Development of a Model to Identify Febrile Children at Low Risk for Multisystem Inflammatory Syndrome.

OBJECTIVES: The case definition for multisystem inflammatory syndrome in children (MIS-C) is broad and encompasses symptoms and signs commonly seen in children with fever. Our aim was to identify clinical predictors that, independently or in combination, identify febrile children presenting to the emergency department (ED) as low risk for MIS-C. METHODS: We conducted a retrospective single-center study of otherwise healthy children 2 months to 20 years of age presenting to the ED with fever and who had a laboratory evaluation for MIS-C between April 15, 2020, and October 31, 2020. We excluded children with a diagnosis of Kawasaki disease. Our outcome was an MIS-C diagnosis defined by the Centers for Disease Control and Prevention criteria. We conducted multivariable logistic regression analyses to identify variables independently associated with MIS-C. RESULTS: Thirty-three patients with and 128 patients without MIS-C were analyzed. Of those with MIS-C, 16 of 33 (48.5%) had hypotension for age, signs of hypoperfusion, or required ionotropic support. Four variables were independently associated with the presence of MIS-C; known or suspected SARS CoV-2 exposure (adjusted odds ratio [aOR], 4.0; 95% confidence interval [CI], 1.4-11.9) and the following 3 symptoms and signs: abdominal pain on history (aOR, 4.8; 95% CI, 1.7-15.0), conjunctival injection (aOR, 15.2; 95% CI, 5.4-48.1), and rash involving the palms or soles (aOR, 12.2; 95% CI, 2.4-69.4). Children were at low risk of MIS-C if none of the 3 symptoms or signs were present (sensitivity 87.9% [95% CI, 71.8-96.6]; specificity 62.5% [53.5-70.9], negative predictive value 95.2% [88.3-98.7]). Of the 4 MIS-C patients without any of these 3 factors, 2 were ill-appearing in the ED and the other 2 had no cardiovascular involvement during their clinical course. CONCLUSIONS: A combination of 3 clinical symptoms and signs had moderate to high sensitivity and high negative predictive value for identifying febrile children at low risk of MIS-C. If validated, these factors could aid clinicians in determining the need to obtain or forego an MIS-C laboratory evaluation during SARS-CoV-2 prevalent periods in febrile children.

Bacteremia in Pediatric Liver Transplant Recipients.

BACKGROUND: We aimed to determine the frequency of bacteremia, septic shock and bacterial meningitis in pediatric liver transplant recipients (pLTRs) in the outpatient setting and to identify clinical factors associated with bacteremia. METHODS: Multicenter retrospective study of pLTRs evaluated in the emergency department or outpatient clinic between 2010 and 2018 for suspected infection, defined as fever ≥38 °C or a blood culture obtained. We excluded patients with nontransplant immunodeficiency, multiorgan transplants or intestinal failure. The primary outcome was bacteremia; secondary outcomes included fluid-refractory septic shock, bacterial meningitis and antibiotic resistance. The unit of analysis was the encounter. RESULTS: A total of 151 children had 336 encounters for infection evaluation within 2 years of transplant. Of 307 (91.4%) encounters with blood cultures, 17 (5.5%) had bacteremia, with 10 (58.8%) occurring within 3 months of transplant. Fluid-refractory septic shock and bacterial meningitis occurred in 7 of 307 (2.8%) and 0 of 307 encounters, respectively. Factors associated with bacteremia included closer proximity to transplant (<3 months) [odds ratio (OR): 3.6; 95% confidence interval (CI): 1.3-9.8; P = 0 .01], shorter duration of illness (OR: 4.3; 95% CI: 1.5-12.0; P < 0.01) and the presence of a central venous catheter (CVC) (OR: 12.7; 95% CI: 4.4-36.6; P < 0.01). However, 5 (29.4%) encounters with bacteremia had none of these factors. Among Gram-positive pathogens, 1 of 7 (14.2%) isolates were resistant to vancomycin. Among Gram-negative pathogens, 3 of 13 (23.1%) isolates were resistant to 3rd generation cephalosporins. CONCLUSIONS: Bacteremia was an important cause of infection within 2 years of pLTR. Clinical factors increased the risk of bacteremia. Further, large sample studies should derive multivariable models to identify those at high and low risk of bacteremia to optimize antibiotic use.

Accuracy of NGAL as a Biomarker for Urinary Tract Infection in Young Febrile Children: An Individual Patient Data Meta-Analysis.

OBJECTIVE: To compare the accuracy of urine neutrophil gelatinase-associated lipocalin (NGAL) and leukocyte esterase (LE) for the diagnosis of urinary tract infection (UTI) in children. STUDY DESIGN: We performed a systematic review and individual patient data meta-analysis of studies that examined urine NGAL as a marker of UTI in children <18 years of age. We created a standardized definition of UTI and applied it to all included children. We compared sensitivity, specificity, and the area under the receiver operating characteristic curve (AUC) of NGAL with LE. RESULTS: We included individual patient data from 3 studies for a total of 845 children. Included children had a mean age of 0.9 years (SD, 0.6 years). Using a cutoff of 32.7 ng/mL, NGAL had a sensitivity of 90.3% (95% CI: 83.2%-95.0%) and specificity of 93.7% (95% CI: 91.7%-95.4%) for the diagnosis of UTI. LE, using a cutoff of ≧ trace had a sensitivity of 81.1% (95% CI: 72.5%-87.9%) and specificity of 97.0% (95% CI: 95.4%-98.1%). The AUC for NGAL was 0.95 (95% CI: 0.92-0.98). The AUC for LE was 0.90 (95% CI: 0.86-0.93). CONCLUSION: In young, febrile children, urinary NGAL is more sensitive for the diagnosis of UTI than LE but is slightly less specific.

Frequency of Bacteremia and Urinary Tract Infection in Pediatric Renal Transplant Recipients.

BACKGROUND: Our primary goal was to determine the frequency of bacteremia and urinary tract infections (UTI) in pediatric renal transplant recipients presenting with suspected infection within 2 years of transplant and to identify clinical and laboratory factors associated with bacteremia. METHODS: We conducted a retrospective cross-sectional study for all pediatric ( < 18 years old) renal transplant recipients seen at 3 large children's hospitals from 2011 to 2018 for suspected infection within 2 years of transplant date, defined as pyrexia ( > 38°C) or a blood culture being ordered. Patients with primary immunodeficiencies, nontransplant immunosuppression, intestinal failure, and patients who had moved out of the local area were excluded. The primary outcome was bacteremia or UTI; secondary outcomes included pneumonia, bacterial or fungal meningitis, respiratory viral infections, and antibiotic resistance. The unit of analysis was the visit. RESULTS: One hundred fifteen children had 267 visits for infection evaluation within 2 years of transplant. Bacteremia (with or without UTI) was diagnosed in 9/213 (4.2%) and UTIs in 63/189 (33.3%). Tachycardia and hypotension were present in 66.7% and 0% of visits with documented bacteremia, respectively. White blood cell (12,700 cells/mm 3 vs. 10,900 cells/mm 3 ; P = 0.43) and absolute neutrophil count (10,700 vs. 8200 cells/mm 3 ; P = 0.24) were no different in bacteremic and nonbacteremic patients. The absolute band count was higher in children with bacteremia (1900 vs. 600 cells/mm 3 ; P = 0.02). Among Gram-negative pathogens, antibiotic resistance was seen to 3rd (14.5%) and 4th (3.6%) generation cephalosporins, 12.7% to semisynthetic penicillins, and 3.6% to carbapenems. CONCLUSIONS: Bacteremia or UTIs were diagnosed in one-quarter of all pediatric renal transplant recipients presenting with suspected infection within 2 years of transplant. Evaluations were highly variable, with one-third of visits not having urine cultures obtained. No single demographic, clinical or laboratory variable accurately identified patients with bacteremia, although combinations of findings may identify a high-risk population.

Upregulation of type 1 conventional dendritic cells implicates antigen cross-presentation in multisystem inflammatory syndrome.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is an acute, febrile, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated syndrome, often with cardiohemodynamic dysfunction. Insight into mechanism of disease is still incomplete. OBJECTIVE: Our objective was to analyze immunologic features of MIS-C patients compared to febrile controls (FC). METHODS: MIS-C patients were defined by narrow criteria, including having evidence of cardiohemodynamic involvement and no macrophage activation syndrome. Samples were collected from 8 completely treatment-naive patients with MIS-C (SARS-CoV-2 serology positive), 3 patients with unclassified MIS-C-like disease (serology negative), 14 FC, and 5 MIS-C recovery (RCV). Three healthy controls (HCs) were used for comparisons of normal range. Using spectral flow cytometry, we assessed 36 parameters in antigen-presenting cells (APCs) and 29 in T cells. We used biaxial analysis and uniform manifold approximation and projection (UMAP). RESULTS: Significant elevations in cytokines including CXCL9, M-CSF, and IL-27 were found in MIS-C compared to FC. Classic monocytes and type 2 dendritic cells (DCs) were downregulated (decreased CD86, HLA-DR) versus HCs; however, type 1 DCs (CD11c+CD141+CLEC9A+) were highly activated in MIS-C patients versus FC, expressing higher levels of CD86, CD275, and atypical conventional DC markers such as CD64, CD115, and CX3CR1. CD169 and CD38 were upregulated in multiple monocyte subtypes. CD56dim/CD57-/KLRGhi/CD161+/CD38- natural killer (NK) cells were a unique subset in MIS-C versus FC without macrophage activation syndrome. CONCLUSION: Orchestrated by complex cytokine signaling, type 1 DC activation and NK dysregulation are key features in the pathophysiology of MIS-C. NK cell findings may suggest a relationship with macrophage activation syndrome, while type 1 DC upregulation implies a role for antigen cross-presentation.

Urinary tract infections in children: Testing a novel, noninvasive, point-of-care diagnostic marker.

OBJECTIVES: Urinary neutrophil gelatinase-associated lipocalin (uNGAL) appears highly accurate to identify urinary tract infections (UTIs) when obtained via catheterization. Our primary aim was to determine the agreement in uNGAL levels between paired catheter and bag urine specimens. Our secondary aim was to compare the diagnostic test characteristics of quantitative uNGAL, dipstick uNGAL (a potential point-of-care test), and urinalysis (UA). METHODS: This was a prospective study of febrile children < 24 months evaluated for UTIs. We evaluated quantitative uNGAL at a previously identified threshold of 39.1 ng/mL, dipstick uNGAL at its built-in threshold of >50 ng/mL, and UA at standard thresholds for leukocyte esterase (LE). A positive urine culture was defined as >100,000 CFUs/mL of a pathogen. RESULTS: A total of 211 patients were included (10% with positive urine cultures); 116 had paired catheterized and bagged samples. The agreement between catheterized and bagged samples at a quantitative uNGAL cutoff of ≥39.1 ng/mL was 0.76 (95% confidence interval [CI] = 0.67 to 0.83) and 0.77 (95% CI = 0.68 to 0.84) at a uNGAL dipstick threshold of >50 ng/mL. The area under the receiver operating characteristic curve for uNGAL from a catheterized sample was 0.96 (95% CI = 0.89 to 1.00) compared to 0.93 (95% CI = 0.87 to -0.99) from a bagged sample. The sensitivities of catheterized sample quantitative and dipstick uNGAL (90.5%) were higher than UA at a LE threshold of ≥1+ (57.1%). Bagged-sample uNGAL had lower quantitative and dipstick specificities (both 73.8%) than from catheterized samples (94.3% and 95.3% respectively), similar to UA. CONCLUSIONS: uNGAL from bagged and catheterized samples showed insufficient agreement to be used interchangeably. The low specificity of uNGAL from bagged samples suggests that sampling technique affects uNGAL levels.

Intranasal ketorolac versus intravenous ketorolac for treatment of migraine headaches in children: A randomized clinical trial.

BACKGROUND: Intravenous ketorolac is commonly used for treating migraine headaches in children. However, the prerequisite placement of an intravenous line can be technically challenging, time-consuming, and associated with pain and distress. Intranasal ketorolac may be an effective alternative that is needle-free and easier to administer. We aimed to determine whether intranasal ketorolac is non-inferior to intravenous ketorolac for reducing pain in children with migraine headaches. METHODS: We conducted a randomized double-blind non-inferiority clinical trial. Children aged 8-17 years with migraine headaches, moderate to severe pain, and requiring parenteral analgesics received intranasal ketorolac (1 mg/kg) or intravenous ketorolac (0.5 mg/kg). Primary outcome was reduction in pain at 60 min after administration measured using the Faces Pain Scale-Revised (scored 0-10). Non-inferiority margin was 2/10. Secondary outcomes included time to onset of clinically meaningful decrease in pain; ancillary emergency department outcomes (e.g. receipt of rescue medications, headache relief, headache freedom, percentage improvement); 24-h follow-up outcomes; functional disability; and adverse events. RESULTS: Fifty-nine children were enrolled. We analyzed 27 children who received intranasal ketorolac and 29 who received intravenous ketorolac. The difference in mean pain reduction at 60 min between groups was 0.2 (95% CI -0.9, 1.3), with the upper limit of the 95% CI being less than the non-inferiority margin. There were no statistical differences between groups for secondary outcomes. CONCLUSIONS: Intranasal ketorolac was non-inferior to intravenous ketorolac for reducing migraine headache pain in the emergency department.

Presence and Duration of Symptoms in Febrile Infants With and Without SARS-CoV-2 Infection.

The clinical course of SARS-CoV-2 infection in young infants is not well understood. In this prospective cohort study, we compared the presence and duration of symptoms in febrile infants ≤60 days with (n = 7) and without (n = 16) SARS-CoV-2 infection. Overall, we observed overlapping symptoms and duration of illness, with longer length of cough and nasal congestion among the SARS-CoV-2-positive infants.

Novel Coronavirus Infection in Febrile Infants Aged 60 Days and Younger.

In this case series, we describe the clinical course and outcomes of 7 febrile infants aged ≤60 days with confirmed severe acute respiratory syndrome coronavirus 2 infection. No infant had severe outcomes, including the need for mechanical ventilation or ICU level of care. Two infants had concurrent urinary tract infections, which were treated with antibiotics. Although a small sample, our data suggest that febrile infants with severe acute respiratory syndrome coronavirus 2 infection often have mild illness.

Urinary Neutrophil Gelatinase-Associated Lipocalin for the Diagnosis of Urinary Tract Infections.

OBJECTIVES: To determine the accuracy of the novel biomarker urinary neutrophil gelatinase-associated lipocalin (uNGAL) to diagnose urinary tract infections (UTIs) in febrile infants and young children. METHODS: Prospective cross-sectional study of febrile infants <3 months ( ≥ 38.0°C) and children 3 to 24 months (≥ 39.0°C) evaluated for UTIs. uNGAL levels, urinalysis, Gram-stain and culture were obtained. UTI was defined by colony counts. RESULTS: Of 260 patients, 35 (13.5%) had UTIs. Median uNGAL levels were 215.1 ng/mL (interquartile range: 100.3-917.8) and 4.4 ng/mL (interquartile range: 1.6-11.8) in the groups diagnosed with and without UTIs, respectively. The area under the receiver-operating characteristic curve for uNGAL was 0.978 (95% confidence interval [CI]: 0.948-1.000). At a threshold uNGAL level of 39.1 ng/mL, sensitivity was 97.1% (95% CI: 83.4-99.9) and specificity was 95.6% (95% CI: 91.7-97.7). uNGAL had higher sensitivity than the combination of leukocyte esterase (in trace or greater amounts) or nitrite (+) (97.1%, 95% CI: 83.4-99.9 vs 74.3%, 95% CI: 56.4-86.9), with similar specificity (95.6%, 95% CI: 91.7-97.7 vs 97.3%, 95% CI: 94.0-98.9). uNGAL had higher sensitivity than Gram-stain (97.1%, 95% CI: 83.4-99.9 vs 74.3%, 95%: CI: 56.4-86.9), with similar specificity (95.6%, 95% CI: 91.7-97.7 vs 100.0%, 95% CI: 97.9-100.0). CONCLUSIONS: uNGAL has substantial accuracy to identify those with and without UTIs in infants and young children. Further studies will need to confirm our findings and determine if uNGAL is a more cost-effective test than standard screening tests.

Comparison of Febrile Infants With Enterococcal and Gram-negative Urinary Tract Infections.

BACKGROUND: Few data exist on the presentations and clinical courses of infants with enterococcal urinary tract infections (UTI). The objective of this study was to compare the clinical presentation, sensitivity of urinalysis (UA) and Gram's stain, radiological abnormalities and adverse events of febrile infants with enterococcal UTIs to those with Gram-negative UTIs. METHODS: Retrospective study of febrile (≥38.0°C) infants 29-60 days of age with UTIs at 20 emergency departments. UTI was defined as growth of (1) ≥50,000 colony forming units (CFUs)/mL of a single pathogen; or (2) either 10,000 to <50,000 CFUs/mL or 10,000-100,000 CFUs/mL (depending on laboratory reporting) with a positive UA or Gram's stain. RESULTS: Thirty-seven (2.0%) of 1870 infants with febrile UTIs had enterococcal UTIs. On bivariable analysis, infants with enterococcal UTIs more frequently had histories of prematurity, previous hospitalizations, histories of genitourinary abnormalities, previous UTIs and ill-appearance in the emergency department compared with infants with Gram-negative UTIs (all P <0.05). On multivariable analysis, ≥ grade 3 vesicoureteral reflux (adjusted odds ratio 3.2, 95% confidence interval: 1.4, 7.6) and hydronephrosis (adjusted odds ratio 3.3, 95% confidence interval: 1.4, 7.9) were associated with enterococcal UTIs. Both groups had similar low risks of adverse events or severe clinical courses. The urine white blood cell count alone or in combination with leukocyte esterase was more sensitive for Gram-negative than enterococcal UTIs (range 80.4%-93.9% vs. 50.0%-75.9%). CONCLUSIONS: Febrile infants with enterococcal UTIs had a low likelihood of adverse events or severe clinical course, similar to those with Gram-negative UTIs. Infants with enterococcal UTIs frequently had underlying hydronephrosis and/or vesicoureteral reflux. The preliminary diagnosis of enterococcal UTIs may be inaccurate if based on UA.

Nuking the radiation: minimizing radiation exposure in the evaluation of pediatric blunt trauma.

PURPOSE OF REVIEW: Our objective is to highlight recent literature investigating low-radiation diagnostic strategies in the evaluation of pediatric trauma. RECENT FINDINGS: In the area of minor head injury, research has focused on implementation of validated clinical decision rules into practice to reduce unnecessary computed tomography scans. Clinical observation may also serve as an adjunct to initial assessment and a potential substitute for computed tomography imaging. Subgroups of children with special needs or severe injury mechanisms may also be safely characterized by the clinical decision rule and spared radiation exposure. Physical examination techniques may be useful in diagnosing mandibular fractures. In addition, evidence suggests that plain radiography for evaluation of blunt thoracic trauma may be sufficient in many cases, and computed tomography could be reserved for those with abnormal radiographs, high-risk mechanisms, or abnormal physical findings. Clinical decision rules are able to predict intra-abdominal injury with high sensitivity. Data suggest that skeletal surveys may be modified to limit radiation exposure in the case of suspected nonaccidental trauma. SUMMARY: More research is needed in development of pediatric-specific clinical decision rules and risk stratification and in testing low-radiation diagnostic modalities in the pediatric trauma population.