Showing papers in "Journal of the Pediatric Infectious Diseases Society in 2017"

Epidemiology of Invasive Fungal Disease in Children.

Abstract: Considerable progress has been made in the prevention, diagnosis, and management of pediatric patients with invasive fungal disease (IFD). The reported decreasing trend in the incidence of invasive candidiasis (IC) over the past 15 years in both neonates and children has been encouraging. Nevertheless, due to the growing number of immunocompromised children at risk for IFD, this disease continues to be associated with significant morbidity and death and with increased financial burden to the health care system. Therefore, it is important to understand the contemporary epidemiology of IFD. Incidence rates of IFD in children are affected by geographical, population, and time variability. There is an ongoing effort to constantly document and update the incidence of IFD and species distribution among different pediatric populations as a means to direct preventative, diagnostic, and therapeutic resources to the most appropriate subset of patients. Children with a hematologic malignancy or a primary or secondary immunodeficiency, those undergoing solid organ or hematopoietic stem cell transplantation, and premature neonates are the major subsets of pediatric patients at risk of developing IFD. In this review, we focus on fungal disease epidemiology with a specific emphasis on the 2 most common pediatric IFDs, IC and invasive aspergillosis (IA).

Determinants and Impact of Giardia Infection in the First 2 Years of Life in the MAL-ED Birth Cohort.

Abstract: Background. Giardia are among the most common enteropathogens detected in children in low-resource settings. We describe here the epidemiology of infection with Giardia in the first 2 years of life in the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED), a multisite birth-cohort study. Methods. From 2089 children, 34916 stool samples collected during monthly surveillance and episodes of diarrhea were tested for Giardia using an enzyme immunoassay. We quantified the risk of Giardia detection, identified risk factors, and assessed the associations with micronutrients, markers of gut inflammation and permeability, diarrhea, and growth using multivariable linear regression. Results. The incidence of at least 1 Giardia detection varied according to site (range, 37.7%-96.4%) and was higher in the second year of life. Exclusive breastfeeding (HR for first Giardia detection in a monthly surveillance stool sample, 0.46 [95% confidence interval (CI), 0.28-0.75]), higher socioeconomic status (HR, 0.74 [95% CI, 0.56-0.97]), and recent metronidazole treatment (risk ratio for any surveillance stool detection, 0.69 [95% CI, 0.56-0.84]) were protective. Persistence of Giardia (consecutive detections) in the first 6 months of life was associated with reduced subsequent diarrheal rates in Naushahro Feroze, Pakistan but not at any other site. Giardia detection was also associated with an increased lactulose/mannitol ratio. Persistence of Giardia before 6 months of age was associated with a -0.29 (95% CI, -0.53 to -0.05) deficit in weight-for-age z score and -0.29 (95% CI, -0.64 to 0.07) deficit in length-for-age z score at 2 years. Conclusions. Infection with Giardia occurred across epidemiological contexts, and repeated detections in 40% of the children suggest that persistent infections were common. Early persistent infection with Giardia, independent of diarrhea, might contribute to intestinal permeability and stunted growth.

Neurobrucellosis: Unexpected Answer From Metagenomic Next-Generation Sequencing.

Abstract: A diagnosis of brucellosis can be difficult because routine culture and serological methods exhibit variable sensitivity and specificity. We present the use of a metagenomic next- generation sequencing assay to diagnose a case of neurobrucellosis from cerebrospinal fluid, resulting in the institution of appropriate antibiotic treatment and a favorable clinical outcome.

Role of Molecular Biomarkers in the Diagnosis of Invasive Fungal Diseases in Children

Abstract: Invasive fungal diseases are important clinical problems that are often complicated by severe illness and therefore the inability to use invasive measures to definitively diagnose the disease. Tests for a range of fungal biomarkers that do not require an invasive sample-collection procedure have been incorporated into adult clinical practice, but pediatric data and pediatric-specific recommendations for some of these diagnostic tools are lacking. In this review, we summarize the published literature and contemporary strategies for using the biomarkers galactomannan, (1→3)-β-d-glucan, Candida mannan antigen and anti-mannan antibody, and fungal polymerase chain reaction for diagnosing invasive fungal disease in children. Data on biomarker use in neonates and children with cancer, history of hematopoietic stem cell transplant, or primary immunodeficiency are included. Fungal biomarker tests performed on blood, other body fluids, or tissue specimens represent promising adjuncts to the diagnostic armamentarium in populations with a high prevalence of invasive fungal disease, but substantial gaps exist in the correct use and interpretation of these diagnostic tools in pediatric patients.

Diagnostic Imaging and Invasive Fungal Diseases in Children.

Abstract: Invasive fungal disease (IFD) is a life-threatening condition, especially in immunocompromised children. The role of diagnostic imaging in children at risk for an IFD is multifactorial, including initially detecting it, evaluating for dissemination of infection beyond the primary site of disease, monitoring the response to antifungal therapy, and assessing for potential relapse. The objective of this review was to synthesize the published literature relevant to the use of various imaging modalities for the diagnosis and management of IFD in children.

Prospective Longitudinal Analysis of Immune Responses in Pediatric Subjects After Pharyngeal Acquisition of Group A Streptococci.

Abstract: Background. Despite the significant burden of disease associated with infection by group A streptococcus (GAS), little is known about the human immune response to GAS antigens after natural infection. Methods. We evaluated 195 serum samples obtained prospectively over a consecutive 24-month period from 41 pediatric subjects who experienced a new pharyngeal GAS acquisition. An enzyme-linked immunoassay was used to determine the kinetics and antigen specificity of antibodies against 13 shared GAS antigens and 18 type-specific M peptides. The majority of the antigens tested are currently being considered as vaccine candidates. Results. Twelve M types of GAS were recovered from 41 subjects who experienced 51 new GAS acquisitions that elicited antibody responses against at least 1 of the 31 antigens tested (immunologically significant new GAS acquisitions). The immune responses to the 13 shared antigens were highly variable. Increases in antibody levels were detected against a mean of 3.5 shared antigens (range, 1-8). Antibody responses to the homologous M peptide were observed in 32 (63%) of the 51 episodes. Seven subjects acquired more than 1 M type of GAS. There were no new immunologically significant acquisitions of an M type against which the subject had preexisting antibodies to the homologous M peptide. Of the subjects with new GAS acquisition, 65% were asymptomatic, yet immune responses were detected against 1 or more GAS antigens. Immune responses to streptolysin O and/or deoxyribonuclease B were observed after 67% of the new GAS acquisitions. Persistently positive (>12 weeks) throat culture results were returned for 20% of the 41 subjects despite immune responses to homologous M peptides and/or shared antigens. Conclusions. The availability of throat culture results, GAS isolates, and serial serum samples collected prospectively over a 2-year period of observation provided a unique opportunity for us to assess the serologic status of pediatric subjects before and after new pharyngeal acquisitions of GAS. With the exception of antibody responses to the homologous M peptides, no clear pattern of immune responses against the remaining GAS antigens was seen. There were no new immunologically significant acquisitions of emm types of GAS against which the subjects had preexisting elevated levels of antibodies against the homologous M peptide. The observation that 65% of new GAS acquisitions caused no symptoms yet were immunologically significant suggests that the majority of infections are not detected, which would result in missed opportunities for primary prevention of rheumatic fever and rheumatic heart disease with appropriate antimicrobial therapy.

Recognition and Clinical Presentation of Invasive Fungal Disease in Neonates and Children

Abstract: Invasive fungal diseases (IFDs) are devastating opportunistic infections that result in significant morbidity and death in a broad range of pediatric patients, particularly those with a compromised immune system. Recognizing them can be difficult, because nonspecific clinical signs and symptoms or isolated fever are frequently the only presenting features. Therefore, a high index of clinical suspicion is necessary in patients at increased risk of IFD, which requires knowledge of the pediatric patient population at risk, additional predisposing factors within this population, and the clinical signs and symptoms of IFD. With this review, we aim to summarize current knowledge regarding the recognition and clinical presentation of IFD in neonates and children.

High Reported Rates of Antimicrobial Resistance in Indian Neonatal and Pediatric Blood Stream Infections

Abstract: Background.: There is real shortage of national data on antimicrobial resistance rates in Indian neonates and children. A descriptive review was conducted to determine the patterns of antimicrobial resistance in isolates of blood stream infection among hospitalized children in India. Methods.: Published and gray literature on antibiotic resistance in children was searched using "Google Scholar", "Scopus", and "PubMed" databases between January 2000 and July 2015. Studies were included if they were original articles that reported a minimum of 10 pathogenic bacterial isolates from the bloodstream within a pediatric population in India, and studies were excluded if they reported studies done during an outbreak or epidemic. Results.: A total of 1179 studies were screened, and 82 papers were identified as eligible for inclusion. Most studies (78.7%) were reported from neonatal intensive care units. Among a total of 50545 reported blood cultures, 14704 (29.1%) were positive. Staphylococcus aureus (median, 14.7%; IQR, 7.4%-25.6%) and Klebsiella pneumoniae (median, 26%; IQR, 16.7%-35.4%) were the commonest reported Gram-positive and Gram-negative pathogens, respectively. Approximately half of all S aureus isolates were reported as methicillin-resistant S aureus (median, 50%; IQR, 31.4%-65.1%). After age stratification, the median rate of resistance of common Gram-negative pathogens to ampicillin and gentamicin/amikacin were extremely high (K pneumoniae/ampicillin 95.9%; K pneumoniae/gentamicin 75%; Escherichia coli/ampicillin 92.9%; E coli/gentamicin 55.6%). Likewise, the median resistance of common Gram-negative blood stream isolates to cephalosporins were also high (K pneumoniae/cefotaxime 62.6%; E coli/cefotaxime 47.5%). Conclusions.: High rates of resistance to World Health Organization-recommended first-line treatment options for neonates and children have been identified in blood stream infections across India. There is an urgent need to both enhance antibiotic stewardship and infection prevention and control measures and consider urgently how to repurpose older antibiotics back into routine care in India.

Clinical Care Guideline for Improving Pediatric Acute Musculoskeletal Infection Outcomes

Abstract: Background Acute pediatric musculoskeletal infections are common, leading to significant use of resources and antimicrobial exposure. In order to decrease variability and improve the quality of care, Children's Hospital Colorado implemented a clinical care guideline (CCG) for these infections. The purpose of this study is to evaluate clinical and resource outcomes PRE and POST this CCG. Methods Retrospective chart review evaluated patients admitted to a large pediatric quaternary referral center (CHCO) diagnosed with acute osteomyelitis, septic arthritis, pyomyositis, and/or musculoskeletal abscess prior to and after guideline implementation. Primary outcomes included length of stay and overall antibiotic use, with additional secondary clinical, process, and therapeutic outcomes examined. Results 82 patients were identified in both the pre-CCG and post-CCG cohorts. There was a reduction in the median of all primary outcomes, including length of stay (0.6 median days decrease, P = .04), length of IV antibiotic therapy (4.9 median days decrease, P < .0001), and days of IV antibiotic therapy (6.4 median days decrease, P = .0004). Our median length of stay post-CCG was 4.9 days, the shortest reported length of stay for pediatric acute musculoskeletal infections to date. Additionally, there was a 24.5 hour reduction in median length of fever (P = .02), faster CRP normalization (P < .0001), 50% decrease in the number of related readmissions (P = .02), 34% decrease in central venous catheters placed (P < .0001), decreased time to first culture (P = .02), and 79% pathogen identification post-CCG (P = .056). Conclusions Implementation of a CCG for acute musculoskeletal infections improves patient, process and resource outcomes.

Renal Toxicity in Pediatric Patients Receiving Cidofovir for the Treatment of Adenovirus Infection

Abstract: Treatment options for adenovirus infection in immunocompromised children are limited. Nephrotoxicity has been associated with cidofovir use, but the rate of cidofovir-associated nephrotoxicity in pediatric patients is unclear. In a retrospective review of patients with adenovirus infection treated with cidofovir, neonates (n = 5) had higher viral loads and shorter times to renal insufficiency than older children (n = 24). Higher weekly doses of cidofovir were associated with greater increases in creatinine levels. Of 29 courses of cidofovir, 9 were complicated by acute kidney injury; in these children, mortality was high. Cidofovir dosing in children needs to be optimized, and other therapeutic alternatives should be developed.

Rule-Out Outbreak: 24-Hour Metagenomic Next-Generation Sequencing for Characterizing Respiratory Virus Source for Infection Prevention.

Abstract: Background. Metagenomic next-generation sequencing (mNGS) has been used to uncover unusual causes of infectious diseases but has not been used routinely for the investigation of putative nosocomial outbreaks. Here, we describe the use of mNGS during investigation of a cluster of human rhinovirus (HRV)-positive infections on a high-risk pulmonary ward. Methods. We performed mNGS on 6 midnasal turbinate swabs from 4 case-patients and 10 swabs from 9 control outpatients that tested positive for enterovirus/rhinovirus by the FilmArray system. Results. HRV reads were recovered in 15 (94%) of the 16 samples sequenced. Phylogenetic analysis of HRV whole genomes from the 4 case-patients and 5 outpatient controls along with partial genomes from additional outpatient controls revealed that isolates from the case-patients were not directly related and that the 2 closest case HRV genomes had an estimated time to most recent common ancestor of 172 years. Our turnaround time from receipt of the sample to phylogenetic analysis was 24 hours. Conclusions. We found the use of mNGS downstream of a rapid polymerase chain reaction respiratory panel during an investigation of 4 hospital-acquired rhinovirus infections to rapidly dispel concern of a single-source transmission event.

The Effect of 13-Valent Pneumococcal Conjugate Vaccine on the Serotype Distribution and Antibiotic Resistance Profiles in Children With Invasive Pneumococcal Disease.

Abstract: Background. Invasive pneumococcal disease (IPD) continues to be a significant burden in children despite the implementation of two generations of conjugate vaccines. Serotype replacement by nonvaccine serotypes is reported in multiple areas around the world. This study is a continuation of previous studies and describes the incidence, serotype distribution, and antibiotic resistance pattern of Streptococcus pneumoniae serotypes causing IPD at Children’s Medical Center Dallas after introduction of 13-valent pneumococcal conjugate vaccine (PCV13). Methods. Streptococcus pneumoniae isolates from normally sterile sites were collected from January 1, 1999 to June 30, 2014. Demographic and clinical information was extracted for analysis. Incidence of IPD was calculated using inpatient and emergency center admissions to Children’s Medical Center of Dallas as the denominator. Isolates were serotyped and penicillin/cefotaxime susceptibilities were determined. Selected nontypeable isolates were further characterized by multilocus sequence typing. A χ 2 test and the Cochran– Armitage Trend Test for trend analysis were used to evaluate change in serotype and antibiotic susceptibility patterns over time. Results. Comparison of the different study periods showed a significant reduction in the incidence of IPD in PCV13 eracompared with prevaccine era and PCV7 era (P< .05). Children younger than 24 months showed the largest reduction of disease incidence. More than 40% of patients with IPD had a documented comorbidity. Cases of pneumonia continued to decrease in the PCV13 era (P < .002). The most common non-PCV13 serotypes after vaccine introduction were as follows: 23B, 6C, 23A, 9N/L, and 12. Penicillin resistance by meningitis breakpoint decreased significantly in the PCV13 era. Conclusions. After introduction of PCV13 in Dallas, incidence of IPD caused by strains contained in the vaccine and penicillin resistance continued to decrease. Serotype replacement phenomena and persistence of PCV7 serotypes were documented. Patients with comorbidities represented a large percentage of patients with IPD. Concerns for geographic variation in serotype replacement phenomena arise from the present study.

Pediatric Dental Clinic-Associated Outbreak of Mycobacterium abscessus Infection

Abstract: Background Mycobacterium abscessus is an uncommon cause of invasive odontogenic infection. Methods M abscessus-associated odontogenic infections occurred in a group of children after they each underwent a pulpotomy. A probable case-child was defined as a child with facial or neck swelling and biopsy-confirmed granulomatous inflammation after a pulpotomy between October 1, 2013, and September 30, 2015. M abscessus was isolated by culture in confirmed case-children. Clinical presentation, management, and outcomes were determined by medical record abstraction. Results Among 24 children, 14 (58%) were confirmed case-children. Their median age was 7.3 years (interquartile range, 5.8-8.2 years), and the median time from pulpotomy to symptom onset was 74 days (range, 14-262 days). Clinical diagnoses included cervical lymphadenitis (24 [100%] of 24), mandibular or maxillary osteomyelitis (11 [48%] of 23), and pulmonary nodules (7 [37%] of 19). Each child had ≥1 hospitalization and a median of 2 surgeries (range, 1-6). Of the 24 children, 12 (50%) had surgery alone and 11 (46%) received intravenous (IV) antibiotics. Nineteen of the 24 (79%) children experienced complications, including vascular access malfunction (7 [64%] of 11), high-frequency hearing loss (5 [56%] of 9), permanent tooth loss (11 [48%] of 23), facial nerve palsy (7 [29%] of 24), urticarial rash (3 [25%] of 12), elevated liver enzyme levels (1 [20%] of 5), acute kidney injury (2 [18%] of 11), incision dehiscence/fibrosis (3 [13%] of 24), and neutropenia (1 [9%] of 11). Conclusions M abscessus infection was associated with significant medical morbidity and treatment complications. Unique manifestations included extranodal mandibular or maxillary osteomyelitis and pulmonary nodules. Challenges in the identification of case-children resulted from an extended incubation period and various clinical manifestations. Clinicians should consider the association between M abscessus infection and pulpotomy in children who present with subacute cervical lymphadenitis. The use of treated/sterile water during pulpotomy might prevent further outbreaks.

Blastomycosis in Children: An Analysis of Clinical, Epidemiologic, and Genetic Features.

Abstract: Background Blastomyces spp. are endemic in regions of the United States and result in blastomycosis, a serious and potentially fatal infection. Little is known about the presentation, clinic course, epidemiology, and genetics of blastomycosis in children. Methods A retrospective review of children with blastomycosis confirmed by culture or cytopathology between 1999 and 2014 was completed. Blastomyces sp. isolates were genotyped by using microsatellite typing, and species were typed by sequencing of internal transcribed spacer 2 (its2). Results Of the 114 children with blastomycosis identified, 79% had isolated pulmonary involvement and 21% had extrapulmonary disease. There were more systemic findings, including fever (P = .01), poor intake (P = .01), elevated white blood cell count (P < .01), and elevated C-reactive protein level (P < .01), in children with isolated pulmonary disease than in children with extrapulmonary disease. Children with extrapulmonary disease had more surgeries (P = .01) and delays in diagnosis (P < .01) than those with isolated pulmonary infection. Of 52 samples genotyped, 48 (92%) were Blastomyces gilchristii and 4 (8%) were Blastomyces dermatitidis. Conclusion This is the first large-scale study of the clinical, epidemiologic, and genetic features of blastomycosis in children. The majority of the children had isolated pulmonary disease with systemic findings. Patients with extrapulmonary disease were less likely to have systemic symptoms or additional laboratory evidence of infection, which made delays in diagnosis more common. More than 90% of the pediatric cases were caused by B gilchristii.

Fungal Infections of the Central Nervous System in Children

Abstract: Although uncommon in children, fungal infections of the central nervous system can be devastating and difficult to treat. A better understanding of basic mycologic, immunologic, and pharmacologic processes has led to important advances in the diagnosis and management of these diseases, but their mortality rates remain unacceptably high. In this focused review, we examine the epidemiology and clinical features of the most common fungal pathogens of the central nervous system in children and explore recent advances in diagnosis and antifungal therapy.

Prediction of Resistance to Intravenous Immunoglobulin in Children With Kawasaki Disease.

Abstract: Background Approximately 10%-20% of patients with Kawasaki disease (KD) are refractory to initial intravenous immunoglobulin (IVIg) therapy, and these "nonresponders" are at higher risk of coronary artery abnormalities. Early identification of these patients, who may benefit from additional therapy, is challenging. The aim of the present study is to identify predictors for IVIg resistance. Methods We reviewed clinical records of 312 consecutive KD patients from 9 medical centers in Israel (development dataset) and 186 patients from additional 5 centers (validation dataset). Using multivariate analysis, we identified predictors of IVIg resistance. A third small prospective cohort of consecutive KD patients from a single medical center was used to test the accuracy of the predictors. Results Coronary artery abnormalities in the initial echocardiogram and presenting before day 5 of fever were independent predictors of IVIg nonresponse. Using either of these variables generated an area under the receiver-operating-characteristics curve of 0.7 (95% confidence interval [CI], 0.6-0.8). Sensitivity to predict nonresponse was 81% (95% CI, 67-90) and specificity was 50% (95% CI, 44-56). Similar results were found in the validation dataset and in the small prospective cohort. Conclusions Coronary artery abnormalities in the initial echocardiogram and presenting before day 5 of fever show high sensitivity in identifying IVIg nonresponders among our KD patients.

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

Abstract: 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.

Colonization With Antimicrobial-Resistant Gram-Negative Bacilli at Neonatal Intensive Care Unit Discharge.

Abstract: In multivariable analysis, prolonged antimicrobial treatment was a predictor of infant colonization with antimicrobial-resistant Gram-negative bacilli within 7 days of discharge from a neonatal intensive care unit. Background. The epidemiology of the colonization of infants with antimicrobial-resistant Gram-negative bacilli (GNB) at discharge from the neonatal intensive care unit (NICU) is not well understood. Methods. A multicenter study in which rectal surveillance samples for culture were obtained at NICU discharge from infants hospitalized 14 days was performed. Factors associated with colonization with GNB resistant to gentamicin, third/fourth-generation cephalosporin agents, or carbapenem agents were assessed by using a fixed-effects model. Results. Of these infants, 9% (119 of 1320) were colonized with 1 antimicrobial-resistant GNB. Prolonged treatment (10 days) with meropenem or third/fourth-generation cephalosporin agents or treatment for 5 days with a β-lactam/β-lactamase combination agent were associated with an increased risk of colonization with GNB resistant to gentamicin. Surgery and 5 days of treatment with third/fourth-generation cephalosporin agents, a β-lactam/β-lactamase combination agent, or metronidazole were associated with an increased risk of colonization with GNB resistant to third/fourth-generation cephalosporin agents. Female sex and prolonged treatment (10 days) with meropenem were associated with colonization with GNB resistant to carbapenem agents. Conclusions. Prolonged treatment with broad-spectrum antibiotics was associated with the colonization of infants with antimicrobial-resistant GNB within 7 days of NICU discharge. These findings suggest the potential for dissemination of resistant GNB from colonized infants to other NICUs, the community, or pediatric longterm care facilities. Antimicrobial stewardship efforts aimed at improving appropriate antibiotic use could havea beneficial effect on the emergence of antimicrobial-resistant GNB in the NICU population.

Defining Pediatric Diarrhea in Low-Resource Settings.

Abstract: Differences in definitions of acute pediatric diarrhea result in variable estimates of morbidity and mortality, treatment coverage, and associations with risk factors and outcomes. We reviewed published literature and guidelines focused on acute pediatric diarrhea in low- and middle-income countries. Clinical guidelines most commonly defined diarrhea in terms of quantity of loose or watery stool with consideration of normal stool patterns, whereas research studies often relied exclusively on a quantitative definition. The most commonly used quantitative definition, ≥3 loose or watery stools in a 24-hour period, has been compared to gold standards of caregiver perception and visual inspection of stool, with variable agreement. Age, breast-feeding status, and setting (facility vs household-based) influence the performance of quantitative diarrhea definitions in children. Universal adoption of a set of valid gold standard definitions specifically aligned with various programmatic and research goals will lead to more accurate coverage estimates and better-informed resource prioritization.

Time to Change Dosing of Inactivated Quadrivalent Influenza Vaccine in Young Children: Evidence From a Phase III, Randomized, Controlled Trial

Abstract: Background. Children under 3 years of age may benefit from a double-dose of inactivated quadrivalent influenza vaccine (IIV4) instead of the standard-dose. Methods. We compared the only United States-licensed standard-dose IIV4 (0.25 mL, 7.5 µg hemagglutinin per influenza strain) versus double-dose IIV4 manufactured by a different process (0.5 mL, 15 µg per strain) in a phase III, randomized, observer-blind trial in children 6-35 months of age (NCT02242643). The primary objective was to demonstrate immunogenic noninferiority of the double-dose for all vaccine strains 28 days after last vaccination. Immunogenic superiority of the double-dose was evaluated post hoc. Immunogenicity was assessed in the per-protocol cohort (N = 2041), and safety was assessed in the intent-to-treat cohort (N = 2424). Results. Immunogenic noninferiority of double-dose versus standard-dose IIV4 was demonstrated in terms of geometric mean titer (GMT) ratio and seroconversion rate difference. Superior immunogenicity against both vaccine B strains was observed with double-dose IIV4 in children 6-17 months of age (GMT ratio = 1.89, 95% confidence interval [CI] = 1.64-2.17, B/Yamagata; GMT ratio = 2.13, 95% CI = 1.82-2.50, B/Victoria) and in unprimed children of any age (GMT ratio = 1.85, 95% CI = 1.59-2.13, B/Yamagata; GMT ratio = 2.04, 95% CI = 1.79-2.33, B/Victoria). Safety and reactogenicity, including fever, were similar despite the higher antigen content and volume of the double-dose IIV4. There were no attributable serious adverse events. Conclusions. Double-dose IIV4 may improve protection against influenza B in some young children and simplifies annual influenza vaccination by allowing the same vaccine dose to be used for all eligible children and adults.

Time to Positivity of Blood Cultures in Infants 0 to 90 Days Old Presenting to the Emergency Department: Is 36 Hours Enough?

Abstract: Background Continuous monitoring blood culture systems (CMBCS) now allow for more rapid detection of microbial growth. We aimed to determine whether a 36-hour period was sufficient to detect all blood cultures positive for pathogenic bacteria in infants 0 to 90 days old undergoing a septic workup in the emergency department of a tertiary care pediatric center. Methods We performed a retrospective study of all positive blood cultures collected in these infants over a 5-year time period (from March 13, 2008 to July 29, 2013). Bottles were incubated in a CMBCS. The time to positivity (TTP) was calculated from time of blood culture registration into the laboratory system to time of Gram stain. Medical charts were reviewed for relevant clinical information. Cultures were classified as pathogenic or contaminant using microorganism type and clinical presentation. Results Three thousand five hundred fifty-nine blood cultures were collected. Of these, 98 (2.8%) were positive. Fifty-two (53.1%) were deemed pathogenic and 46 (46.9%) were deemed contaminant, for a true prevalence of bacteremia of 1.5%. At 24, 36, 48, and 50 hours, 87.8% (86 of 98), 96.9% (95 of 98), 99% (97 of 98), and 100% (98 of 98) of all cultures were positive. Considering only pathogenic organisms, 96.1% (50 of 52) and 100% (52 of 52) were positive at 24 and 36 hours. Mean TTP for pathogens and contaminants was 14.40 and 23.18 hours, respectively (P < .001). Conclusions An incubation period of 36 hours is sufficient to detect 100% of blood cultures positive for a pathogenic organism in our population.

Characterization of Children With Recurrent Episodes of Stevens Johnson Syndrome.

Abstract: We performed a retrospective chart review for all cases of recurrent Stevens Johnson Syndrome (SJS) from March 2013 to March 2016. Nine children had 29 episodes of SJS or incomplete SJS; all children were male and 8 (88%) were white. Episodes affected mucus membranes with minimal skin involvement. Mycoplasma infections and HLA-B27/-B51 were common.

Geographic Disparities in Cytomegalovirus Infection During Pregnancy.

Abstract: Background Cytomegalovirus (CMV) is the most common infectious cause of fetal malformations and childhood hearing loss. CMV is more common among socially disadvantaged groups, and it clusters geographically in poor communities. We conducted a geospatial analysis of chronic and primary CMV infection among pregnant women around Durham, NC. Methods We performed a geospatial analysis of subjects from an ongoing study of CMV infection among pregnant women using geographic information systems and spatial statistics. Subjects were categorized on the basis of results of their CMV immunoglobulin G avidity testing as seronegative, seropositive, or primary infection. We used generalized additive models to analyze the spatial distributions of individuals who fell into each category and to control for confounders such as race and age. We used a generalized estimating equation to correlate community-level variables with CMV status. Results Of 3527 pregnant women aged 15 to 59 years, 93.4% were either white or black. CMV seropositivity was significantly more common among non-Hispanic white subjects than among minority subjects (odds ratio, 3.76 [95% confidence interval, 3.25-4.34]). We identified a cluster in which women had elevated odds of CMV seropositivity in the urban neighborhoods of Durham. Cases of primary CMV infection were more common in areas with higher-than-average CMV seroprevalence. Neighborhood median family income was associated inversely with the prevalence of chronic CMV. Conclusions We found a high prevalence of CMV seropositivity in urban low-income neighborhoods among pregnant women, particularly among racial and ethnic minorities. Seronegative pregnant women from these communities might be at heightened risk for primary CMV infection.

Association Between Vancomycin Trough Concentrations and Duration of Methicillin-Resistant Staphylococcus aureus Bacteremia in Children.

Abstract: In a multicenter retrospective study, we sought to determine the optimal vancomycin trough concentration that would impact the duration of methicillin-resistant Staphylococcus aureus bacteremia in children. We found that a median vancomycin trough concentration of <10 µg/mL within the first 72 hours may be associated with a longer duration of bacteremia compared to a median trough concentration of ≥10 µg/mL.

Hyponatremia Is a Feature of Kawasaki Disease Shock Syndrome: A Case-Control Study.

Abstract: Kawasaki disease (KD) shock syndrome (KDSS) is hypotension with KD. We compared children with KDSS and matched control children with KD. Children with KDSS more often were female, had a lower platelet count and sodium concentration, had a condition refractory to immunoglobulin, and had abnormal echocardiography results. KDSS is a unique subset of KD.

Ethanol Lock Therapy for the Treatment of Intravenous Catheter Infections That Have Failed Standard Treatment.

Abstract: This study used ethanol lock therapy (ELT) to treat intravenous catheter infections that had failed standard intravenous antimicrobial treatment. Of 15 patients enrolled, 13 were successfully treated with ELT. Twenty-one organisms were identified: 12 bacteria, 9 fungi. Eight of the 9 fungi were eradicated, and no patient became hemodynamically unstable on treatment.

Allograft Inflammatory Factor-1 Links T-Cell Activation, Interferon Response, and Macrophage Activation in Chronic Kawasaki Disease Arteritis.

Abstract: Background Kawasaki disease (KD) is widely viewed as an acute arteritis. However, our pathologic studies show that chronic coronary arteritis can persist long after disease onset and is closely linked with arterial stenosis. Transcriptome profiling of acute KD arteritis tissues revealed upregulation of T lymphocyte, type I interferon, and allograft inflammatory factor-1 (AIF1) genes. We determined whether these immune responses persist in chronic KD arteritis, and we investigated the role of AIF1 in these responses. Methods Gene expression in chronic KD and childhood control arteries was determined by real-time reverse-transcriptase polymerase chain reaction, and arterial protein expression was determined by immunohistochemistry and immunofluorescence. Allograft inflammatory factor-1 small-interfering ribonucleic acid macrophage treatment was performed to investigate the role of AIF1 in macrophage and T lymphocyte activation. Results Allograft inflammatory factor-1 protein was highly expressed in stenotic KD arteries and colocalized with the macrophage marker CD68. T lymphocyte and interferon pathway genes were significantly upregulated in chronic KD coronary artery tissues. Alpha interferon-induced macrophage expression of CD80 and major histocompatibility complex class II was dependent on AIF1, and macrophage expression of AIF1 was required for antigen-specific T lymphocyte activation. Conclusions Allograft inflammatory factor-1, originally identified in posttransplant arterial stenosis, is markedly upregulated in KD stenotic arterial tissues. T lymphocyte and type I interferon responses persist in chronic KD arteritis. Allograft inflammatory factor-1 may play multiple roles linking type I interferon response, macrophage activation, and antigen-specific T lymphocyte activation. These results suggest the likely importance of lymphocyte-myeloid cell cross-talk in the pathogenesis of KD arteritis and can inform selection of new immunotherapies for clinical trials in high-risk KD children.

Case-Control Assessment of the Roles of Noroviruses, Human Bocaviruses 2, 3, and 4, and Novel Polyomaviruses and Astroviruses in Acute Childhood Diarrhea.

Abstract: Background The etiology of acute childhood diarrhea often eludes identification. We used a case-control study-stool archive to determine if nucleic acid tests for established and newly identified viruses diminish our previously published 32% rate of microbiologically unexplained episodes. Methods Using polymerase chain reaction, we sought to detect noroviruses GI and GII, classic and novel astroviruses, and human bocaviruses (HBoVs) 2, 3, and 4 among 178 case and 178 matched control stool samples and St. Louis and Malawi polyomaviruses among a subset of 98 case and control stool samples. We calculated adjusted odds ratios and 95% confidence intervals using conditional logistic regression. Results Noroviruses were more common in cases (GI, 2.2%; GII, 16.9%) than in controls (GI, 0%; GII, 4.5%) (adjusted odds ratio, 5.2 [95% confidence interval, 2.5-11.3]). Astroviruses and HBoVs 2, 3, and 4 were overrepresented among the cases, although this difference was not statistically significant. Malawi polyomavirus was not associated with case status, and St. Louis polyomavirus was identified in only 1 subject (a control). When identified in cases, HBoVs 2, 3, and 4 were frequently (77%) found in conjunction with a bona fide diarrheagenic pathogen. Thirty-five (20%) case and 3 (2%) control stool samples contained more than 1 organism of interest. Overall, a bona fide or plausible pathogen was identified in 79% of the case stool samples. Preceding antibiotic use was more common among cases (adjusted odds ratio, 4.5 [95% confidence interval, 2.3-8.5]). Conclusion Noroviruses were found to cause one-third of the diarrhea cases that previously had no identified etiology. Future work should attempt to ascertain etiologic agents in the approximately one-fifth of cases without a plausible microbial cause, understand the significance of multiple agents in stools, and guide interpretation of nonculture diagnostics.

The Molecular and Clinical Epidemiology of Extended-Spectrum Cephalosporin- and Carbapenem-Resistant Enterobacteriaceae at 4 US Pediatric Hospitals.

Abstract: Objective In this report, we aim to describe the epidemiology of extended-spectrum cephalosporin-resistant (ESC-R) and carbapenem-resistant (CR) Enterobacteriaceae infections in children. Methods ESC-R and CR Enterobacteriaceae isolates from normally sterile sites of patients aged <22 years from 4 freestanding pediatric medical centers were collected along with the associated clinical data. Results The overall frequencies of ESC-R and CR isolates according to hospital over the 4-year study period ranged from 0.7% to 2.8%. Rates of ESC-R or CR Escherichia coli and Klebsiella pneumoniae varied according to hospital and ranged from 0.75 to 3.41 resistant isolates per 100 isolates (P < .001 for any differences). E coli accounted for 272 (77%) of the resistant isolates; however, a higher rate of resistance was observed in K pneumoniae isolates (1.78 vs 1.27 resistant isolates per 100 same-species isolates, respectively; P = .005). One-third of the infections caused by ESC-R or CR E coli were community-associated. In contrast, infections caused by ESC-R or CR K pneumoniae were more likely than those caused by resistant E coli to be healthcare- or hospital-associated and to occur in patients with an indwelling device (P ≤ .003 for any differences, multivariable logistic regression). Nonsusceptibility to 3 common non-β-lactam agents (ciprofloxacin, gentamicin, and trimethoprim-sulfamethoxazole) occurred in 23% of the ESC-R isolates. The sequence type 131-associated fumC/fimH-type 40-30 was the most prevalent sequence type among all resistant E coli isolates (30%), and the clonal group 258-associated allele tonB79 was the most prevalent allele among all resistant K pneumoniae isolates (10%). Conclusions The epidemiology of ESC-R and CR Enterobacteriaceae varied according to hospital and species (E coli vs K pneumoniae). Both community and hospital settings should be considered in future research addressing pediatric ESC-R Enterobacteriaceae infection.

Hepatic, Renal, Hematologic, and Inflammatory Markers in HIV-Infected Children on Long-term Suppressive Antiretroviral Therapy.

Abstract: Background Data on long-term toxicity of antiretroviral therapy (ART) in HIV-infected children are sparse. PENPACT-1 was an open-label trial in which HIV-infected children were assigned randomly to receive protease inhibitor (PI)- or nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based ART. Methods We examined changes in clinical, immunologic, and inflammatory markers from baseline to year 4 in the subset of children in the PENPACT-1 study who experienced viral suppression between week 24 and year 4 of ART. Liver enzyme, creatinine, and cholesterol levels and hematologic parameters were assessed during the trial. Cystatin C, high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), d-dimer, and soluble CD14 (sCD14) were assayed from cryopreserved specimens. Results Ninety-nine children (52 on PI-based and 47 on NNRTI-based ART) met inclusion criteria. The median age at initiation of ART was 6.5 years (interquartile range [IQR], 3.7-13.4 years), and 22% were aged <3 years at ART initiation; 56% of the PI-treated children received lopinavir/ritonavir, and 70% of NNRTI-treated children received efavirenz initially. We found no evidence of significant clinical toxicity in either group; growth, liver, kidney, and hematologic parameters either remained unchanged or improved between baseline and year 4. Total cholesterol levels increased modestly, but no difference between the groups was found. IL-6 and hs-CRP levels decreased more after 4 years in the NNRTI-based ART group. The median change in IL-6 level was -0.35 pg/ml in the PI-based ART group and -1.0 in the NNRTI-based ART group (P = .05), and the median change in hs-CRP level was 0.25 µg/ml in the PI-based ART group and -0.95 µg/ml in the NNRTI-based ART group (P = .005). Conclusion These results support the safety of prolonged ART use in HIV-infected children and suggest that suppressive NNRTI-based regimens can be associated with lower levels of systemic inflammation.