rash resolved over 7–14 days with no residual scarring. Samples from the oropharynx, rectum, and vesicles from these patients were sent to the Centers for Disease Control and Prevention (Atlanta, GA, USA) for analysis. Reverse transcription PCR and sequencing by using primers specific for a portion of the viral protein 1 coding region identified CVA6 (1) (Table). Figure Manifestations of hand, foot, and mouth disease in patients, Boston, Massachusetts, USA, 2012. Discrete superficial crusted erosions and vesicles symmetrically distributed in the perioral region (A), in the perianal region (B), and on the dorsum of the ... Outbreaks of HFMD caused by CVA6 have been described in Singapore, Finland, Taiwan, and most recently in Japan; most cases have occurred in the warmer months (2–6). Cases in the cluster described here are likely related to an emerging outbreak of CVA6-associated HFMD in the United States (7). The atypical seasonality of the outbreak, during the winter in Boston, could be related to the unusually mild temperatures in the winter of 2012. Recent CVA6 outbreaks have been characterized by a febrile illness associated with an oral enanthem and lesions on the palms, soles, and buttocks. CVA6 infections in Taiwan during 2004–2009 were associated with HFMD in 13% of cases, with disease defined as oral ulcers on the tongue or buccal mucosa and vesicular rashes on the palms, soles, knees, or buttocks (2). In Singapore, where CVA6 accounted for 24% of HFMD cases, patients had oral lesions and <5 peripheral papules, placing them on a spectrum closer to the herpangina more typically observed in CVA6 infection (8). The patients we report in this cluster most typically had perioral and perirectal papules in addition to vesicles on the dorsum of their hands. Two reports of CVA6-associated HFMD outbreaks describe cases that more closely resemble patients in the Boston outbreak. In a series from Finland in 2008, representative patients had both perioral lesions and vesicles on the dorsum of their hands (6). In a large series of patients with HFMD in Taiwan in 2010, patients with CVA6 had perioral lesions in addition to an enanthem (3). Outbreaks of CVA6-associated HFMD in Finland, Taiwan, and Japan were associated with onychomadesis, with the loss of nails occurring 1–2 months after initial symptoms (3,4,6). The association between more typical HFMD and onychomadesis has additionally been described in the United States and Europe but without a link to specific serotype or with a small percentage of CVA6-associated cases (9). Cases from the Boston epidemic may fit into an emerging clinical phenotype of CVA6, and it will be interesting to see whether nail loss develops in those patients. Given the numerous CVA6 outbreaks in multiple countries in 2008 and a US population that may be relatively naive to this serotype, CVA6 is likely to spread throughout North America. Clinicians should be aware that, although standard precautions are routinely recommended for managing enteroviral infections in health care settings, contact precautions are indicated for children in diapers to control institutional outbreaks (10). In addition, the presence of perioral lesions and peripheral vesicles on the dorsum rather than palmar/plantar surface of the hands and feet represents a unique phenotype of HFMD that could be confused with herpes simplex or varicella-zoster virus infections. Because of the atypical presentation of CVA6-associated HFMD, clinical vigilance is needed to recognize emerging regional outbreaks. More detailed epidemiologic and genetic analyses will be required to characterize the role of CVA6 in US outbreaks of HFMD.

Genetic variation of a bacterial pathogen within individuals with cystic fibrosis provides a record of selective pressures

Advances in sequencing technologies have enabled the identification of mutations acquired by bacterial pathogens during infection. However, it remains unclear whether adaptive mutations fix in the population or lead to pathogen diversification within the patient. Here we study the genotypic diversity of Burkholderia dolosa within individuals with cystic fibrosis by resequencing individual colonies and whole populations from single sputum samples. We find extensive intrasample diversity, suggesting that mutations rarely fix in a patients pathogen population—instead, diversifying lineages coexist for many years. Under strong selection, multiple adaptive mutations arise, but none of these sweep to fixation, generating lasting allele diversity that provides a recorded signature of past selection. Genes involved in outer-membrane components, iron scavenging and antibiotic resistance all showed this signature of within-patient selection. These results offer a general and rapid approach for identifying the selective pressures acting on a pathogen in individual patients based on single clinical samples.

Outpatient Course and Complications Associated With Home Oxygen Therapy for Mild Bronchiolitis

BACKGROUND: Home oxygen has been incorporated into the emergency department management of bronchiolitis in high-altitude settings. However, the outpatient course on oxygen therapy and factors associated with subsequent admission have not been fully defined. METHODS: We conducted a retrospective cohort study in consecutive patients discharged on home oxygen from the pediatric emergency department at Denver Health Medical Center from 2003 to 2009. The integration of inpatient and outpatient care at our study institution allowed comprehensive assessment of follow-up rates, outpatient visits, time on oxygen, and subsequent admission. Admitted and nonadmitted patients were compared by using a χ2 test and multivariable logistic regression. RESULTS: We identified 234 unique visits with adequate follow-up for inclusion. The median age was 10 months (interquartile range [IQR]: 7–14 months). Eighty-three percent of patients were followed up within 24 hours and 94% within 48 hours. The median length of oxygen use was 6 days (IQR: 4–9 days), and the median number of associated encounters was 3 (range: 0–9; IQR: 2–3). Ninety-three percent of patients were on room air at 14 days. Twenty-two patients (9.4%) required subsequent admission. Fever at the initial visit (>38.0°C) was associated with admission (P < .02) but had a positive predictive value of 15.4%. Age, prematurity, respiratory rate, oxygen saturation, and history of previous bronchiolitis or wheeze were not associated with admission. CONCLUSIONS: There is a significant outpatient burden associated with home oxygen use. Although fever was associated with admission, we were unable to identify predictors that could modify current protocols.

Global and local selection acting on the pathogen Stenotrophomonas maltophilia in the human lung.

Bacterial populations diversify during infection into distinct subpopulations that coexist within the human body. Yet, it is unknown to what extent subpopulations adapt to location-specific selective pressures as they migrate and evolve across space. Here we identify bacterial genes under local and global selection by testing for spatial co-occurrence of adaptive mutations. We sequence 552 genomes of the pathogen Stenotrophomonas maltophilia across 23 sites of the lungs from a patient with cystic fibrosis. We show that although genetically close isolates colocalize in space, distant lineages with distinct phenotypes separated by adaptive mutations spread throughout the lung, suggesting global selective pressures. Yet, for one gene (a distant homologue of the merC gene implicated in metal resistance), mutations arising independently in two lineages colocalize in space, providing evidence for location-specific selection. Our work presents a general framework for understanding how selection acts upon a pathogen that colonizes and evolves across the complex environment of the human body.

Impact of Mandatory Public Reporting of Central Line–Associated Bloodstream Infections on Blood Culture and Antibiotic Utilization in Pediatric and Neonatal Intensive Care Units

BACKGROUND As mandatory public reporting of healthcare-associated infections increases, there is concern that clinicians could attempt to decrease rates by avoiding the diagnosis of reportable infections. OBJECTIVE To determine whether blood culture and antibiotic utilization changed after mandatory public reporting of central line-associated bloodstream infection (CLABSI). DESIGN Interrupted time-series of blood culture and antibiotic rates before and after state-specific implementation of mandatory public reporting. We analyzed data from pediatric and neonatal intensive care units (ICUs) at 17 childrens hospitals that contributed to the Pediatric Health Information System administrative database. We used multivariable regression with generalized linear mixed-effects models to determine adjusted rate ratios (ARRs) after implementation of mandatory public reporting. We conducted subgroup analysis on patients with central venous catheters. To assess temporal trends, we separately analyzed data from 4 pediatric hospitals in states without mandatory public reporting. RESULTS There was no significant effect of mandatory public reporting on rates of blood culture (pediatric ICU ARR, 1.03 [95% CI, 0.82-1.28]; neonatal ICU ARR, 1.06 [0.85-1.33]) or antibiotic utilization (pediatric ICU ARR, 0.86 [0.72-1.04]; neonatal ICU ARR, 1.09 [0.87-1.35]). Results were similar in the subgroup of patients with central venous catheter codes. Hospitals with and without mandatory public reporting experienced small decreases in blood culture and antibiotic use across the study period. CONCLUSIONS Mandatory public reporting of central line-associated bloodstream infection did not impact blood culture and antibiotic utilization, suggesting that clinicians have not shifted their practice in an attempt to detect fewer infections.

Long-Term Outcomes and Risk Factors Associated With Acute Encephalitis in Children

Background Factors associated with poor outcomes of children with encephalitis are not well known. We sought to determine whether electroencephalography (EEG) findings, magnetic resonance imaging (MRI) abnormalities, or the presence of seizures at presentation were associated with poor outcomes. Methods A retrospective review of patients aged 0 to 21 years who met criteria for a diagnosis of encephalitis admitted between 2000 and 2010 was conducted. Parents of eligible children were contacted and completed 2 questionnaires that assessed current physical and emotional quality of life and neurological deficits at least 1 year after discharge. Results During the study period, we identified 142 patients with an International Classification of Diseases 9th Revision diagnosis of meningitis, meningoencephalitis, or encephalitis. Of these patients, 114 met criteria for a diagnosis of encephalitis, and 76 of these patients (representing 77 hospitalizations) had complete data available. Forty-nine (64%) patients were available for follow-up. Patients admitted to the intensive care unit were more likely to have abnormal EEG results (P = .001). The presence of seizures on admission was associated with ongoing seizure disorder at follow-up. One or more years after hospitalization, 78% of the patients had persistent symptoms, including 35% with seizures. Four (5%) of the patients died. Abnormal MRI findings and the number of abnormal findings on initial presentation were associated with lower quality-of-life scores. Conclusions Encephalitis leads to significant morbidity and death, and incomplete recovery is achieved in the majority of hospitalized patients. Abnormal EEG results were found more frequently in critically ill children, patients with abnormal MRI results had lower quality-of-life scores on follow-up, and the presence of seizures on admission was associated with ongoing seizure disorder and lower physical quality-of-life scores.

Multicenter Study of the Risk Factors for Colonization or Infection with Carbapenem-Resistant Enterobacteriaceae in Children

ABSTRACT Carbapenem-resistant Enterobacteriaceae (CRE) are increasingly identified in children in the United States, but data on the epidemiology of CRE in this population are limited. The objectives of this study were to characterize the risk factors for colonization or infection with CRE and describe the microbiologic characteristics of pediatric CRE isolates. We performed a multicenter matched case-control study from January 2011 to October 2015 at three tertiary care pediatric centers. Case patients were hospitalized children with CRE isolated from clinical cultures and were matched in a 2:1 ratio to control patients with carbapenem-susceptible Enterobacteriaceae (CSE). Risk factors for colonization or infection with CRE were then evaluated using a multivariable conditional logistic regression. Additionally, we comprehensively reported the antimicrobial susceptibility pattern for CRE isolates. Sixty-three case patients were identified and matched to 126 control patients. On multivariable analysis, antipseudomonal antibiotic exposure within the previous 3 months (odds ratio [OR], 5.20; 95% confidence interval [CI], 1.71 to 15.9; P = 0.004), prior surgery (OR, 6.30; 95% CI, 1.83 to 21.6; P = 0.003), and mechanical ventilation (OR, 12.4; 95% CI, 1.26 to 122; P = 0.031) were identified as risk factors for colonization or infection with CRE. Pediatric CRE isolates demonstrated relatively low rates of resistance to amikacin (5%) and ciprofloxacin (25%). Our findings support an important role for antibiotic stewardship interventions limiting the unnecessary use of antipseudomonal antibiotics as a strategy to prevent widespread emergence of CRE in children. Future studies should further characterize molecular determinants of antibiotic resistance among pediatric CRE isolates.

Variability in the Diagnosis of Encephalitis by Pediatric Subspecialists: The Need For a Uniform Definition

Research definitions of encephalitis vary widely. When surveyed on the criteria used in clinical diagnosis, 88 pediatric specialists demonstrated diverse responses, with pediatric neurologists and pediatric infectious disease specialists differing significantly in their consideration of cerebrospinal fluid pleocytosis and abnormal neuroimaging. Results emphasize the need for a uniform definition.

Increased 30-Day Mortality Associated With Carbapenem-Resistant Enterobacteriaceae in Children.

Abstract In this multicenter study, we identified an increased risk of 30-day mortality among hospitalized children with carbapenem-resistant Enterobacteriaceae (CRE) isolated from clinical cultures compared with those with carbapenem-susceptible Enterobacteriaceae. We additionally report significant variation in antibiotic treatment for children with CRE infections with infrequent use of combination therapy.

Reducing Redundant Anaerobic Therapy Through Spaced Education and Antimicrobial Stewardship Interventions

Background Decreasing the use of redundant anaerobic therapy is a key target for antimicrobial stewardship. Education techniques that optimize knowledge retention could be an important component of reducing these regimens. Methods We implemented a quality improvement project that incorporated spaced education to reduce the use of redundant anaerobic therapy. The initial interventions (November through December 2015) included education in a hospital-wide newsletter and review of redundant anaerobic regimens by the antimicrobial stewardship program. A spaced education module was then developed with the gastroenterology (GI) service, which had a relatively high rate of redundant anaerobic therapy use. Ten questions with teaching points were delivered to GI physicians at spaced intervals over 2 to 4 weeks (February through March 2016). Knowledge scores were compared at initial and final question presentation using generalized estimating equations. Interrupted time-series analysis was used to compare the rates of redundant-metronidazole-days per 1000 patient-days among patients in the patients admitted to the GI service and those in the non-GI group before and after the intervention. Results Of 66 GI physicians, 56 (85%) participated in the spaced education activity. After the intervention, their knowledge scores on all the questions improved, and their mean knowledge score increased from 57% to 86% (P < .001). Nearly all (91%) of the participants were very or generally satisfied with the activity. In the GI group, the rate of redundant-metronidazole-days decreased from 26.2 to 13.0 per 1000 patient-days (relative risk [RR], 0.45 [95% confidence interval (CI), 0.27-0.73]; P = .001). This rate in the non-GI group also decreased from 5.47 to 2.18 per 1000 patient-days (RR, 0.47 [95% CI, 0.36-0.60]; P < .001) after our interventions. Conclusions Spaced education is an effective approach for teaching antimicrobial stewardship topics. Focused provider education was associated with a sustained reduction in the use of redundant anaerobic therapy.