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Updates in pediatric emergency medicine for 2021

Journal logoUnlabelled imageAmerican Journal of Emergency Medicine 56 (2022) 244-253

Contents lists available at ScienceDirect

American Journal of Emergency Medicine

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Updates in pediatric emergency medicine for 2021

Joshua Easter, MD a,?, Frank Petruzella, MD b

a Department of Emergency Medicine, University of Virginia, 200 Jeanette Lancaster Way, Charlottesville, VA 22903, United States of America

b Department of Emergency Medicine, Virginia Commonwealth University, Box 980401, Richmond, VA, 23298-0401, United States of America

a r t i c l e i n f o

Article history:

Received 2 January 2022

Received in revised form 3 February 2022 Accepted 14 February 2022

Keywords:

Pediatric trauma Fever Pneumonia

herpes simplex virus

Brief resolved unexplained event

a b s t r a c t

Physicians routinely treat sick children in the emergency department (ED). Many relevant articles on pediatric medicine are published in journals that are not typically read by many general emergency medicine physicians. We reviewed salient pediatric emergency medicine literature from the past year and identified ten impactful articles for general emergency physicians. This review includes studies of pediatric pneumonia, brief resolved un- explained events, covid-19, Hemorrhage control, Retropharyngeal abscess, infant fever, diabetic ketoacidosis, mastitis, buckle fractures, and invasive herpes simplex virus infection.

(C) 2022

  1. Introduction

Physicians routinely treat sick children in the emergency depart- ment (ED). Many relevant articles on pediatric medicine are published in journals that are not typically read by many general emergency medicine physicians. We reviewed salient pediatric emergency medicine literature from the past year and identified ten impactful arti- cles for general emergency physicians. This review includes studies of pediatric pneumonia, brief resolved unexplained events, covid-19, hem- orrhage control, retropharyngeal abscess, infant fever, diabetic ketoaci- dosis, mastitis, buckle fractures, and invasive herpes simplex virus infection. Table 1 includes a summary of the articles and key findings.

  1. Dose and duration of antibiotics for community acquired pneumonia

Bielicki JA et al. and the CAP-IT Trial Group. Effect of Amoxicillin Dose and Treatment Duration on the Need for Antibiotic Re-treatment in Children With Community-Acquired Pneumonia: The CAP-IT Randomized Clinical Trial. JAMA. 2021 Nov 2;326(17):17131724. https://doi.org/ 10.1001/jama.2021.17843.

Respiratory infections are a quite common cause for young children to present to the ED. In children diagnosed with Community acquired pneumonia , only 1/3 of these infections have been shown to have a bacterial origin, and neither radiography nor inflammatory markers can reliably differentiate these from those with a viral etiology

* Corresponding author.

E-mail address: [email protected] (J. Easter).

[1-6]. This potentially leads to overprescribing of antibiotics and thereby contributes to antibiotic resistance. Compared with the Primary care setting, patients seen in the ED are much more likely to be prescribed systemic antibiotics for presumed pneumonia [7,8]. Optimization of dosing and duration of antibiotic therapy for CAP is important for antibiotic stewardship as well as patient safety. While no studies have compared high (70-90 mg/kg/day) and low dose (30-50 mg/kg/day) amoxicillin in CAP, prior studies in Low- and middle-income countries have shown successful treatment of mild to moderate CAP with a shorter duration of 3 to 5 days with amoxicillin [9,10]. It is unclear, whether these results can be generalized to other settings.

In this multicenter, randomized, blinded, placebo-controlled nonin- feriority study, Bielicki et al. compared both the duration of, and the total Daily dosing of amoxicillin in the treatment of childhood CAP [11]. The study randomized children over 6 months of age seen either in the ED or inpatient wards with a diagnosis of CAP to receive one of four treatment courses with amoxicillin: 1) 35-50 mg/kg/d for 3 days,

2) 35-50 mg/kg/d for 7 days, 3) 70-90 mg/kg/d for 3 days, or 4) 70-90 mg/kg/d for 7 days. The primary endpoint in the study was the need for additional systemic antibiotic therapy for any respiratory ill- ness within 28 days of randomization. To determine the primary endpoint, each case was reviewed by a blinded review committee. Secondary endpoints included duration and severity of CAP symptoms, adherence to the trial medication regimen, adverse reactions to the reg- imen, and presence of ?-lactam resistant S pneumoniae in nasopharyn- geal cultures at 28 days. Inclusion criteria were weight of 6-24 kg and clinically diagnosed CAP for which monotherapy with amoxicillin was planned upon discharge from either the ED or inpatient ward. The au- thors excluded children with prior ?-lactam treatment for >48 h, any prior non-?-lactam treatment, severe underlying chronic disease,

https://doi.org/10.1016/j.ajem.2022.02.019

0735-6757/(C) 2022

Table 1

Summary of articles and key findings.

Article Clinical topic Study type Key findings

Bielicki JA et al. and the CAP-IT Trial Group. Effect of Amoxicillin Dose and Treatment Duration on the Need for Antibiotic Re-treatment in Children With Community-Acquired Pneumonia: The CAP-IT Randomized Clinical Trial. JAMA. 2021 Nov 2;326 (17):1713-1724.

Bochner et al. Explanatory diagnoses following hospitalization for a brief resolved unexplained event. Pediatrics 2021, November; 148(5).

Community acquired pneumonia

Brief resolved unexplained events (BRUE)

Multicenter, randomized, blinded, placebo-controlled trial

Multicenter, retrospective cohort analysis

-3 day duration of amoxicillin non-inferior to 7 day duration of amoxicillin

-Lower dose (30-50 mg/kg/d) non-inferior to higher dose (70-90 mg/kg/d) of amoxicillin

-Shorter duration and lower dose were inferior for patients with severe disease

-Serious diagnosis for BRUE identified in 1.5% of hospitalizations

-Most common serious diagnoses were seizures, infantile spasms, and lower respiratory tract infections

Graff et al. Risk factors for severe COVID-19 infection. Pediatric Infect Dis J 2021, April; 40(4).

Spinella et al. Use of antifibrinolytics in pediatric Life-threatening hemorrhage: a prospective

observational multicenter study. Crit Care Med 2021, October; 34,661,553.

Goenka PK et al. Corticosteroids in the Treatment of Pediatric Retropharyngeal and Parapharyngeal Abscesses. Pediatrics. 2021 Nov;148(5).

Covid-19 Multicenter, retrospective cohort analysis

Hemorrhage Multicenter, prospective observational analysis

Retropharyngeal abscess Multicenter, retrospective

cohort analysis

-Younger (<4 months) or older (>20 years) age,

co-morbidities, and shortness of breath had increased risk of severe disease

-Male sex, obesity, and neurologic did not have increased risk

-Children receiving antifibrinolytics had reduced mortality at 6 h (OR = 0.3) and 24 h (OR = 0.5)

-No differences in mortality between TXA and ACA

-Steroid administration was associated with reduced need for surgery (OR = 0.28)

-There were no differences in the duration of hospitalization with and without steroid administration

-Children receiving steroids were more likely to return to the ED within 7 days (OR = 2.2)

Pantell et al. Evaluation and management of well-appearing febrile infants 8 to 60 days old. Pediatrics 2021, August; 148(2).

Infant fever Consensus guidelines -Full sepsis evaluation, antibiotics, and admission if <22

days old

-Urine and blood cultures if 22-60 days old

-Inflammatory markers to risk stratify and determine need for CSF acquisition and admission, if 22-60 days old

Glaser NS et al.. Serum sodium concentration and Mental Status in Children With Diabetic Ketoacidosis.

Pediatrics. 2021 Sep;148(3).

Diabetic ketoacidosis Secondary analysis of

multicenter, randomized controlled trial

-There were no differences in mental status between children with declining Sodium levels during treatment and stable or increasing sodium levels

-Declining sodium levels during treatment were more common in patients with higher initial sodium levels

Kaplan RL et al. Neonatal Mastitis and Concurrent serious bacterial infection. Pediatrics. 2021 Jul;148(1).

Colaco et al. Home Management Versus Primary Care Physician Follow-up of Patients With Distal Radius Buckle Fractures: A Randomized Controlled Trial. Ann Emerg Med. 2021 Feb;77(2):163-173.

Cruz et al. Predictors of invasive herpes simplex virus infection in young infants. Pediatrics. 2021, September; 148(3).

Concurrent bacterial infection with mastitis

Buckle fracture of the radius

Invasive herpes simplex virus infection

Multicenter, retrospective cross-sectional study

Single center, randomized, controlled, single blinded trial

Multicenter, retrospective Nested case-control study

-Serious bacterial infection occurred in <1% of patients, but all of these patients were well appearing

-Contamination of blood cultures occurred in 4% of patients

-Patient self-removal of a pre-made splint at 1 week without PCP follow-up and with PCP follow-up resulted in similar compliance, disability, and patient satisfaction

-Self-removal was less costly

-Age <= 28 days, vesicular rash, and seizure were associated with invasive HSV

-Thrombocytopenia, CSF pleocytosis were associated with invasive HSV

Abbreviations: TXA = Tranexamic acid; ACA = aminocaproic acid; OR = odds ratio; PCP = primary care physician; CSF = cerebrospinal fluid; HSV = herpes simplex virus.

complicated pneumonia (i.e., sepsis or local parenchymal or pleural complications), bilateral wheezing, or any prior adverse reaction to amoxicillin. Diagnosis of CAP was consistent with British Thoracic Society guidelines [12].

Over a 26 month period in 29 hospitals in the United Kingdom and Ireland, 824 children were enrolled, and 814 participated. Nearly three quarters (73%) of participants were discharged from the ED, and 27% had inpatient stays of less than 48 h. The authors were able to collect primary endpoint data for 97% (789) of children, and 100 patients (12%) required additional systemic antibiotics. Between the treatment groups, there was no significant difference in the frequency of patients requiring additional systemic antibiotics (12.6% (51/410) in the lower- dose group and 12.4% (49/404) in the higher-dose group (difference, 0.2% [1-sided 95% CI, -? to 4.0%]), and 12.5% (51/413) in the shorter-

two or more abnormal Physiological parameters present at the time of enrollment. In both subgroups the analysis failed to show noninferior- ity, with a trend toward favoring higher dose amoxicillin, and longer du- ration of therapy.

Secondary outcomes analysis showed a small increase in cough du- ration and sleep disruption in patients receiving a shorter course of amoxicillin, but no difference in cough severity or the time to resolution of fever, rapid breathing, wheezing, interference with normal activity, vomiting, reduced appetite, phlegm production. When assessing for any difference in penicillin or amoxicillin resistance between duration

Table 2 Frequency of the need for subsequent systemic antibiotics in children treated with various amoxicillin regimens.

duration group vs 12.5% (49/401) in the longer-duration group (differ- ence, 0.1% [1-sided 95% CI, -? to 3.9%]), indicating noninferiority between treatment groups (Table 2). Subgroup analysis of the primary endpoint was performed comparing patients who had received prior in- patient antibiotics to those who had not, as well as those with severe CAP versus those with Non-severe CAP. Severe CAP was defined as

antibiotics

Dose (%)

Dose (%)

Duration (%)

Duration (%)

All patients

12.6

12.4

12.5

12.5

Severe CAP

17.3

13.5

16.0

14.8

Prior inpatient

15.3

11.5

15.2

11.3

Lower

Higher

Shorter

Longer

or dosage groups, the authors used Streptococcus pneumoniae culture results obtained by nasopharyngeal swab. Although not explicitly stated in the study, this was presumably done due to the fact that S. pneumoniae is the most common etiology of bacterial CAP in children. Resistance was determined based on standard Minimal inhibitory concentrations (MIC) of nasopharyngeal cultures. Analysis showed no difference in resistance to penicillin or amoxicillin between dosage groups or duration groups. Finally, there were no significant differences between groups in adherence to the medication regimen or frequency of drug-related adverse events.

The authors discussed several limitations. The first was the impre- cise identification of those patients with bacterial CAP. Given the signif- icant overlap in symptoms between bacterial CAP and viral CAP, as well as obstructive processes such as viral induced wheezing, asthma, and bronchiolitis, there were likely children included in the study without true bacterial CAP. An attempt was made to mitigate this by excluding those children with bilateral wheezing and no lateralizing findings on exam. While there is no single physical exam finding, laboratory test, or Imaging study that can reliably differentiate between bacterial and viral CAP, the authors could have attempted to further distill the study group by excluding patients with a known cause of viral pneumonia, such as those with a positive influenza test.

Second, there were no children in the study hospitalized for more

than 48 h, and therefore results are not applicable to children receiving prolonged inpatient treatment. Third, the exclusion of children with underlying comorbidities makes the study ungeneralizable to these po- tentially ill children. Finally, given the number of comparisons being made between the four subgroups for secondary endpoints, the authors recognize the propensity for type 1 error, and caution that these second- ary endpoint analyses should be interpreted as exploratory.

In this large, multicenter, randomized controlled trial, Bielicki et al. found that a 3 day course of amoxicillin was noninferior to a 7 day course, and that low dose was noninferior to high dose treatment for CAP in previously healthy patients discharged from the ED or from a short inpatient stay. Although perhaps not generalizable to children with chronic medical conditions or those with severe illness requiring intensive care or prolonged admission, these findings are applicable to a large proportion of children with uncomplicated CAP evaluated in the ED. Reducing the duration or strength of amoxicillin therapy in this population has the potential to have a significantly mitigate antibi- otic resistance.

  1. Outcomes of brief resolved unexplained events

Bochner et al. Explanatory diagnoses following hospitalization for a brief resolved unexplained event. Pediatrics 2021, November; 148(5); e2021052673.

In 2016 the American Academy of Pediatrics published guidelines that replaced apparent life threatening events (ALTE) with a new condition, brief resolved unexplained event (BRUE) for infants <1 year of age presenting with transient alterations in their breathing, ap- pearance, or behavior that cannot be explained based on their history or physical examination [13]. With a BRUE a child may present with al- terations in their breathing, tone, or responsiveness. Unlike ALTE, for a child with a BRUE there is no clear explanation for the event on presen- tation to the ED. BRUEs are classified as low risk, if the child is >60 days of age and was born >=32 weeks, there is no history of prior BRUEs, and CPR (by a health care provider) was not performed during the event. If these features are present, infants are potentially at higher risk of re- current events or adverse outcomes. While small retrospective studies suggest it might be safe to discharge children with low risk BRUEs, there is little evidence for the management of high risk BRUEs [14,15]. A tiered approach of testing in the ED followed by admission has been proposed but is not validated [16]. It is unclear how often admission re- sults in identification of a serious Underlying etiology for the BRUE.

Bochner et al. aimed to assess the benefits of inpatient hospitaliza- tion for children with BRUEs [17]. They performed a multicenter retro- spective cohort study of children <1 year of age with a BRUE admitted to 15 hospitals in the BRUE Research and Quality Improvement Network between 2015 and 2018. Children with BRUEs were identified through International Classification of Diseases, 10th Revision (ICD-10) codes consistent with BRUEs, including common BRUE symptoms such as Altered consciousness. The investigators reviewed medical records to confirm children met criteria for BRUE as well to determine discharge and follow-up diagnoses. They reviewed all ED visits, clinic visits, and hospitalizations for children until they reached one year of age. The out- comes were diagnoses that explained the BRUE and serious diagnoses, where a Delay in diagnosis or treatment could potentially increase morbidity or mortality. A review committee determined these out- comes. If the diagnosis only “possibly” explained the event, it was not considered in the outcome. Secondary outcomes were the frequency with which diagnostic tests or subspecialty consultations contributed to the establishment of diagnoses.

During the study period, 2036 infants presented to the ED for a BRUE and nearly two thirds (63%) were hospitalized. For over one third (37%) of infants an explanatory diagnosis was identified during hospitaliza- tion. Only 1.5% of infants admitted with a BRUE had a serious diagnosis during their admission. The most frequent serious diagnoses identified during admission were seizures (54%), infantile spasms (14%), severe lower respiratory tract infections requiring respiratory support (11%), and airway abnormalities (7%) (e.g., laryngomalacia requiring surgery). Less serious etiologies were much more common, such as gastroesoph- ageal reflux, choking, and viral infections. Diagnostic tests (7%) and Subspecialty consultation (10%) rarely contributed to the establishment of diagnoses. Interestingly, after discharge from the hospital, a small proportion (9%) of patients went on to receive a diagnosis before one year of age and nearly one quarter of these (22%) were serious.

The primary limitation of this study is that it was performed retro- spectively and relied on abstraction from the medical record. While it is possible that the investigators missed diagnoses utilizing this approach, it is less likely that serious diagnoses would not be clear in the medical record. In addition, the study was performed during the early stages of the introduction of the term BRUE, and it is possible clini- cians may have admitted BRUEs deemed low risk by the guidelines, thereby reducing the frequency of serious etiologies for the events. It would have been useful for the investigators to distinguish between the frequency of serious etiologies for low and high risk BRUEs. If the preponderance of serious etiologies arose in patients with high risk fea- tures, it would provide further evidence that low risk BRUEs can be safely discharged from the ED. Finally, after discharge the investigators were only able to review follow-up visits that happened at their institu- tions, and it is possible patients went elsewhere for care and received serious diagnoses.

Despite these limitations, this large cohort study demonstrates the relatively low yield of hospitalization for infants with BRUEs, with

<2% of infants receiving a serious diagnosis during their hospital admis- sion. Similarly, diagnostic testing and subspecialty consultations were rarely useful. This frequency of serious diagnosis is lower than prior studies [18,19]. Given the relatively low yield of hospitalization, we recommend a shared decision-making approach for patients with BRUE, including a candid discussion about the risks and benefits of hos- pitalization. Future studies may help determine if there are particular risk factors that might identify patients, who are more likely to have se- rious underlying diagnoses and therefore benefit from hospitalization.

  1. Predictors of severe covid-19 disease

Graff et al. Risk factors for severe COVID-19 infection. Pediatric Infect Dis J 2021, April; 40(4); 33,538,539.

In contrast to adults, the risk factors for severe disease in children with Covid-19 are relatively unknown. For adults, older age, male

sex, obesity, and co-morbidities are associated with severe covid-19 [20,21]. These risk factors for severe disease in adults help guide decision making about treatments, including monoclonal antibody infusions. A better understanding of risk factors for severe disease in children would help facilitate similar Treatment decisions as well as public health planning.

In this study, Graff et al. assessed risks for severe covid-19 infection, as defined by the need for hospital admission, respiratory support, or critical care [22]. They conducted a retrospective cohort study of all children <21 years of age presenting to two hospitals and 13 outpatient locations in Colorado with a positive SARS-CoV-2 test in the spring of 2020. For the initial 4 weeks of the study only admitted patients under- went covid-19 testing. Subsequently, outpatients were tested as well. The authors reviewed the electronic health record to measure risk fac- tors for severe covid-19 infection, including age, symptoms, co-morbid- ities, and laboratory values. They excluded patients with aSymptomatic COVID-19 infection. They performed multivariable regression to identify predictors.

During the four months of the study, 454 children with covid-19 were enrolled, and over 2/3 s (69%) were symptomatic. Slightly over half (55%) were Hispanic or Latino, and nearly half (45%) of chil- dren had >=1 comorbid condition. Almost one fifth (19%) of patients were admitted. Over half (55%) of admitted patients required respi- ratory support, with 72%of these receiving supplemental oxygen via nasal cannula, 14% via noninvasive positive pressure ventilation, and 6% via intubation. Nearly one fifth (17%) of children required critical care. One child (1%) with multiple co-morbidities died. In multivari- able models, infants <4 months of age (OR = 7.9; 95% CI, 3-20)) and children >20 years (OR = 5.1; 95% CI, 1.2-21) were more likely to require admission. The presence of any comorbidity increased the risks of admission (OR = 2.7; 95% CI, 1.6-4.7), with the risk greatest for cardiac disease (OR = 6.6; 95% CI, 1.1-40), immunocompromise (OR = 3.5; 95% CI, 1.5-8.1), and prematurity (OR = 3.5; 95% CI, 1.1-

11). Similarly, age < 4 months (OR = 4.6; 95% CI, 1.4-15), age > 20 years (OR = 6.4; 95% CI, 1.4-30), pulmonary comorbidities (OR = 3.1; 95% CI, 1.4-6.9) and gastrointestinal disease (OR = 4.0; 95% CI, 1.7-9.0) were associated with the need for respiratory support. In terms of symptoms, fever >100.4o F (OR = 5.3; 95% CI, 2.2-13), shortness of breath (OR = 16; 95% CI 6.4-39), and abdominal pain (OR = 3.9; 95% CI, 1.4-11) were associated with the need for respi- ratory support. An elevated C-reactive protein (CRP) was also associ- ated with need for critical care (OR = 1.2; 95% CI, 1.0-1.4). Notably, male sex, neurologic disease, obesity, psychiatric disease, and chest pain were not significantly associated with the need for admission or respiratory support in children.

The greatest limitation of this study is that the decision to admit pa- tients was not standardized and therefore identified predictors may have been confounders. This issue was exacerbated, because during the initial phase of the study only admitted patients were enrolled; although, only 6% of the cohort was enrolled during this time. In con- trast to hospitalization, the outcome of need for respiratory support was less subjective. With many of the same risk factors regarding need for admission also present for need for respiratory support, the conclusions of the study likely remain valid. It is also uncertain how well these results translate to the new strains of covid-19 currently cir- culating. Finally, it is unclear if the authors defined the risk factors a priori.

As covid-19 infection in children becomes more prevalent, this large study of children with covid-19, provides clues about several risk factors that should raise concern for more severe disease. In particular, young age (<4 months), presence of co-morbidities, and shortness of breath on presentation were associated with need for admission and respira- tory support. Unlike in adults, male sex, neurologic disease, and obesity were not associated with more severe disease. Future studies will need to validate these findings in larger cohorts to determine the impact on outcomes.

  1. Antifibrinolytics for hemorrhage

Spinella et al. Use of antifibrinolytics in pediatric life-threatening hem- orrhage: a prospective observational multicenter study. Crit Care Med 2021, October; 34,661,553.

Studies in hemorrhaging adults have shown varied impact from administration of antifibrinolytics [23-25]. Children’s coagulation and physiologic response to bleeding differs from adults. While children are less likely to experience life threatening hemorrhage than adults, their mortality remains high (24-65%) when bleeding is severe [26,27]. Small or retrospective studies in children suggest there may be a benefit to administering Tranexamic acid or aminocaproic acid (ACA) to children, but a recent systematic review concluded there was insufficient evidence to render a recommendation about their routine administration [28-31]. Perhaps as a result, antifibrinolytics are administered less commonly to children than adults with hemorrhage [32,33].

This study was a secondary analysis of a large multicenter prospec- tive observational study of children with life threatening bleeding (Mas- sive transfusion epidemiology and outcomes in children study) [34]. The authors aimed to determine the effects of antifibrinolytics on sur- vival from life threatening hemorrhage. They reviewed data collected from 24 hospitals on children <18 years of age with life threatening hemorrhage, as defined by the activation of a massive transfusion proto- col, administration of >40 ml/kg of any blood product, or administration of blood products for >=6 h. The study was observational and hence the decision to administer antifibrinolytics was made by the treating physi- cian. The primary outcomes were survival at 6 and 24 h with a second- ary outcome of survival at 28 days. Cox proportional hazards regression modeling was employed to identify predictors of survival.

The study enrolled 449 children with life threatening bleeding, with 34% stemming from trauma, 46% from an operative procedure, and 20% from a medical etiology. bleeding events were approximately equally divided between the ED, ICU, and operating room. Only 12% of patients received antifibrinolytics, and nearly two thirds (65%) received TXA (median dose of 20 mg/kg; IQR: 14-43 mg/kg). Patients receiving antifibrinolytics were not statistically different from those not receiving antifibrinolytics in terms of their pediatric risk of Mortality score (a composite score including vital signs, laboratory values, and Glasgow Coma Scale scores), etiology of their bleeding, presence of hypotension, tachycardia, baseline hemoglobin, platelet count, or International normalized ratio . They were more likely to have prolonged life- threatening bleeding (383 min versus 196 min for patients not receiving antifibrinolytics) and more likely to receive larger overall volumes of blood products (89 ml/kg versus 56 ml/kg respectively), and receive re- combinant factor VIIa replacement (29% vs 10% respectively). There were no significant differences in administration of antifibrinolytics be- tween participating sites.

Patients receiving antifibrinolytics had significantly lower 6 h mor- tality (6%) compared to patients not receiving antifibrinolytics (17%). There were no significant differences in bivariate analyses between groups for mortality at 24 h (13% versus 23%) or 28 days (38% versus 38%). In contrast Cox Proportional-hazards regression modeling includ- ing age, etiology of the bleeding, and the pediatric risk of mortality score, revealed that patients receiving antifibrinolytics had reduced mortality at 6 h (OR = 0.29 95% CI, 0.09-0.93) and 24 h (OR = 0.45;

95% CI, 0.21-0.98) but not 28 days (OR = 0.78; 95% CI, 0.49-1.3).

Other variables, such as participating center, blood product volume, crystalloid volume, and administration of factor VIIa, were ultimately not included in this model, as they did not improve the model’s fit. There were no mortality differences between TXA and ACA. No children experienced seizures, a rare side effect of TXA. Over half of children receiving ACA developed acute kidney injury.

There are a few limitations to this study. First, there was not a benefit to antifibrinolytics at 28 days. However, mortality during this period likely stems from factors apart from the impact of the antifibrinolytic,

such as progression of the underlying cause of the bleeding. Second, this was an observational study and therefore there was no standardization regarding timing and dose of antifibrinolytics (e.g., most children received a lower dose of TXA than recommended in the literature). In addition, most patients received TXA but the investigators did not differentiate between the particular antifibrinolytic agents. It is possible that ACA does not provide the same benefits as TXA. Finally, most of the patients did not undergo functional coagulation tests (e.g., thromboelastography), and these could impact the results.

This is the first multicenter prospective study of antifibrinolytics in children showing a Survival benefit. Few studies in children are able to show Mortality benefits, and therefore these results are potentially im- pactful. Moreover, they demonstrated a mortality benefit in children with various etiologies of their hemorrhage, including both trauma and medical etiologies. In the future, a randomized control trial would help validate these findings and mitigate confounders. In the meantime, we consider TXA relatively safe and recommend its administration for children with life threatening hemorrhage.

  1. Steroids for retropharyngeal abscesses

Goenka PK et al. Corticosteroids in the Treatment of Pediatric Retropharyngeal and Parapharyngeal Abscesses. Pediatrics. 2021 Nov;148 (5):e2020037010. https://doi.org/10.1542/peds.2020-037010. Epub 2021 Oct 25. PMID: 34697219.

For the past 20 years, the incidence of retropharyngeal abscess and parapharyngeal abscess has increased [35-37]. These infections predominate in young children, as they are the result of infection of retropharyngeal lymph nodes, which typically disappear by late school age. Treatment for retropharyngeal and parapharyngeal abscesses ranges from medical management alone, to a combination of medical and surgical management. When possible, medical management alone is advantageous to both patients and health systems, as patients are not exposed to the risks of anesthesia and surgery, require fewer overall resources, and incur lower health care expenses [38]. One therapy that has been used to attempt to improve the success of medical management is the addition of Systemic corticosteroids to intravenous

(IV) antibiotics. While their anti-inflammatory effects can reduce symp- tomatology, there is concern that by masking these symptoms steroids may impede the ability to recognize worsening infection.

In this retrospective study of data from the Pediatric Health Informa- tion System (PHIS), Goenka et al. sought to evaluate the relationship be- tween adjunctive therapy with Systemic corticosteroids and surgical drainage of retropharyngeal and parapharyngeal abscesses [39]. The PHIS database contains clinical and resource utilization data from 46 tertiary care pediatric hospitals. Patients eligible for inclusion in the study were admitted between January 2016 and December 2019 and were between the ages of 2 months and 8 years with a diagnosis of retropharyngeal or parapharyngeal abscess as indicated by ICD-10 codes. Patients with complex chronic conditions, congenital airway malformations, history of trauma, or history of a comorbidity requiring daily or frequent corticosteroid (both systemic and inhaled) usage were excluded. The authors were interested in systemic corticosteroid usage before any surgical intervention, and so patients who began corticoste- roids on the day of or after surgery were considered in the non-cortico- steroid group. The primary outcome of the study was the need for surgical drainage. Secondary outcomes included repeat computer tomography (CT) of the neck, use of IV hydration, IV pain management, length of hospital stay , return visit to the ED within 7 days of discharge, Hospital readmission at 30 days, and overall hospital cost. Outcomes were risk-adjusted to account for patient clustering within participating hospitals.

During the study period, 2259 patients were identified who met in-

clusion criteria. The median age of these patients was 3 years, with a slight male predominance (61% male). Few patients had illness severe enough to warrant critical care, with only 3% of patients requiring

intensive care unit (PICU) admission. Roughly one quarter of patients (26%) received systemic corticosteroids, with usage varying signifi- cantly among study hospitals. Dexamethasone was the corticosteroid used in 98% of cases (85% parenterally). There were no differences in the demographics or in illness severity seen between the corticosteroid and non-corticosteroid groups. Antibiotic management differed signifi- cantly between groups, with 35% of the corticosteroid group receiving clindamycin monotherapy, and 36% of the non-corticosteroid group re- ceiving ?-lactam and/or ?-lactamase inhibitor monotherapy (p < .001).

Surgical drainage was much less frequent in the corticosteroid group vs. the non-corticosteroid group (22% vs 52%; P < .001), with an adjusted OR of 0.28 (95% CI 0.22-0.36). Analysis of secondary outcomes showed that the corticosteroid group had an increased frequency of re- peat CT scans (9.8% vs. 6.4% p = .006), required less Opioid analgesia (45.2% vs. 54.4% p < .001), and had lower hospital costs. Length of stay was shortened by 4 h in the corticosteroid group on unadjusted analysis, but this difference disappeared after risk adjustment. While there were no differences in 30 day readmission between groups, the corticosteroid group had increased odds of a return visit to an ED within 7 days (OR 2.2; 95% CI 1.2-4.1).

The authors discuss several limitations to this study. First, the retro- spective, observational design does not allow for determination of cau- sation. Second, the database did not contain clinical details, which could have affected outcomes, such as dosing and frequency of corticosteroid administration. They were also unable to determine the rationale be- hind administration of corticosteroids, which they comment may have allowed for residual confounding by indication. Also, the database did not include any imaging or laboratory studies, and so they were unable to ascertain whether corticosteroid use was associated more frequently with certain imaging findings such as phlegmon or abscess. Finally, the difference between antibiotics used between the two groups could have a significant confounding effect on the primary outcome. Without access to microbiology data, it would be impossible to assess this im- pact. It is possible that this difference in antibiotic choice was accounted for in the risk adjustment model; however, the authors do not list the specific factors incorporated into this adjustment.

In this large, retrospective database analysis, systemic corticoste-

roids were associated with a decrease in the frequency of medical treatment failure and the need for surgical drainage of retropharyngeal and parapharyngeal abscesses. This was accompanied by a decrease in hospital costs and less opioid usage. However, given the retrospective nature of the study, further prospective studies, are needed to further characterize the exact role of systemic corticosteroids in the medical management of these disease processes. In the meantime, we recom- mend administering steroids in the ED as an adjunct therapy.

  1. Evaluation of fever in infants

Pantell et al. Evaluation and management of well-appearing febrile infants 8 to 60 days old. Pediatrics 2021, August; 148(2); e2021052228.

The evaluation of febrile infants <60 days of age is complex, as these children harbor an increased risk of dangerous invasive bacterial infec- tions, such as bacteremia (<2%) and meningitis (0.5%) [40]. As a result, traditionally these children have undergone urine, blood, and cerebrospinal fluid testing to identify infections, followed by admission to the hospital while awaiting culture results. However, these diagnostic studies are difficult to obtain and may be falsely positive, leading to substantial variability in the diagnostic evaluation and treatment of these infants [41]. There is burgeoning evidence that not all febrile in- fants require lumbar puncture and hospital admission [42].

The American Academy of Pediatrics (AAP) recently published new guidelines for the evaluation and management of febrile infants 8-60 days old [43]. These guidelines were formed by consensus after a systematic review and grading of the literature by pediatric emergency, infectious disease, hospitalist, and Family Medicine physicians. The au- thors included well appearing infants with a documented rectal

temperature >= 38o C in the prior 24 h. Infants with upper respiratory symptoms, diarrhea, or acute otitis media were eligible. They excluded infants with concern for HSV (e.g., vesicles), focal bacterial infection on physical examination (e.g., cellulitis), bronchiolitis, premature birth, congenital abnormalities, or immunizations within the past 48

h. Their primary outcomes were urinary tract infection, bacteremia, and Bacterial meningitis.

The guidelines for infants 8-21 days old are similar to prior teaching, recommending a full sepsis evaluation with acquisition of blood, urine, and cerebrospinal fluid followed by administration of parenteral antibi- otics and hospital admission.

In contradistinction to prior guidelines, the AAP recommended a new evaluation for infants 22-28 days old. These children have lower risks of bacteremia and meningitis than younger infants [41]. Therefore, they all do not necessarily require lumbar puncture or hospital admis- sion. The guidelines recommend obtaining urine and blood cultures, and subsequently utilizing inflammatory markers to risk stratify these patients. Children with normal inflammatory markers, as defined by temperatures <38.5o C, absolute Neutrophil count <4000 per mm3,C reactive protein <20 mg/L, and procalcitonin <0.5 ng/ml do not neces- sarily need a lumbar puncture, as their risk of meningitis is quite low (i.e., 1000-1560 Lumbar punctures would be required to identify one case of bacterial meningitis). These children can be admitted to the hospital for observation without CSF acquisition. Antibiotics are not al- ways required, and their administration should be discussed with the admitting physician. Children with any abnormal inflammatory marker should undergo lumbar puncture, receive parenteral antibiotics, and typically be admitted to the hospital.

The risk of invasive bacterial infection is even lower in children

29-60 days old. Therefore, the guidelines recommend a similar step wise evaluation to infants 22-28 days old, with initial acquisition of urine, blood culture, and inflammatory markers. Children with abnor- mal inflammatory markers may undergo lumbar puncture and receive antibiotics. If their cerebrospinal fluid is abnormal, they should be admitted to the hospital. Meanwhile, children with normal inflamma- tory markers are at low risk of meningitis and do not typically need to undergo lumbar puncture (i.e., 4000 lumbar punctures would be required to identify one case of bacterial meningitis). They can be discharged with outpatient follow-up in 24 h.

There are several limitations to these guidelines. Procalcitonin, the inflammatory marker with potentially the greatest diagnostic accuracy for invasive bacterial infection, is not readily available in all EDs. However, the guidelines recommend utilizing it when available, but they indicate it is not necessary to risk stratify patients, which can be done with temperature, absolute neutrophil count, and C-reactive protein. Second, it can be difficult to determine if an infant is well ap- pearing, as they cannot convey their symptoms readily. This distinction is crucial, as the guidelines are not intended for children that do not appear well. Finally, these guidelines were determined by consensus. Individual physicians and patients will have different levels of risk toler- ance, and therefore might elect to deviate from the recommendations. Despite these limitations, the new guidelines provide increased support for a step wise approach to managing well appearing children 22-60 days old with fever.

  1. serum sodium in diabetic ketoacidosis”>Serum sodium in diabetic ketoacidosis

Glaser NS et al. Pediatric Emergency Care Applied Research Network DKA FLUID Study Group. Serum sodium concentration and Men- tal Status in Children With Diabetic Ketoacidosis. Pediatrics. 2021 Sep;148 (3):e2021050243. https://doi.org/10.1542/peds.2021-050243. Epub 2021 Aug 9. PMID: 34373322.

Cerebral edema is a potentially lethal complication of Diabetic ketoacidosis . Based on prior retrospective studies showing an as- sociation between rapidly declining serum sodium levels and cerebral

injury in patients with DKA, most institutional Treatment protocols and practice guidelines recommend strict monitoring of serum sodium, glucose, and osmolality levels during therapy [44,45]. Traditionally, the goal of fluid repletion in patients with DKA is to replenish water loss while preventing rapid decline in serum sodium and glucose levels through conservative infusion of 0.9% sodium chloride to mitigate the risk of Cerebral injury. While a recent large, multicenter, randomized, controlled trial by the Pediatric Emergency Care Applied Research Net- work (PECARN) showed no association between either rate of infusion or type of fluids used in Initial resuscitation and cerebral injury, this ini- tial analysis did not examine the effect that changes in serum sodium concentration had on the risk of injury [46].

In this analysis of data collected during the initial PECARN random- ized control trial of fluids in DKA, Glaser et al. sought to elucidate factors that contribute to changes in serum sodium concentrations during fluid resuscitation, as well as to determine the effect that these changes have on the risk of cerebral injury [47]. The PECARN study enrolled patients at 13 Tertiary care children’s hospitals, and randomized them to one of four groups based on the sodium chloride concentration of the resuscitation fluids and the rate of infusion of these fluids. Patients <=18 years diag- nosed with DKA were assigned to receive either 0.45% or 0.9% sodium chloride intravenous fluids either slowly (10 ml/kg bolus followed by replacement of 5% body weight fluid deficit) or rapidly (20 ml/kg bolus followed by replacement of 10% body weight fluid deficit). Patients were excluded if they had comorbidities which could interfere with accurate assessment of mental status and cerebral injury (i.e. in- toxication, head injury, etc.), or if they had received substantial treatment for DKA prior to arrival to the study site. Serum glucose levels were obtained every hour, and Serum electrolytes were obtained every 2-4 h. To monitor for clinical signs of cerebral injury, Glasgow coma scores (GCS) were obtained hourly, and tests of short-term memory were administered every 4 h.

The authors calculated serum sodium levels corrected for serum glucose levels, at the initiation of treatment, and at 4-, 8-, and 12-h time points. The subjects were then separated into two groups–those with declining corrected sodium levels and those with stable or increas- ing corrected sodium levels. After adjusting for covariates using logistic regression, a decrease in corrected sodium levels was seen in patients who had higher initial sodium and Chloride levels at presentation and a history of previously diagnosed diabetes. These effects persisted across all time points. More rapid rate of infusion of fluids was associated with decreased corrected sodium levels only at the 12 h time point.

There was no difference seen between the groups in the frequency of decline in GCS score to <14, short term memory testing, or in clinically important cerebral injuries. In addition, to further assess for an effect of decreasing corrected sodium levels on mental status, the authors calcu- lated the expected number of instances of mental status deterioration assuming no effect from corrected sodium levels, and compared these expected counts to the observed counts of Mental status change in both groups. Analysis showed no difference between expected and ob- served counts of mental status change in either group.

Limitations noted by the authors include that the treatment proto- cols used in the original study are ones typical in the United States, and therefore may differ from protocols used in other treatment set- tings. Also, there may be other measures of cerebral dysfunction or in- jury that could be useful in assessing Neurological deterioration that were not analyzed in this study.

This is the largest study to date to examine prospective data to evaluate a link between decreasing serum sodium concentration and mental status changes in treatment of DKA. The results of this study demonstrate two important conclusions relevant to emergency medicine practice. First, contrary to prior retrospective data, there is no association between a decrease in serum sodium and either alter- ation in mental status or cerebral injury. Second, changes in serum so- dium levels during resuscitation appear to be more dependent on the

degree of dehydration and electrolyte balance at presentation, as well as the osmolality of intravenous fluids administered rather than on the rate of fluid infusion. These findings, in conjunction with the findings from the original PECARN DKA study can be valuable tools used to guide refinement of DKA treatment protocols in the future.

  1. Risk of concurrent serious bacterial infection with mastitis

Kaplan RL et al. Neonatal Mastitis and Concurrent Serious Bacterial Infection. Pediatrics. 2021 Jul;148(1):e2021051322.

In up to 70% of neonates, the presence of circulating placental and maternal hormones results in the development of physiological breast buds [48-50]. For the majority of infants this is a benign, self-limited oc- currence, typically resolving by several months of age. Rarely, however, this breast tissue can become infected, resulting in neonatal mastitis. This is thought to be secondary to migration of skin flora through the nipple, and into the breast parenchyma. As with other bacterial skin and soft tissue infections, signs of mastitis include erythema, tender- ness, and induration. Abscesses with fluctuance develop in more than 50% of cases [51]. While most cases are due to Staphylococcus aureus, Gram-negative enteric bacteria, anaerobes, and group B Streptococcus have all been implicated as causative organisms [48-54]. Given the young age of patients who develop neonatal mastitis, one must consider the presence of concurrent serious bacterial infection when mak- ing decisions regarding workup, treatment, and disposition for potential sepsis. While there have been several small case series that have de- scribed a low incidence of concurrent SBI, there are no large studies to help guide clinicians in these decisions.

In this large, multicenter, retrospective, cross-sectional study, Kaplan et al. analyzed data from patients under 90 days of age who were seen in the ED and diagnosed with mastitis, with the goal of defin- ing the prevalence of concurrent SBI, as well as identifying adverse out- comes [55]. The study utilized the Pediatric Emergency Medicine Collaborative Research Committee to enroll patients from 28 different pediatric EDs over a 10-year period from 2008 to 2018. Potentially eligi- ble infants were first identified by searching the electronic medical re- cord for an ICD (9th or 10th revision) diagnosis of neonatal mastitis. Records were reviewed to confirm the diagnosis and to exclude patients who had symptoms more consistent with other diagnoses such as ga- lactorrhea and physiological gynecomastia.

The primary outcomes were the presence of SBI and adverse out- comes. SBI was defined as bacteremia, bacterial meningitis, or urinary tract infection . Bacteremia and meningitis were defined as pres- ence of a pathogen in blood or cerebrospinal fluid cultures. UTI was defined as a positive urinalysis and a urine culture growing

>50,000 colony-forming units per mL of a single pathogen. The authors defined adverse outcomes as ICU admission, clinically diagnosed sepsis or shock, severe or necrotizing soft tissue infection, endotracheal intu- bation, administration of vasopressors, or death. They also measured surgical treatment of mastitis and return visits to the ED within 7 days. During the study period, 657 infants met inclusion criteria and were included in the study. Most infants were both full term (94%), and pre- viously healthy (86%) with a median age of 21 days. Nearly all infants (98%) were described as well appearing on presentation, with 21% of patients having fever. Only 10% were described as fussy or having a his- tory of poor feeding. Despite being a relatively homogenous cohort, lab- oratory evaluation was variable, with 88% of infants having a complete blood count and blood cultures obtained, 42% of infants having urinalysis and urine cultures obtained, and 33% having CSF obtained.

wound cultures from the site of infection were obtained in about half (51%) of patients.

Concurrent SBI was rare. Two patients (0.3%; 95% CI, 0.04-1.2%) had bacteremia, 3 (0.4%; 95% CI, 0.1-1.3%) had UTI, and 1 (0.2%; 95% CI,

0-0.8%) had bacterial meningitis. Of these infants with SBI, all were de- scribed as well appearing. Notably, the blood culture contamination rate was 4.3% (25 of 581 cultures). Of the wound cultures obtained, 258

(77%) were positive. S. aureus accounted for 91% of positive wound cul- tures, with methicillin-resistant S. aureus (MRSA) accounting for 54% of positive wound cultures.

Most patients (90%) were admitted, with only 4% admitted to the ICU. Approximately one-fifth (22%) of patients required surgical treat- ment in addition to antibiotics. Only 10 (1.5%) patients had a clinical di- agnosis of sepsis or shock and none needed vasopressors. No infants needed endotracheal intubation or died. Almost a quarter (23%) of the patients discharged from the ED returned within 7 days, with two thirds of these return visits resulting in admission.

The primary limitations of this study stem from the retrospective study design. By relying on medical record review, it is possible that cases of mastitis could have been missed. If mastitis had instead been coded as cellulitis or soft tissue abscess, it would have been inadvertently left out of the study. Similarly, SBI could have been underestimated if the final diagnosis code entered was bacteremia or UTI, without mention of mastitis, thus excluding these cases from this study. Retrospective analysis also limited the ability to determine the reasoning behind why some patients had more extensive workups than others. The authors did not assess interrater reliability with respect to chart review for inclusion and exclusion from the study.

In this large, multicenter cohort of infants with mastitis, the preva- lence of concurrent SBI was very low as were adverse outcomes. While Routine testing for SBI is likely not indicated for most well appear- ing infants with neonatal mastoiditis, it is concerning that every infant with SBI in this cohort was described as well appearing. Based on these findings we typically admit patients with neonatal mastitis, who are not undergoing an evaluation for SBI, to the hospital. There is a need for further research to further delineate those who are at higher risk for invasive infection.

  1. Follow-up for buckle fractures of the radius

Colaco et al. Home Management Versus Primary Care Physician Follow-up of Patients With Distal Radius Buckle Fractures: A Randomized Controlled Trial. Ann Emerg Med. 2021 Feb;77(2):163173. https://doi. org/10.1016/j.annemergmed.2020.07.039. Epub 2020 Oct 21. PMID:

33500115.

Injuries are the second most common reason for children to present to the ED, accounting for over 8 million visits annually in the United States [56]. Buckle fractures of the radius are the most common fracture suffered by children, occurring in up to 4% of children [57]. These fractures are inherently stable, do not involve the growth plates, and generally have an excellent prognosis. As such, treatment has evolved over the years, from casting, to plaster splinting, to the currently ac- cepted standard of application of a prefabricated, removable wrist splint [58-67]. With this evolution has come a similar movement from more conservative follow up care with an orthopedist toward less conserva- tive follow up with a Primary care physician [68-71]. While recov- ery to normal function appears to be similar regardless of where the patient has a follow-up visit, uncertainty remains as to whether there is a difference in timing of recovery and in patient and parent satisfac- tion based on the type of follow-up.

In this randomized, controlled, single blinded trial, Colaco et al. sought to determine whether home removal of a wrist splint was noninferior to a follow-up visit with a PCP in terms of return of function at three weeks after the initial ED visit [72]. In the study, patients were eligible for inclusion if they were aged 5-17 years, presented to the ED within 3 days of injury, and were diagnosed with a distal radial buckle fracture on radiography by the treating ED physician. Patients with con- comitant ulnar styloid fractures were included. Exclusion criteria were recent ipsilateral forearm fracture, pathological fracture, congenital bony abnormalities, and factors that would interfere with the investiga- tors’ ability to evaluate return to function (e.g., developmental delay, in- surmountable language barrier, and no access to phone or electronic communication).

After enrollment patients were placed in a removable wrist splint and randomized to either a scheduled follow up visit with PCP in 1-2 weeks or to home removal of the splint with follow-up with a physician only as needed. Patients were instructed to remove the splint after 1 week and subsequently only utilize it as needed for pain and swelling. The primary endpoint was return to functional baseline at 3 weeks, as determined by performance on the Activities Scale for Kids-38 ques- tionnaire performance version (ASKp-38). The ASKp-38 was adminis- tered at enrollment and repeated at a 3 week follow-up phone call. For patients with no disabilities, the average score on the ASKp-38 is 95%, and 90% for a patient with mild disability. Therefore, noninferiority was considered present if the difference between the two groups was less than 5% at the 3 week follow-up call. Secondary outcomes included parental satisfaction, frequency of splint usage during the follow-up pe- riod, and the cost differences between the groups.

Over an 18 month period, 149 patients were enrolled and random-

ized, and 133 (89%) completed the study and had data analyzed. Of these patients, 114 (86%) completed the study in the group that they were randomized to, with 19 crossing over into the other group. The au- thors completed both intention-to-treat and per-protocol analyses. For the primary outcome, both the intention-to-treat and per-protocol analyses showed that at home management was noninferior to sched- uled PCP follow-up, with a mean score of 95 on the ASKp-38 for home management and 96 for PCP follow-up. The lower limits of 95% CI calcu- lated to be -2.6% and – 1.9%, respectively, indicating non-inferiority.

There were no differences between compliance with splint usage or parental satisfaction between the groups. Two patients required longer immobilization in the PCP group, however, both of these patients were ultimately diagnosed as having Salter-Harris II fractures on the initial ra- diograph after it was over-read by a radiologist. As expected, the at home management group had a significant cost savings, primarily due to no fees from physician visits.

The authors list several limitations to the study. First, there were crossovers between groups, which could have biased the results toward noninferiority. This was addressed by intention-to-treat and per-proto- col analyses, where noninferiority persisted. Secondly, the generaliz- ability of the results could have been affected by the education level of the parents (93% and 90% of parents had postsecondary education in the home management and PCP groups, respectively), and the study site (a tertiary care children’s hospital). Finally, the single center design of the study in Canada may limit generalizability of the cost analysis.

In this randomized controlled trial, Colaco et al. show that home management with a removable splint and adequate anticipatory guid- ance is noninferior to strict PCP follow-up with regards to return to functional baseline in children and adolescents with a distal radius buckle fractures. Similarly, they show no difference in parental satisfac- tion and complication rates between the groups. Although a larger study is needed to ensure that the results are generalizable to other set- tings, at home management in a removable splint without scheduled physician follow-up is a viable option for patients seen in the ED with this common injury.

  1. Risk factors for invasive herpes simplex virus infection

Cruz et al. Predictors of invasive herpes simplex virus infection in young infants. Pediatrics. 2021, September; 148(3); e2021050052.

injury. Prior studies suggest vaginal delivery, primary HSV infection in the mother, and prolonged rupture of the membranes increase the risk of neonatal HSV [75]. However, these prior studies are limited by their small sample size. This study aimed to determine risk factors for invasive HSV infection in infants in a larger sample.

Cruz et al. performed a retrospective nested case-control study of in- fants <=60 days presenting to 24 EDs between 2005 and 2013, who had CSF obtained or a positive HSV test from any source, including non- CSF locations [76]. Cases consisted of all infants with positive HSV tests via Polymerase chain reaction or culture from any source. In- vestigators subclassified cases according to the source of the infection, which could be localized (skin, eyes, and mouth) or invasive (central nervous system or disseminated disease). Cases were each matched with nine controls, representing infants presenting to the ED closest in time to the patients, closest in age to the case, or randomly selected. Controls could have bacterial or non-HSV viral infections. If controls were not tested for HSV, they were assumed not to be infected. Investi- gators reviewed the medical record to identify risk factors. If certain factors were not documented (rash, seizure, intubation, ICU admission, and death), they were assumed not to be present. The primary outcome measure was invasive HSV disease, as defined by a positive CSF HSV re- sult, end-organ damage, or pneumonitis. The secondary outcome was any HSV disease, including involvement of the skin, eyes, or mouth as detected by a positive HSV test. The investigators performed a backward stepwise conditional logistic regression model to identify predictors of these outcomes. They performed sensitivity analyses and imputed miss- ing data. Transaminase levels were not included in this study, as they were often missing. Finally, they created a risk score by assigning points to each independent predictor variable and then calculated the diagnos- tic accuracy of the score.

During the eight year period, they identified 149 cases of HSV with 60% of these patients having invasive disease. The preponderance (89%) of invasive disease was in infants <=28 days. The authors matched HSV cases with 1340 controls, and 39% of these controls underwent HSV testing. Multivariable regression identified several predictors associated with invasive disease (Table 3). These variables remained significantly associated with invasive disease in sensitivity analyses excluding patients with invasive bacterial illness or no HSV testing. The authors then derived a risk score incorporating all of these associations, with a cutoff of >=3 having a sensitivity of 96% (95% CI, 85-100%) and specificity of 40% (95% CI, 37-44%) (Table 3).

There are several important limitations to this study. First the risk score only resulted in a sensitivity of 96% with a lower bound of the 95% confidence interval of 85%. We suspect most clinicians would not be comfortable missing a disease, such as invasive HSV with such mor- bidity, in 4-15% of neonates. Moreover, the derived risk score would suggest testing and Empiric therapy are necessary for all febrile infants

<=28 days. This mitigates the potential impact of the score on HSV testing. The study also relied on retrospective chart abstraction and there was a high frequency of missing data. The sensitivity analyses helped to miti- gate the potential impact of this missing data. Finally, the authors were not able to assess the association of two known predictors of HSV

Table 3

Significant predictors of invasive HSV infection.

Neonatal Herpes simplex virus infection has high morbidity

Predictor

Odds Ratio

95% CI

Risk Score Points

Vesicular Rash

55

(17-181)

4

Age < 14 days

9.1

(3.4-25)

3

Age 14-28 days

6.4

(2.3-18)

2

Seizure

6.1

(2.3-16)

2

Thrombocytopenia

4.4

(1.6-12)

2

Ill appearance

4.2

(2.0-8.4)

2

CSF pleocytosis

3.5

(1.2-10)

2

Temperature > 38.0o C or < 36.4o C

2.9

(1.6-5.3)

1

Prematurity

2.3

(1.1-5.1)

1

and mortality, particularly for invasive disease that spreads beyond the skin, eyes, and mouth. The presentation can be highly variable for

invasive disease with neonates often displaying only nonspecific symp- toms, such as irritability and poor feeding [73]. As a result, guidelines often suggest testing and Empiric treatment of HSV for neonates undergoing CSF testing for bacterial infection [74]. Such empiric acyclo- vir treatment carries risks, as it prolongs hospitalization, acyclovir

extravasation can lead to Skin necrosis, and rapid infusion of acyclovir to children with underlying kidney disease can produce acute kidney

disease, transaminitis and maternal HSV history, due to excessive amounts of missing data for these variables.

Prior to implementation this risk score requires prospective valida- tion and analysis of its impact. Despite these limitations, this large study provides valuable evidence about features that can help predict invasive HSV disease and should prompt HSV testing and empiric acy- clovir administration, including nonspecific predictors such as prematu- rity, seizure, young age, and thrombocytopenia.

Funding

None.

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