Metabolomic and Immunologic Discriminators of MIS-C at Emergency Room Presentation.

Multisystem Inflammatory Syndrome in Childhood (MIS-C) follows SARS-CoV-2 infection and frequently leads to intensive care unit admission. The inability to rapidly discriminate MIS-C from similar febrile illnesses delays treatment and leads to misdiagnosis. To identify diagnostic discriminators at the time of emergency department presentation, we enrolled 104 children who met MIS-C screening criteria, 14 of whom were eventually diagnosed with MIS-C. Before treatment, we collected breath samples for volatiles and peripheral blood for measurement of plasma proteins and immune cell features. Clinical and laboratory features were used as inputs for a machine learning model to determine diagnostic importance. MIS-C was associated with significant changes in breath volatile organic compound (VOC) composition as well as increased plasma levels of secretory phospholipase A2 (PLA2G2A) and lipopolysaccharide binding protein (LBP). In an integrated model of all analytes, the proportion of TCRVß21.3+ non-naive CD4 T cells expressing Ki-67 had a high sensitivity and specificity for MIS-C, with diagnostic accuracy further enhanced by low sodium and high PLA2G2A. We anticipate that accurate diagnosis will become increasingly difficult as MIS-C becomes less common. Clinical validation and application of this diagnostic model may improve outcomes in children presenting with multisystem febrile illnesses.

Developmental progression of the nasopharyngeal microbiome during childhood and association with the lower airway microbiome.

Background: The upper (URT) and lower (LRT) respiratory tract feature distinct environments and responses affecting microbial colonization but investigating the relationship between them is technically challenging. We aimed to identify relationships between taxa colonizing the URT and LRT and explore their relationship with development during childhood. Methods: We employed V4 16S rDNA sequencing to profile nasopharyngeal swabs and tracheal aspirates collected from 183 subjects between 20 weeks and 18 years of age. These samples were collected prior to elective procedures at the Children's Hospital of Philadelphia over the course of 20 weeks in 2020, from otherwise healthy subjects enrolled in a study investigating potential reservoirs of SARS-CoV-2. Findings: After extraction, sequencing, and quality control, we studied the remaining 124 nasopharyngeal swabs and 98 tracheal aspirates, including 85 subject-matched pairs of samples. V4 16S rDNA sequencing revealed that the nasopharynx is colonized by few, highly-abundant taxa, while the tracheal aspirates feature a diverse assembly of microbes. While no taxa co-occur in the URT and LRT of the same subject, clusters of microbiomes in the URT correlate with clusters of microbiomes in the LRT. The clusters identified in the URT correlate with subject age across childhood development. Interpretations: The correlation between clusters of taxa across sites may suggest a mutual influence from either a third site, such as the oropharynx, or host-extrinsic, environmental features. The identification of a pattern of upper respiratory microbiota development across the first 18 years of life suggests that the patterns observed in early childhood may extend beyond the early life window.

Severe COVID-19 and Multisystem Inflammatory Syndrome in Children in Children and Adolescents.

Severe complications related to COVID-19 occur infrequently in children and adolescents. these life-threatening complications are mainly acute respiratory failure from acute COVID-19 and multisystem inflammatory syndrome in children (MIS-C). MIS-C is a postinfectious complication occurring approximately 3 to 6 weeks mostly after an asymptomatic or mild SARS-CoV-2 infection. For both types of complications, supportive ICU care is often required. For MIS-C critical illness, immunomodulation is prescribed to reverse hyperinflammation and its cardiac and other sequelae.

Acute Respiratory Failure With Hemoptysis in a Teenager Due to Cystic Echinococcosis.

A previously healthy 14-year-old male presented with abrupt onset respiratory failure with hemoptysis and anaphylaxis. Imaging demonstrated a large, cystic lesion with bronchopleural fistula that was consistent with cystic echinococcosis. He underwent thoracotomy for cyst removal and bronchopleural fistula repair, then completed 3 months of albendazole therapy. He developed recurrence of a bronchopleural fistula 4 months after surgery which improved over time with conservative management. This case highlights pathognomonic imaging and pathology findings for cystic echinococcosis.

Characterization and Outcomes of Hospitalized Children With Coronavirus Disease 2019: A Report From a Multicenter, Viral Infection and Respiratory Illness Universal Study (Coronavirus Disease 2019) Registry.

OBJECTIVES: Multicenter data on the characteristics and outcomes of children hospitalized with coronavirus disease 2019 are limited. Our objective was to describe the characteristics, ICU admissions, and outcomes among children hospitalized with coronavirus disease 2019 using Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study: Coronavirus Disease 2019 registry. DESIGN: Retrospective study. SETTING: Society of Critical Care Medicine Viral Infection and Respiratory Illness Universal Study (Coronavirus Disease 2019) registry. PATIENTS: Children (< 18 yr) hospitalized with coronavirus disease 2019 at participating hospitals from February 2020 to January 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was ICU admission. Secondary outcomes included hospital and ICU duration of stay and ICU, hospital, and 28-day mortality. A total of 874 children with coronavirus disease 2019 were reported to Viral Infection and Respiratory Illness Universal Study registry from 51 participating centers, majority in the United States. Median age was 8 years (interquartile range, 1.25-14 yr) with a male:female ratio of 1:2. A majority were non-Hispanic (492/874; 62.9%). Median body mass index (n = 817) was 19.4 kg/m2 (16-25.8 kg/m2), with 110 (13.4%) overweight and 300 (36.6%) obese. A majority (67%) presented with fever, and 43.2% had comorbidities. A total of 238 of 838 (28.2%) met the Centers for Disease Control and Prevention criteria for multisystem inflammatory syndrome in children, and 404 of 874 (46.2%) were admitted to the ICU. In multivariate logistic regression, age, fever, multisystem inflammatory syndrome in children, and pre-existing seizure disorder were independently associated with a greater odds of ICU admission. Hospital mortality was 16 of 874 (1.8%). Median (interquartile range) duration of ICU (n = 379) and hospital (n = 857) stay were 3.9 days (2-7.7 d) and 4 days (1.9-7.5 d), respectively. For patients with 28-day data, survival was 679 of 787, 86.3% with 13.4% lost to follow-up, and 0.3% deceased. CONCLUSIONS: In this observational, multicenter registry of children with coronavirus disease 2019, ICU admission was common. Older age, fever, multisystem inflammatory syndrome in children, and seizure disorder were independently associated with ICU admission, and mortality was lower among children than mortality reported in adults.

Cutaneous Findings in SARS-CoV-2-Associated Multisystem Inflammatory Disease in Children.

Rash is a common feature of multisystem inflammatory syndrome in children (MIS-C), a postinfectious hyperinflammatory disease associated with prior severe acute respiratory syndrome coronavirus 2 infection. Because the differential diagnosis of fever and rash in children is broad, understanding clinical characteristics of MIS-C may assist with diagnosis. Here we describe the cutaneous findings observed in a series of children with MIS-C-associated rash.

Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations.

Most children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have mild or minimal disease, with a small proportion developing severe disease or multisystem inflammatory syndrome in children (MIS-C). Complement-mediated thrombotic microangiopathy (TMA) has been associated with SARS-CoV-2 infection in adults but has not been studied in the pediatric population. We hypothesized that complement activation plays an important role in SARS-CoV-2 infection in children and sought to understand if TMA was present in these patients. We enrolled 50 hospitalized pediatric patients with acute SARS-CoV-2 infection (n = 21, minimal coronavirus disease 2019 [COVID-19]; n = 11, severe COVID-19) or MIS-C (n = 18). As a biomarker of complement activation and TMA, soluble C5b9 (sC5b9, normal 247 ng/mL) was measured in plasma, and elevations were found in patients with minimal disease (median, 392 ng/mL; interquartile range [IQR], 244-622 ng/mL), severe disease (median, 646 ng/mL; IQR, 203-728 ng/mL), and MIS-C (median, 630 ng/mL; IQR, 359-932 ng/mL) compared with 26 healthy control subjects (median, 57 ng/mL; IQR, 9-163 ng/mL; P < .001). Higher sC5b9 levels were associated with higher serum creatinine (P = .01) but not age. Of the 19 patients for whom complete clinical criteria were available, 17 (89%) met criteria for TMA. A high proportion of tested children with SARS-CoV-2 infection had evidence of complement activation and met clinical and diagnostic criteria for TMA. Future studies are needed to determine if hospitalized children with SARS-CoV-2 should be screened for TMA, if TMA-directed management is helpful, and if there are any short- or long-term clinical consequences of complement activation and endothelial damage in children with COVID-19 or MIS-C.

Convalescent plasma for pediatric patients with SARS-CoV-2-associated acute respiratory distress syndrome.

There are no proven safe and effective therapies for children who develop life-threatening complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Convalescent plasma (CP) has demonstrated potential benefit in adults with SARS-CoV-2, but has theoretical risks.We present the first report of CP in children with life-threatening coronavirus disease 2019 (COVID-19), providing data on four pediatric patients with acute respiratory distress syndrome. We measured donor antibody levels and recipient antibody response prior to and following CP infusion. Infusion of CP was not associated with antibody-dependent enhancement (ADE) and did not suppress endogenous antibody response. We found CP was safe and possibly efficacious. Randomized pediatric trials are needed.

Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-2.

BACKGROUNDInitial reports from the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic described children as being less susceptible to coronavirus disease 2019 (COVID-19) than adults. Subsequently, a severe and novel pediatric disorder termed multisystem inflammatory syndrome in children (MIS-C) emerged. We report on unique hematologic and immunologic parameters that distinguish between COVID-19 and MIS-C and provide insight into pathophysiology.METHODSWe prospectively enrolled hospitalized patients with evidence of SARS-CoV-2 infection and classified them as having MIS-C or COVID-19. Patients with COVID-19 were classified as having either minimal or severe disease. Cytokine profiles, viral cycle thresholds (Cts), blood smears, and soluble C5b-9 values were analyzed with clinical data.RESULTSTwenty patients were enrolled (9 severe COVID-19, 5 minimal COVID-19, and 6 MIS-C). Five cytokines (IFN-γ, IL-10, IL-6, IL-8, and TNF-α) contributed to the analysis. TNF-α and IL-10 discriminated between patients with MIS-C and severe COVID-19. The presence of burr cells on blood smears, as well as Cts, differentiated between patients with severe COVID-19 and those with MIS-C.CONCLUSIONPediatric patients with SARS-CoV-2 are at risk for critical illness with severe COVID-19 and MIS-C. Cytokine profiling and examination of peripheral blood smears may distinguish between patients with MIS-C and those with severe COVID-19.FUNDINGFinancial support for this project was provided by CHOP Frontiers Program Immune Dysregulation Team; National Institute of Allergy and Infectious Diseases; National Cancer Institute; the Leukemia and Lymphoma Society; Cookies for Kids Cancer; Alex's Lemonade Stand Foundation for Childhood Cancer; Children's Oncology Group; Stand UP 2 Cancer; Team Connor; the Kate Amato Foundations; Burroughs Wellcome Fund CAMS; the Clinical Immunology Society; the American Academy of Allergy, Asthma, and Immunology; and the Institute for Translational Medicine and Therapeutics.

Multisystem Inflammatory Syndrome in Children During the Coronavirus 2019 Pandemic: A Case Series.

We present a series of 6 critically ill children with multisystem inflammatory syndrome in children. Key findings of this syndrome include fever, diarrhea, shock, and variable presence of rash, conjunctivitis, extremity edema, and mucous membrane changes.

Factors Associated With Nonaccidental Trauma Evaluation Among Patients Below 36 Months Old Presenting With Femur Fractures at a Level-1 Pediatric Trauma Center.

BACKGROUND: In 2009, the American Academy of Orthopedic Surgeons published clinical practice guidelines (CPGs) on the treatment of pediatric diaphyseal femur fractures, which recommended a nonaccidental trauma (NAT) evaluation for all patients below 36 months of age. A recent study of these guidelines found <50% clinical compliance with this treatment recommendation. We aimed to identify areas for improvement in compliance with this guideline. METHODS: A retrospective review was performed of all patients presenting to a single pediatric tertiary care hospital with a diaphyseal femur fracture from January 2007 to June 2013 who were below 36 months old. Medical records were reviewed for documentation of a NAT evaluation, patient characteristics, presence of other fractures or injuries, and hospital of presentation. Radiographs were reviewed for fracture pattern. Statistical analysis was performed to assess for differences overall and before and after CPG publication. RESULTS: During the study period, 281 children below 36 months presented with femur fractures; 41% were evaluated for NAT. Overall, the following factors were significantly associated with receipt of a NAT evaluation: younger age (P<0.001), transfer from an outside facility (P=0.027), and identification of another fracture (P=0.004). Before publication of the CPG, nonwhite patients were much more likely to undergo NAT evaluation compared with white patients (43% vs. 19%; P=0.014). After publication of the CPGs, this differential disappeared (43% vs. 47%; P=0.685). Fracture pattern and patient sex did not influence receipt of NAT evaluation. CONCLUSIONS: We found poor utilization of NAT evaluation for patients below 36 months old presenting with femur fracture. Despite CPG publication, only modest improvements in this evaluation occurred over the study period, with less than half of all patients being evaluated. Younger children, patients transferred from other institutions, and patients presenting with concomitant fractures were more likely to undergo NAT evaluation. Compliance with the CPG may be improved by focusing on older children, patients who initially present to tertiary care centers, and those with an isolated femur fracture. LEVEL OF EVIDENCE: Level III-retrospective comparative study.

Maintenance of Pain in Children With Functional Abdominal Pain.

OBJECTIVES: A significant proportion of children with functional abdominal pain develop chronic pain. Identifying clinical characteristics predicting pain persistence is important in targeting interventions. We examined whether child anxiety and/or pain-stooling relations were related to maintenance of abdominal pain frequency and compared the predictive value of 3 methods for assessing pain-stooling relations (ie, diary, parent report, child report). METHODS: Seventy-six children (7-10 years old at baseline) who presented for medical treatment of functional abdominal pain were followed up 18 to 24 months later. Baseline anxiety and abdominal pain-stooling relations based on pain and stooling diaries and child- and parent questionnaires were examined in relationship to the persistence of abdominal pain frequency. RESULTS: Children's baseline anxiety was not related to persistence of pain frequency. Children who, however, displayed irritable bowel syndrome (IBS) symptoms at baseline maintained pain frequency at follow-up, whereas in children in whom there was no relationship between pain and stooling, pain frequency decreased. Pain and stool diaries and parent report of pain-stooling relations were predictive of pain persistence but child-report questionnaires were not. CONCLUSIONS: The presence of IBS symptoms in school-age children with functional abdominal pain appears to predict persistence of abdominal pain over time, whereas anxiety does not. Prospective pain and stooling diaries and parent report of IBS symptoms were predictors of pain maintenance, but child report of symptoms was not.

Impact of Clinical Practice Guideline on the Treatment of Pediatric Femoral Fractures in a Pediatric Hospital.

BACKGROUND: Clinical practice guidelines are being developed for a number of topics in medicine to decrease practice variability and to improve evidenced-based care. Within orthopaedic surgery, the American Academy of Orthopaedic Surgeons (AAOS) has a dedicated committee that produces these clinical practice guidelines on a variety of issues. One such issue was the treatment of pediatric diaphyseal femoral fractures, with the clinical practice guideline being published in 2009. We performed a retrospective review of the treatment of pediatric diaphyseal femoral fractures at a single institution from 2007 to 2012 to assess the clinical impact of this clinical practice guideline on the treatment of this condition. METHODS: A retrospective review of all patients treated at a single pediatric hospital between 2007 and 2012 for a pediatric diaphyseal femoral fracture was conducted. The 2009 AAOS clinical practice guideline on the treatment of this condition was assessed and each patient record was analyzed to determine if the clinical practice guideline was followed, based on the age-specific recommendations. The percentage of treatment rendered adhering to the clinical practice guideline recommendations was compared in the pre-guideline group (prior to June 2009) and the post-guideline group (after June 2009). RESULTS: A total of 361 patients were treated for a diaphyseal femoral fracture during this time frame and were included in this study. Overall, little change in treatment was found following the publication of this clinical practice guideline. The only significant change noted over this time period was a decrease (p = 0.03) in the percentage of patients between the ages of five and eleven years who were treated with flexible nails, at odds with this specific clinical practice guideline recommendation. CONCLUSIONS: We found little direct clinical impact of the recently published AAOS clinical practice guideline on the treatment of pediatric diaphyseal femoral fractures. This analysis suggests an important role for clinical assessment after guideline publication to identify areas of potentially important future clinical research and to assess the utility of this guideline.