A transient apical extracellular matrix relays cytoskeletal patterns to shape permanent acellular ridges on the surface of adult C. elegans.

Epithelial cells secrete apical extracellular matrices to form protruding structures such as denticles, ridges, scales, or teeth. The mechanisms that shape these structures remain poorly understood. Here, we show how the actin cytoskeleton and a provisional matrix work together to sculpt acellular longitudinal alae ridges in the cuticle of adult C. elegans. Transient assembly of longitudinal actomyosin filaments in the underlying lateral epidermis accompanies deposition of the provisional matrix at the earliest stages of alae formation. Actin is required to pattern the provisional matrix into longitudinal bands that are initially offset from the pattern of longitudinal actin filaments. These bands appear ultrastructurally as alternating regions of adhesion and separation within laminated provisional matrix layers. The provisional matrix is required to establish these demarcated zones of adhesion and separation, which ultimately give rise to alae ridges and their intervening valleys, respectively. Provisional matrix proteins shape the alae ridges and valleys but are not present within the final structure. We propose a morphogenetic mechanism wherein cortical actin patterns are relayed to the laminated provisional matrix to set up distinct zones of matrix layer separation and accretion that shape a permanent and acellular matrix structure.

Low In-School COVID-19 Transmission and Asymptomatic Infection Despite High Community Prevalence.

There is concern that in-person schooling during the coronavirus disease 2019 (COVID-19) pandemic will facilitate disease transmission. Through asymptomatic surveillance and contact tracing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we found low rates of asymptomatic SARS-CoV-2 infection and little in-school transmission of COVID-19 when physical distancing and masking strategies were enforced despite a high community prevalence of COVID-19.

Multisystem Inflammatory Syndrome in Children: Survey of Protocols for Early Hospital Evaluation and Management.

OBJECTIVE: To describe the similarities and differences in the evaluation and treatment of multisystem inflammatory syndrome in children (MIS-C) at hospitals in the US. STUDY DESIGN: We conducted a cross-sectional survey from June 16 to July 16, 2020, of US children's hospitals regarding protocols for management of patients with MIS-C. Elements included characteristics of the hospital, clinical definition of MIS-C, evaluation, treatment, and follow-up. We summarized key findings and compared results from centers in which >5 patients had been treated vs those in which ≤5 patients had been treated. RESULTS: In all, 40 centers of varying size and experience with MIS-C participated in this protocol survey. Overall, 21 of 40 centers required only 1 day of fever for MIS-C to be considered. In the evaluation of patients, there was often a tiered approach. Intravenous immunoglobulin was the most widely recommended medication to treat MIS-C (98% of centers). Corticosteroids were listed in 93% of protocols primarily for moderate or severe cases. Aspirin was commonly recommended for mild cases, whereas heparin or low molecular weight heparin were to be used primarily in severe cases. In severe cases, anakinra and vasopressors frequently were recommended; 39 of 40 centers recommended follow-up with cardiology. There were similar findings between centers in which >5 patients vs ≤5 patients had been managed. Supplemental materials containing hospital protocols are provided. CONCLUSIONS: There are many similarities yet key differences between hospital protocols for MIS-C. These findings can help healthcare providers learn from others regarding options for managing MIS-C.

Impact of a Rapid Blood Culture Diagnostic Test in a Children's Hospital Depends on Gram-Positive versus Gram-Negative Organism and Day versus Night Shift.

Rapid diagnostic tests (RDTs) for bloodstream infections (BSIs) decrease the time to organism identification and resistance detection. RDTs are associated with early deescalation of therapy for Gram-positive BSIs. However, it is less clear how RDTs influence antibiotic management for Gram-negative BSIs and whether RDT results are acted on during off-hours. We performed a single-center, retrospective review of children with BSI and Verigene (VG) testing at a children's hospital. Of the 301 positive cultures included in the study (196 Gram-positive, 44 Gram-negative, 32 polymicrobial, and 29 non-VG targets), the VG result had potential to impact antibiotic selection in 171 cases; among these, antibiotic changes occurred in 119 (70%) cases. For Gram-negative cultures, the Verigene result correlated with unnecessary antibiotic escalation and exposure to broader-spectrum antibiotics than needed. In contrast, for Gram-positive cultures, the VG results correlated with appropriate antibiotic selection. VG results permitted early deescalation for methicillin-susceptible Staphylococcus aureus (MSSA) (19/24 [79%]) and avoidance of antibiotics for skin contaminants (30/85 [35%]). Antibiotic changes occurred more quickly during the day than at night (4.6 versus 11.7 h, respectively; P < 0.05), and antibiotic escalations occurred more quickly than did deescalations (4.1 versus 10.1 h, P < 0.01). In a pediatric institution with a low prevalence of Gram-negative resistance, the VG RDT facilitated antibiotic optimization for Gram-positive BSIs but led to unnecessary escalation of antibiotics for Gram-negative BSIs. The time to action was slower for RDT results reported at night than during the day. Laboratories should consider these factors when implementing blood culture RDTs.

Impact of mandatory indications for outpatient antibiotic orders on accurate tracking of antibiotic indications.

OBJECTIVE: We sought to evaluate whether implementing mandatory indications for outpatient electronic antibiotic orders or using encounter International Classification of Diseases, Tenth Revision (ICD10) codes more accurately reflected clinicians' charted diagnosis in encounter notes. Secondarily, we examined the appropriateness of antibiotic prescriptions. DESIGN: Cross-sectional study. METHODS: Mandatory indications were added to all outpatient electronic antibiotic orders on May 18, 2022. A randomly selected convenience sample of 1300 outpatient encounters with antibiotics from walk-in clinics was reviewed. Adjusted logistic regression was used to compare the congruence between encounter ICD10 code and charted diagnosis for encounters from July 15 to September 15, 2021 (pre-implementation period) to the congruence between encounter ICD10 code, charted diagnosis, and mandatory indication for encounters from July 15 to September 15, 2022 (post-implementation period). Antibiotic appropriateness based on charted diagnosis was also evaluated. RESULTS: Among 1300 outpatient encounters, congruence between charted diagnosis and ICD10 code significantly increased in the post-implementation period (87.7% (565/644)) versus pre-implementation (83.3% (540/648), adjusted odds ratio (aOR) 1.52; 95% CI 1.03-2.25). Congruence between charted diagnosis and mandatory indication during post-implementation was 95.2% (613/644) and >5 times more likely to be congruent than charted diagnosis and ICD10 code during pre-implementation (aOR 5.45; 95% CI 3.26-9.11). Antibiotic prescribing based on charted diagnosis was twice as likely to be appropriate in the post-implementation period (aOR1.99; 95% CI 1.32-2.98). CONCLUSIONS: Mandatory indications within antibiotic orders show better congruence with charted diagnosis than ICD10 codes and may increase antibiotic appropriateness and congruence between ICD10 code and charted diagnosis.

"Give Me Five": The Case for 5 Days of Antibiotics as the Default Duration for Acute Respiratory Tract Infections.

Acute respiratory tract infections (ARTIs) account for most antibiotic prescriptions in pediatrics. Although US guidelines continue to recommend ≥10 days antibiotics for common ARTIs, evidence suggests that 5-day courses can be safe and effective. Academic imprinting seems to play a major role in the continued use of prolonged antibiotic durations. In this report, we discuss the evidence supporting short antibiotic courses for group A streptococcal pharyngitis, acute otitis media, and acute bacterial rhinosinusitis. We discuss the basis for prolonged antibiotic course recommendations and recent literature investigating shorter courses. Prescribers in the United States should overcome academic imprinting and follow international trends to reduce antibiotic durations for common ARTIs, where 5 days is a safe and efficacious course when antibiotics are prescribed.

Intravenous antibiotics for urinary tract infections in children with neurologic impairment.

BACKGROUND: Children with high-intensity neurologic impairment (HINI) have an increased risk of urinary tract infection (UTI) and prolonged intravenous (IV) antibiotic exposure. OBJECTIVE: To determine the association between short (≤3 days) and long (>3 days) IV antibiotic courses and UTI treatment failure in hospitalized children with HINI. METHODS: We performed a retrospective cohort study examining UTI hospitalizations at 49 hospitals in the Pediatric Health Information System from 2016 to 2021 for children (1-18 years) with HINI. The primary outcome was UTI readmission within 30 days. Our secondary outcome was the association of hospital-level variation in short IV antibiotic course use with readmission. Readmission rates were compared between short and long courses using multivariable regression. RESULTS: Of 5612 hospitalizations, 3840 (68.4%) had short IV antibiotic courses. In our adjusted model, children with short IV courses were less likely than with long courses to have a 30-day UTI readmission (4.0%, 95% CI [3.6%, 4.5%] vs. 6.3%, 95% CI [5.1%, 7.8%]). Despite marked hospital-level variation in short IV course use (50.0%-87.5% of hospitalizations), there was no correlation with readmissions. CONCLUSIONS: Children with HINI hospitalized with UTI had low UTI readmission rates, but those who received long IV antibiotic courses were more likely to experience UTI readmission versus those receiving short courses. While residual confounding may influence our results, we did not find that short IV courses impacted readmission at the hospital level despite variation in use across institutions. Long IV antibiotic courses are associated with risks and may not confer benefit in this population.

Provider-ordered viral testing and antibiotic administration practices among children with acute respiratory infections across healthcare settings in Nashville, Tennessee.

Objective: Evaluate the association between provider-ordered viral testing and antibiotic treatment practices among children discharged from an ED or hospitalized with an acute respiratory infection (ARI). Design: Active, prospective ARI surveillance study from November 2017 to February 2020. Setting: Pediatric hospital and emergency department in Nashville, Tennessee. Participants: Children 30 days to 17 years old seeking medical care for fever and/or respiratory symptoms. Methods: Antibiotics prescribed during the child's ED visit or administered during hospitalization were categorized into (1) None administered; (2) Narrow-spectrum; and (3) Broad-spectrum. Setting-specific models were built using unconditional polytomous logistic regression with robust sandwich estimators to estimate the adjusted odds ratios and 95% confidence intervals between provider-ordered viral testing (ie, tested versus not tested) and viral test result (ie, positive test versus not tested and negative test versus not tested) and three-level antibiotic administration. Results: 4,107 children were enrolled and tested, of which 2,616 (64%) were seen in the ED and 1,491 (36%) were hospitalized. In the ED, children who received a provider-ordered viral test had 25% decreased odds (aOR: 0.75; 95% CI: 0.54, 0.98) of receiving a narrow-spectrum antibiotic during their visit than those without testing. In the inpatient setting, children with a negative provider-ordered viral test had 57% increased odds (aOR: 1.57; 95% CI: 1.01, 2.44) of being administered a broad-spectrum antibiotic compared to children without testing. Conclusions: In our study, the impact of provider-ordered viral testing on antibiotic practices differed by setting. Additional studies evaluating the influence of viral testing on antibiotic stewardship and antibiotic prescribing practices are needed.

Principal Component Patterns of Pediatric Respiratory Viral Testing Across Health Care Settings.

BACKGROUND AND OBJECTIVES: Factors prompting clinicians to request viral testing in children are unclear. We assessed patterns prompting clinicians to perform viral testing in children discharged from an emergency department (ED) or hospitalized with an acute respiratory infection (ARI). METHODS: Using active ARI surveillance data collected from November 2017 through February 2020, children aged between 30 days and 17 years with fever or respiratory symptoms who had a research respiratory specimen tested were included. Children's presentation patterns from their initial evaluation at each health care setting were analyzed using principal components (PCs) analysis. PC-specific models using logistic regression with robust sandwich estimators were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) between PCs and provider-ordered viral testing. PCs were assigned respiratory virus/viruses names a priori based on the patterns represented. RESULTS: In total, 4107 children were enrolled and tested, with 2616 (64%) discharged from the ED and 1491 (36%) hospitalized. In the ED, children with a coviral presentation pattern had a 1.44-fold (95% CI, 1.24-1.68) increased odds of receiving a provider-ordered viral test than children showing clinical symptoms less representative of coviral-like infection. Whereas children in the ED and hospitalized with rhinovirus-like symptoms had 71% (OR, 0.29; 95% CI, 0.24-0.34) and 39% (OR, 0.61; 95% CI, 0.49-0.76) decreased odds, respectively, of receiving a provider-ordered viral test during their medical encounter. CONCLUSIONS: Viral tests are frequently ordered by clinicians, but presentation patterns vary by setting and influence the initiation of testing. Additional assessments of factors affecting provider decisions to use viral testing in pediatric ARI management are needed to maximize patient benefits of testing.

Clinical prediction model: Multisystem inflammatory syndrome in children versus Kawasaki disease.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious complication of severe acute respiratory syndrome coronavirus 2 infection. Features of MIS-C overlap with those of Kawasaki disease (KD). OBJECTIVE: The study objective was to develop a prediction model to assist with this diagnostic dilemma. METHODS: Data from a retrospective cohort of children hospitalized with KD before the coronavirus disease 2019 pandemic were compared to a prospective cohort of children hospitalized with MIS-C. A bootstrapped backwards selection process was used to develop a logistic regression model predicting the probability of MIS-C diagnosis. A nomogram was created for application to individual patients. RESULTS: Compared to children with incomplete and complete KD (N = 602), children with MIS-C (N = 105) were older and had longer hospitalizations; more frequent intensive care unit admissions and vasopressor use; lower white blood cell count, lymphocyte count, erythrocyte sedimentation rate, platelet count, sodium, and alanine aminotransferase; and higher hemoglobin and C-reactive protein (CRP) at admission. Left ventricular dysfunction was more frequent in patients with MIS-C, whereas coronary abnormalities were more common in those with KD. The final prediction model included age, sodium, platelet count, alanine aminotransferase, reduction in left ventricular ejection fraction, and CRP. The model exhibited good discrimination with AUC 0.96 (95% confidence interval: [0.94-0.98]) and was well calibrated (optimism-corrected intercept of -0.020 and slope of 0.99). CONCLUSIONS: A diagnostic prediction model utilizing admission information provides excellent discrimination between MIS-C and KD. This model may be useful for diagnosis of MIS-C but requires external validation.

New insights into the treatment of acute otitis media.

INTRODUCTION: Acute otitis media (AOM) affects most (80%) children by 5 years of age and is the most common reason children are prescribed antibiotics. The epidemiology of AOM has changed considerably since the widespread use of pneumococcal conjugate vaccines, which has broad-reaching implications for management. AREAS COVERED: In this narrative review, we cover the epidemiology of AOM, best practices for diagnosis and management, new diagnostic technology, effective stewardship interventions, and future directions of the field. Literature review was performed using PubMed and ClinicalTrials.gov. EXPERT OPINION: Inaccurate diagnoses, unnecessary antibiotic use, and increasing antimicrobial resistance remain major challenges in AOM management. Fortunately, effective tools and interventions to improve diagnostic accuracy, de-implement unnecessary antibiotic use, and individualize care are on the horizon. Successful scaling of these tools and interventions will be critical to improving overall care for children.

AACC Guidance Document on the Clinical Use of Procalcitonin.

BACKGROUND: Procalcitonin (PCT), a peptide precursor of the hormone calcitonin, is a biomarker whose serum concentrations are elevated in response to systemic inflammation caused by bacterial infection and sepsis. Clinical adoption of PCT in the United States has only recently gained traction with an increasing number of Food and Drug Administration-approved assays and expanded indications for use. There is interest in the use of PCT as an outcomes predictor as well as an antibiotic stewardship tool. However, PCT has limitations in specificity, and conclusions surrounding its utility have been mixed. Further, there is a lack of consensus regarding appropriate timing of measurements and interpretation of results. There is also a lack of method harmonization for PCT assays, and questions remain regarding whether the same clinical decision points may be used across different methods. CONTENT: This guidance document aims to address key questions related to the use of PCT to manage adult, pediatric, and neonatal patients with suspected sepsis and/or bacterial infections, particularly respiratory infections. The document explores the evidence for PCT utility for antimicrobial therapy decisions and outcomes prediction. Additionally, the document discusses analytical and preanalytical considerations for PCT analysis and confounding factors that may affect the interpretation of PCT results. SUMMARY: While PCT has been studied widely in various clinical settings, there is considerable variability in study designs and study populations. Evidence to support the use of PCT to guide antibiotic cessation is compelling in the critically ill and in some lower respiratory tract infections but is lacking in other clinical scenarios, and evidence is also limited in the pediatric and neonatal populations. Interpretation of PCT results requires guidance from multidisciplinary care teams of clinicians, pharmacists, and clinical laboratorians.

Diagnostic models predicting paediatric viral acute respiratory infections: a systematic review.

OBJECTIVES: To systematically review and evaluate diagnostic models used to predict viral acute respiratory infections (ARIs) in children. DESIGN: Systematic review. DATA SOURCES: PubMed and Embase were searched from 1 January 1975 to 3 February 2022. ELIGIBILITY CRITERIA: We included diagnostic models predicting viral ARIs in children (<18 years) who sought medical attention from a healthcare setting and were written in English. Prediction model studies specific to SARS-CoV-2, COVID-19 or multisystem inflammatory syndrome in children were excluded. DATA EXTRACTION AND SYNTHESIS: Study screening, data extraction and quality assessment were performed by two independent reviewers. Study characteristics, including population, methods and results, were extracted and evaluated for bias and applicability using the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies and PROBAST (Prediction model Risk Of Bias Assessment Tool). RESULTS: Of 7049 unique studies screened, 196 underwent full text review and 18 were included. The most common outcome was viral-specific influenza (n=7; 58%). Internal validation was performed in 8 studies (44%), 10 studies (56%) reported discrimination measures, 4 studies (22%) reported calibration measures and none performed external validation. According to PROBAST, a high risk of bias was identified in the analytic aspects in all studies. However, the existing studies had minimal bias concerns related to the study populations, inclusion and modelling of predictors, and outcome ascertainment. CONCLUSIONS: Diagnostic prediction can aid clinicians in aetiological diagnoses of viral ARIs. External validation should be performed on rigorously internally validated models with populations intended for model application. PROSPERO REGISTRATION NUMBER: CRD42022308917.

Reducing length of antibiotics for children with ear infections: protocol for a cluster-randomized trial in the USA.

Aim: Preventing unnecessarily long durations of antibiotic therapy is a key opportunity to reduce antibiotic overuse in children 2 years of age and older with acute otitis media (AOM). Pragmatic interventions to reduce durations of therapy that can be effectively scaled and sustained are urgently needed. This study aims to fill this gap by evaluating the effectiveness and implementation outcomes of two low-cost interventions of differing intensities to increase guideline-concordant antibiotic durations in children with AOM. Methods: The higher intensity intervention will consist of clinician education regarding guideline-recommended short durations of antibiotic therapy; electronic health record (EHR) prescription field changes to promote prescribing of recommended short durations; and individualized clinician audit and feedback on adherence to recommended short durations of therapy in comparison to peers, while the lower intensity intervention will consist only of clinician education and EHR changes. We will explore the differences in implementation effectiveness by patient population served, clinician type, clinical setting and organization as well as intervention type. The fidelity, feasibility, acceptability and perceived appropriateness of the interventions among different clinician types, patient populations, clinical settings and intervention type will be compared. We will also conduct formative qualitative interviews with clinicians and administrators and focus groups with parents of patients to further inform the interventions and study. The formative evaluation will take place over 1.5 years, the interventions will be implemented over 2 years and evaluation of the interventions will take place over 1.5 years. Discussion: The results of this study will provide a framework for other healthcare systems to address the widespread problem of excessive durations of therapy for AOM and inform national antibiotic stewardship policy development. Clinical Trial Registration: NCT05608993 (ClinicalTrials.gov).

Dynamics of urinary polyomavirus shedding in healthy adult women.

The hypothesis was examined that physiologic variation of estrogen concentrations during the menstrual cycle can provoke BK virus (BKV) excretion. BKV and JCV viral loads were determined in urine specimens obtained almost daily from 20 healthy, non-pregnant women over 2 months. Asymptomatic urinary shedding of BKV was observed in 123 (12.0%) of 1,021 specimens from 11 (55%) study subjects. Two subjects excreted JCV in their urine, with one subject excreting detectable JCV in all urine specimens. Analysis of 36 complete menstrual cycles revealed no difference in the prevalence of BKV excretion between pre-ovulatory and post-ovulatory phases of the menstrual cycle. The unexpected day-to-day variability in BKV excretion suggests that as yet unidentified factors may contribute to the periodic shedding of BKV by healthy women.

A qualitative assessment of nonclinical drivers of pediatric outpatient antibiotic prescribing: The importance of continuity.

Background and objectives: Antibiotic overuse is common in outpatient pediatrics and varies across clinical setting and clinician type. We sought to identify social, behavioral, and environmental drivers of outpatient antibiotic prescribing for pediatric patients. Methods: We conducted semistructured interviews with physicians and advanced practice providers (APPs) across diverse outpatient settings including pediatric primary, urgent, and retail care. We used the grounded theory constant comparative method and a thematic approach to analysis. We developed a conceptual model, building on domains of continuity to map common themes and their relationships within the healthcare system. Results: We interviewed 55 physicians and APPs. Clinicians across all settings prioritized provision of guideline-concordant care but implemented these guidelines with varying degrees of success. The provision of guideline-concordant care was influenced by the patient-clinician relationship and patient or parent expectations (relational continuity); the clinician's access to patient clinical history (informational continuity); and the consistency of care delivered (management continuity). No difference in described themes was determined by setting or clinician type; however, clinicians in primary care described having more reliable relational and informational continuity. Conclusions: Clinicians described the absence of long-term relationships (relational continuity) and lack of availability of prior clinical history (informational continuity) as factors that may influence outpatient antibiotic prescribing. Guideline-concordant outpatient antibiotic prescribing was facilitated by consistent practice across settings (management continuity) and the presence of relational and informational continuity, which are common only in primary care. Management continuity may be more modifiable than informational and relational continuity and thus a focus for outpatient stewardship programs.

Improvements in appropriate ambulatory antibiotic prescribing using a bundled antibiotic stewardship intervention in general pediatrics practices.

OBJECTIVE: To improve appropriate antibiotic prescribing for children in Tennessee. DESIGN: We performed a before-and-after intervention study with 3 comparison periods: period 1 (P1, baseline) May 2018-September 2019; period 2 (P2, intervention before the COVID-19 pandemic) November 11, 2019-March 20, 2020; and period 3 (P3, intervention during the coronavirus disease 2019 [COVID-19] pandemic) March 21, 2020-November 10, 2020. We additionally surveyed participating providers to assess acceptance of the intervention. SETTING: Community general pediatrics practices. PARTICIPANTS: In total, 81 general pediatricians, family medicine physicians, and nurse practitioners in 5 general pediatrics practices participated in this study. INTERVENTIONS: Each practice identified a practice and operations champion for the project. Practices chose 2-4 implementation strategies previously shown to be effective at reducing outpatient antibiotic use to implement in their practice throughout the study intervention period. Study personnel also held quarterly meetings with all providers to review deidentified peer comparison feedback both across practices enrolled in the study and at the provider level within each practice. RESULTS: We detected improvements in guideline-concordant antibiotic use in the pre-COVID-19 intervention period, and they were sustained in the study period during the pandemic (P3): otitis media (P1 72.14% vs P2 81.42% vs P3 86.11%), group A streptococcal pharyngitis (P1 66.13% vs P2 81.56% vs P3 80.44%), pneumonia (P1 70.6% vs P2 76.2% vs P3 100%), sinusitis (P1 76.2% vs P2 83.78% vs P3 82.86%), skin and soft-tissue infections (P1 97.18% vs P2 100% vs P3 100%). CONCLUSIONS: Bundled implementation strategies led to significant increases in guideline-concordant antibiotic prescribing for all diagnoses. Survey results demonstrate that the bundled implementation strategies were well-accepted by providers.

Multisystem inflammatory syndrome in a fully vaccinated 18-year-old without known SARS-CoV-2 infection.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a febrile syndrome that is observed in the pediatric population following severe acute respiratory syndrome 2 (SARS-CoV-2) infection. Vaccines have prevented or lessened the severity of the initial acute respiratory infection, while their effectiveness against severe MIS-C is just beginning to be reported. CASE PRESENTATION: Here we report a fully vaccinated teenage female with no known history of SARS-CoV-2 infection who presented with shock and heart failure. Her presentation was initially thought secondary to a retropharyngeal abscess but was later identified as MIS-C after confirmed nucleocapsid antibody. CONCLUSIONS: Given the recent Omicron waves, the ongoing international outbreaks with evolving variants and the continued evolution of the COVID-19 pandemic, this case emphasizes the need to include MIS-C in the differential diagnosis, even in a fully vaccinated, previously healthy child.