Russell J. McCulloh

Variation in Care of the Febrile Young Infant <90 Days in US Pediatric Emergency Departments

BACKGROUND AND OBJECTIVES: Variation in patient care or outcomes may indicate an opportunity to improve quality of care. We evaluated the variation in testing, treatment, hospitalization rates, and outcomes of febrile young infants in US pediatric emergency departments (EDs). METHODS: Retrospective cohort study of infants <90 days of age with a diagnosis code of fever who were evaluated in 1 of 37 pediatric EDs between July 1, 2011 and June 30, 2013. We assessed patient- and hospital-level variation in testing, treatment, and disposition for patients in 3 distinct age groups: ≤28, 29 to 56, and 57 to 89 days. We also compared interhospital variation for 3-day revisits and revisits resulting in hospitalization. RESULTS: We identified 35 070 ED visits that met inclusion criteria. The proportion of patients who underwent comprehensive evaluation, defined as urine, serum, and cerebrospinal fluid testing, decreased with increasing patient age: 72.0% (95% confidence interval [CI], 71.0–73.0) of neonates ≤28 days, 49.0% (95% CI, 48.2–49.8) of infants 29 to 56 days, and 13.1% (95% CI, 12.5–13.6) of infants 57 to 89 days. Significant interhospital variation was demonstrated in testing, treatment, and hospitalization rates overall and across all 3 age groups, with little interhospital variation in outcomes. Hospitalization rate in the overall cohort did not correlate with 3-day revisits (R2 = 0.10, P = .06) or revisits resulting in hospitalization (R2 = 0.08, P = .09). CONCLUSIONS: Substantial patient- and hospital-level variation was observed in the ED management of the febrile young infant, without concomitant differences in outcomes. Strategies to understand and address the modifiable sources of variation are needed.

Hemopexin and haptoglobin: allies against heme toxicity from hemoglobin not contenders

The goal here is to describe our current understanding of heme metabolism and the deleterious effects of “free” heme on immunological processes, endothelial function, systemic inflammation, and various end-organ tissues (e.g., kidney, lung, liver, etc.), with particular attention paid to the role of hemopexin (HPX). Because heme toxicity is the impetus for much of the pathology in sepsis, sickle cell disease (SCD), and other hemolytic conditions, the biological importance and clinical relevance of HPX, the predominant heme binding protein, is reinforced. A perspective on the function of HPX and haptoglobin (Hp) is presented, updating how these two proteins and their respective receptors act simultaneously to protect the body in clinical conditions that entail hemolysis and/or systemic intravascular (IVH) inflammation. Evidence from longitudinal studies in patients supports that HPX plays a Hp-independent role in genetic and non-genetic hemolytic diseases without the need for global Hp depletion. Evidence also supports that HPX has an important role in the prognosis of complex illnesses characterized predominantly by the presence of hemolysis, such as SCD, sepsis, hemolytic-uremic syndrome, and conditions involving IVH and extravascular hemolysis (EVH), such as that generated by extracorporeal circulation during cardiopulmonary bypass (CPB) and from blood transfusions. We propose that quantitating the amounts of plasma heme, HPX, Hb-Hp, heme-HPX, and heme-albumin levels in various disease states may aid in the diagnosis and treatment of the above-mentioned conditions, which is crucial to developing targeted plasma protein supplementation (i.e., “replenishment”) therapies for patients with heme toxicity due to HPX depletion.

Treatment of Mycoplasma Pneumonia: A Systematic Review

BACKGROUND AND OBJECTIVE: Children with community-acquired lower respiratory tract infection (CA-LRTI) commonly receive antibiotics for Mycoplasma pneumoniae. The objective was to evaluate the effect of treating M. pneumoniae in children with CA-LRTI. METHODS: PubMed, Cochrane Central Register of Controlled Trials, and bibliography review. A search was conducted by using Medical Subject Headings terms related to CA-LRTI and M. pneumoniae and was not restricted by language. Eligible studies included randomized controlled trials (RCTs) and observational studies of children ≤17 years old with confirmed M. pneumoniae and a diagnosis of CA-LRTI; each must have also compared treatment regimens with and without spectrum of activity against M. pneumoniae. Data extraction and quality assessment were completed independently by multiple reviewers before arriving at a consensus. Data were pooled using a random effects model. RESULTS: Sixteen articles detailing 17 studies were included. The most commonly selected primary outcome was symptomatic improvement. Nine studies examined M. pneumoniae treatment in CA-LRTI secondary to M. pneumoniae, and 5 RCTs met criteria for meta-analysis. The suggested pooled risk difference of 0.12 (95% confidence interval, −0.04 to 0.20) favoring treatment was not significantly different and demonstrated significant heterogeneity. Limitations included substantial bias and subjective outcomes within the individual studies, difficulty interpreting testing modalities, and the inability to correct for mixed infections or timing of intervention. CONCLUSIONS: We identified insufficient evidence to support or refute treatment of M. pneumoniae in CA-LRTI. These data highlight the need for well-designed, prospective RCTs assessing the effect of treating M. pneumoniae in CA-LRTI.

Respiratory viral testing: New frontiers in diagnostics and implications for antimicrobial stewardship

Millions of patients visit the doctor or emergency department annually for illnesses attributed to respiratory viruses, including influenza,1 but accurate and focused antimicrobial therapy often proves elusive.2 Appropriately targeted therapy is vital in cases of severe illness or resource scarcity, both of which can occur in the setting of pandemic influenza.3 The article in this issue of Virulence by Bogoch et al. provides insight into the use of deep respiratory samples for influenza viral detection in patients hospitalized with severe acute respiratory illness.4 They describe a subset of 15 patients undergoing deep respiratory secretions testing for influenza, with 10 patients having positive results. Eight of these 10 were positive by PCR testing from their lower respiratory tract sampling only. These results demonstrate the potential utility of molecular virologic testing of patients requiring invasive ventilator support for severe illness by providing physicians with relevant diagnostic data that would help drive appropriate antiviral use in cases where sampling from other sites or using antigen- or culture-based testing has yielded negative results. Advancement of nucleic acid technology has not only proven pivotal in the clarification of previously unknown and uncultivated microorganisms,5 but has dramatically improved test performance parameters of clinical diagnostic tests compared with the traditional diagnostics of rapid antigen testing, DFA, and viral culture for influenza. Clinicians seek the least expensive and most rapid, comprehensive and accurate (highly sensitive and specific) test to diagnose respiratory viral illnesses. Nucleic acid amplification tests (NAATs), including PCR, have supplanted viral culture because of better turn-around time, accurate diagnosis, ability to detect multiple targets (multiplexing) and potential for positively aiding physician decision-making and patient management.5,6 Other modalities still play important roles in healthcare responses on patient, community and health-system levels. Culture for viruses like influenza will remain important for differentiating prolonged detection of nucleic acids from continued shedding of virus and potential antiviral resistance, subtyping of novel strains and propagation for vaccine manufacturing.6,7 Commonly-used rapid shell vial culturing techniques combined with specific direct fluorescent antibody demonstrated sensitivities ranging from 90–97% and 100% specificity for pandemic H1N1 (pH1N1), but complexity of use and 2–3 d turnarounds still limit their impact on clinical care.5,6,8 Rapid antigen tests are inexpensive and easy to use, making them ideal for point-of-care testing in places like physician offices and emergency rooms and their high specificity in times of high disease prevalence allows their high positive predictive value to aid in timely treatment, limiting unnecessary resource utilization. However, sensitivity for pH1N1 was lackluster (< 50%).8 When seeking best practices for which tests laboratories will adopt it is unlikely a one-size-fits-all solution will work. A combination of tests using a structured protocol will likely be necessary. This ideally would include using a rapid and cost-effective diagnostic test for influenza initially with reflex testing using a more comprehensive multiplexed NAAT-based respiratory panel or individual NAAT with high sensitivity and specificity in cases of negative rapid testing, especially if the patient will be admitted and/or antibiotics are being considered. In their article, Bogoch et al. suggest the use of lower respiratory tract specimens as a potential alternative to nasopharyngeal or upper respiratory sampling. While there are now numerous single analyte NAATs for both influenza as well as respiratory panel assays, none are currently FDA-cleared for lower respiratory specimens. Laboratories must validate these specimen types, which can be a considerable undertaking. In our laboratory, where validation for BAL specimens was done for performing a respiratory panel multiplex assay, 611 specimens were received from November 2010 to September 2012, and 100 have been positive (unpublished data). For those patients who underwent both NP and BAL viral PCR testing (97 patients), 30 were BAL positive and 32 were NP positive. Discordant results occurred in four patients where BAL was positive and NP sampling was negative, and in six patients where NP specimens were positive and BAL specimens negative. The higher rate of discordant results in the authors’ report compared with our data are likely due to the lower performance parameters of DFA, antigen and culture techniques for some of the NP and BAL comparisons. However, the potential for improved diagnosis in patients with active infection limited to the lower respiratory tract nonetheless exists using BAL/lower respiratory specimen sampling. Despite the challenges posed by validating respiratory viral testing from multiple sites, the potential benefits of improving a physician’s ability to accurately determine the etiology of a patient’s acute respiratory symptoms is quite significant. Previous studies have shown that physicians will likely prescribe more anti-influenza medications when presented with positive test results and may decrease their utilization of ancillary diagnostic tests.9 Review of data from our own institution found that, during peak pH1N1 prevalence in our region, physicians increased their use of antiviral medication after a positive test result for influenza, and, perhaps more importantly, discontinued antiviral use in cases where patients were diagnosed with a non-influenza respiratory viral infection or negative NAAT.10 The decrease in antiviral use was more pronounced in patients with a positive non-influenza virus test result than in those with completely negative PCR testing, which likely represents physicians’ concern of a false-negative result similar to that found in the case series by Bogoch et al. Additionally, physicians generally do not change antibiotic prescription practices based on viral testing results even in clinically unambiguous circumstances where a viral etiology is likely.6,11 This illustrates the core challenge facing clinicians and microbiologists alike when integrating respiratory viral testing into antimicrobial stewardship programs: how should a clinician select patients likely to benefit from antimicrobial discontinuation based on NAAT results? Blanket policy decisions will likely lead to misclassification of patients at high risk for bacterial infection not receiving necessary antibiotics, while overly-specific guidelines may be too cumbersome for physicians to utilize, resulting in the continuation of unnecessary antimicrobials for many patients. The key to successfully utilizing these more sensitive virologic assays in clinical practice is to develop targeted interventions in clearly-defined patient populations with easily-recognizable viral syndromes, and to continue to allow physicians appropriate latitude in antimicrobial therapy—and diagnostic testing—in complex or uncertain cases. Deep respiratory specimen testing in patients with severe illness and/or multiple medical co-morbidities could provide the clinician with crucial insight into the etiology of a patient’s illness, prompt the addition of targeted antiviral therapy and help provide insight into the underlying epidemiology of respiratory viruses causing severe illness in the community, particularly during the early stages of a developing epidemic. This study by Bogoch et al. supports the need for reliable, validated respiratory viral testing from a variety of sites for severely-ill patients.

Pediatric sepsis: Important considerations for diagnosing and managing severe infections in infants, children, and adolescents

Sepsis is the leading cause of death in children worldwide. Although the diagnosis and management of sepsis in infants and children is largely influenced by studies done in adults, there are important considerations relevant for pediatrics. This article highlights pediatric-specific issues related to the definition of sepsis and its epidemiology and management. We review how the capacity of the immune system to respond to infection develops over early life. We also bring attention to primary immune deficiencies that should be considered in children recurrently infected with specific types of organisms. The management of pediatric sepsis must be tailored to the child’s age and immune capacity, and to the site, severity, and source of the infection. It is important for clinicians to be aware of infection-related syndromes that primarily affect children. Although children in developed countries are more likely to survive severe infections than adults, many survivors have chronic health impairments.

Assessing the impact of national guidelines on the management of children hospitalized for acute bronchiolitis

Acute bronchiolitis is a common illness accounting for

Distinguishing characteristics between pandemic 2009-2010 influenza A (H1N1) and other viruses in patients hospitalized with respiratory illness.

500 million annually in hospitalizations. Despite the frequency of bronchiolitis, its diagnosis and management is variable. To address this variability, the American Academy of Pediatrics (AAP) published an evidence‐based practice management guideline for bronchiolitis in 2006.

Association of clinical practice guidelines with emergency department management of febrile infants ≤56 days of age

Background Differences in clinical presentation and outcomes among patients infected with pandemic 2009 influenza A H1N1 (pH1N1) compared to other respiratory viruses have not been fully elucidated. Methodology/Principal Findings A retrospective study was performed of all hospitalized patients at the peak of the pH1N1 season in whom a single respiratory virus was detected by a molecular assay targeting 18 viruses/subtypes (RVP, Luminex xTAG). Fifty-two percent (615/1192) of patients from October, 2009 to December, 2009 had a single respiratory virus (291 pH1N1; 207 rhinovirus; 45 RSV A/B; 37 parainfluenza; 27 adenovirus; 6 coronavirus; and 2 metapneumovirus). No seasonal influenza A or B was detected. Individuals with pH1N1, compared to other viruses, were more likely to present with fever (92% & 70%), cough (92% & 86%), sore throat (32% & 16%), nausea (31% & 8%), vomiting (39% & 30%), abdominal pain (14% & 7%), and a lower white blood count (8,500/L & 13,600/L, all p-values<0.05). In patients with cough and gastrointestinal complaints, the presence of subjective fever/chills independently raised the likelihood of pH1N1 (OR 10). Fifty-five percent (336/615) of our cohort received antibacterial agents, 63% (385/615) received oseltamivir, and 41% (252/615) received steroids. The mortality rate of our cohort was 1% (7/615) and was higher in individuals with pH1N1 compared to other viruses (2.1% & 0.3%, respectively; p = 0.04). Conclusions/Significance During the peak pandemic 2009–2010 influenza season in Rhode Island, nearly half of patients admitted with influenza-like symptoms had respiratory viruses other than influenza A. A high proportion of patients were treated with antibiotics and pH1N1 infection had higher mortality compared to other respiratory viruses.

Evaluating the Use of Blood Cultures in the Management of Children Hospitalized for Community-Acquired Pneumonia

BACKGROUND Differences among febrile infant institutional clinical practice guidelines (CPGs) may contribute to practice variation and increased healthcare costs. OBJECTIVE Determine the association between pediatric emergency department (ED) CPGs and laboratory testing, hospitalization, ceftriaxone use, and costs in febrile infants. DESIGN Retrospective cross-sectional study in 2013. SETTING Thirty-three hospitals in the Pediatric Health Information System. PATIENTS Infants aged ≤56 days with a diagnosis of fever. EXPOSURES The presence and content of ED-based febrile infant CPGs assessed by electronic survey. MEASUREMENTS Using generalized estimating equations, we evaluated the association between CPG recommendations and rates of urine, blood, cerebrospinal fluid (CSF) testing, hospitalization, and ceftriaxone use at ED discharge in 2 age groups: ≤28 days and 29 to 56 days. We also assessed CPG impact on healthcare costs. RESULTS We included 9377 ED visits; 21 of 33 EDs (63.6%) had a CPG. For neonates ≤28 days, CPG recommendations did not vary and were not associated with differences in testing, hospitalization, or costs. Among infants 29 to 56 days, CPG recommendations for CSF testing and ceftriaxone use varied. CSF testing occurred less often at EDs with CPGs recommending limited testing compared to hospitals without CPGs (adjusted odds ratio: 0.5, 95% confidence interval: 0.3-0.8). Ceftriaxone use at ED discharge varied significantly based on CPG recommendations. Costs were higher for admitted and discharged infants 29 to 56 days old at hospitals with CPGs. CONCLUSIONS CPG recommendations for febrile infants 29 to 56 days old vary across institutions for CSF testing and ceftriaxone use, correlating with observed practice variation. CPGs were not associated with lower healthcare costs.

Appropriateness of Testing for Serious Bacterial Infection in Children Hospitalized With Bronchiolitis

Background Blood cultures are often recommended for the evaluation of community-acquired pneumonia (CAP). However, institutions vary in their use of blood cultures, and blood cultures have unclear utility in CAP management in hospitalized children. Objective To identify clinical factors associated with obtaining blood cultures in children hospitalized with CAP, and to estimate the association between blood culture obtainment and hospital length of stay (LOS). Methods We performed a multicenter retrospective cohort study of children admitted with a diagnosis of CAP to any of four pediatric hospitals in the United States from January 1, 2011-December 31, 2012. Demographics, medical history, diagnostic testing, and clinical outcomes were abstracted via manual chart review. Multivariable logistic regression evaluated patient and clinical factors for associations with obtaining blood cultures. Propensity score-matched Kaplan-Meier analysis compared patients with and without blood cultures for hospital LOS. Results Six hundred fourteen charts met inclusion criteria; 390 children had blood cultures obtained. Of children with blood cultures, six (1.5%) were positive for a pathogen and nine (2.3%) grew a contaminant. Factors associated with blood culture obtainment included presenting with symptoms of systemic inflammatory response syndrome (OR 1.78, 95% CI 1.10–2.89), receiving intravenous hydration (OR 3.94, 95% CI 3.22–4.83), receiving antibiotics before admission (OR 1.49, 95% CI 1.17–1.89), hospital admission from the ED (OR 1.65, 95% CI 1.05–2.60), and having health insurance (OR 0.42, 95% CI 0.30–0.60). In propensity score-matched analysis, patients with blood cultures had median 0.8 days longer LOS (2.0 vs 1.2 days, P < .0001) without increased odds of readmission (OR 0.94, 95% CI 0.45–1.97) or death (P = .25). Conclusions Obtaining blood cultures in children hospitalized with CAP rarely identifies a causative pathogen and is associated with increased LOS. Our results highlight the need to refine the role of obtaining blood cultures in children hospitalized with CAP.