Abstract In December 2019, the 2019, a novel coronavirus disease (COVID‐19) caused by severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) first emerged in Wuhan, China. This has now spread worldwide and was declared a pandemic by March 2020. Initially, the pediatric population was described as a low risk for severe COVID‐19. However, reports have emerged recently of cases of COVID‐19 in children with a systemic inflammatory disease, with features that overlap with Kawasaki disease (KD). We describe the first 15 cases with the multi‐systeminflammatory syndrome in children (MIS‐C), temporally related to COVID‐19, who presented for care to a tertiary pediatric referral center in New York City. We discuss the disproportionate burden of disease among Hispanic/Latino and Black/African American ancestry, the distinct cytokine signature across the disease spectrum (IL‐1/IL‐6), and the potential role and pathogenesis of SARS‐CoV‐2 in this new clinical entity.
Clinical Implications•A previously healthy 13-month-old boy admitted for pneumonia and presumed multisystem inflammatory syndrome in children and other possible inflammatory conditions was ultimately found to have Mendelian susceptibility to mycobacterial disease caused by a homozygous deletion in IFN-γ receptor 2. •A previously healthy 13-month-old boy admitted for pneumonia and presumed multisystem inflammatory syndrome in children and other possible inflammatory conditions was ultimately found to have Mendelian susceptibility to mycobacterial disease caused by a homozygous deletion in IFN-γ receptor 2. A previously healthy 13-month-old Hispanic boy born to consanguineous parents from Dominican Republic was referred by his pediatrician to the emergency room for 7 days of fever and marked leukocytosis of 40 × 103/μL. Two months earlier his parents experienced upper respiratory symptoms with anosmia but were not tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The patient was subsequently admitted from the emergency room with tachypnea and mild intercostal retractions, normal saturation, leukocytosis, elevated inflammatory markers and D-dimer, and negative SARS-CoV-2 RT-PCR result from a nasopharyngeal swab (Table I). Blood and urine cultures were negative. Chest radiograph showed a patchy consolidation in the right lower lobe. An echocardiogram revealed mild pericardial effusion and hyperdynamic contractility. He failed to respond to 3-day intravenous ceftriaxone, and developed a cough and abdominal distention, for which he was transferred to our hospital because of the concern for decompensated pneumonia and possible multisystem inflammatory syndrome in children (MIS-C).Table ILaboratory valuesCBCNormalOSHAdmitPeakDischargeWBC6.2-15.5 × 103/μL49 (6.5% bands)35.545.317.9Neutrophil %21.3%-69.3%648050.5Absolute neutrophil count1.9-8.0 × 103/μL23.7823.789.71Lymphocyte %17%-63.7%2139.739.4Absolute lymphocyte count1.2-7.0 × 103/μL7.4612.97.1HGB10.3-13.2 g/dL811.29.9PLTS150-500 × 103/μL287689500Inflammatory markers CRP0.0-5.0 mg/L26.7279.2314.244.7 ESR0-10 mm/h81103— LDH170-450 U/L1774450628— Ferritin20-200 ng/mL230236484— Procalcitonin<0.49 ng/mL33.667.9249.21— Uric acid2.2-6.0 mg/dL5.54.76.8— Albumin3.5-4.9 g/dL2.23.7— IL-1β0-5.0 pg/mL1.1—— IL-60-5.0 pg/mL395—— IL-80-5.0 pg/mL38.9—— TNF-α0-22.0 pg/mL95.2——Coagulation/cardiac studies D-Dimer0.00-0.50 μg/mL7.727.659.46— Troponin I<0.03 ng/mLNegative<0.010.02— BNP0-100 pg/mL29.4747.10—Microbiology Respiratory PCRNegativeNegativeNegative—— Respiratory PCR methodFilmArray Respiratory Panel 2—— SARS-CoV-2 PCRNegativeNegativeNegativeNegative— SARS-CoV-2 PCR methodRoche Cobas 6800Roche Cobas 6800Simplexa—BNP, Brain naturetic peptide; CBC, complete blood cell count; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; HGB, hemoglobin; LDH, lactate dehydrogenase; OSH, outside hospital; PLTS, platelets; WBC, white blood cell count.Pediatric ranges for patients aged 13 mo within our hospital are provided.Bolded numbers are abnormal lab values. Open table in a new tab BNP, Brain naturetic peptide; CBC, complete blood cell count; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; HGB, hemoglobin; LDH, lactate dehydrogenase; OSH, outside hospital; PLTS, platelets; WBC, white blood cell count. Pediatric ranges for patients aged 13 mo within our hospital are provided. Bolded numbers are abnormal lab values. Upon transfer on day 12, he was afebrile, with blood pressure of 113/89 mm Hg and tachycardia, but had normal oxygen saturation and physical examination. Chest radiograph demonstrated right middle and lower lobe infiltrates. Laboratory studies revealed leukocytosis, neutrophilia and lymphophilia, microcytic anemia, hypoalbuminemia, and elevated inflammatory markers and D-dimer (Table I). Repeat nasopharyngeal PCR test results for respiratory pathogens and SARS-CoV-2 were negative, whereas coronavirus disease 2019 (COVID-19) antibodies were positive at a titer of 1:960. His initial presentation of pneumonia had a differential including malignancy, HIV, Kawasaki disease, MIS-C, and/or mycobacterial infections. There were no rashes, edema, conjunctival injection, or mucosal changes to suggest Kawasaki, flow cytometry was not consistent with leukemia, and his HIV test result was negative, though the possibility of lymphoma remained. His presentation coincided with the peak of MIS-C cases in New York City.1Dufort E.M. Koumans E.H. Chow E.J. Rosenthal E.M. Muse A. Rowlands J. et al.Multisystem inflammatory syndrome in children in New York State.N Engl J Med. 2020; 383: 347-358Crossref PubMed Scopus (986) Google Scholar Children with COVID-19 generally do well, with a mortality rate of 0.1%.2Shekerdemian L.S. Mahmood N.R. Wolfe K.K. Riggs B.J. Ross C.E. McKiernan C.A. et al.Characteristics and outcomes of children with coronavirus disease 2019 (COVID-19) infection admitted to US and Canadian pediatric intensive care units.JAMA Pediatr. 2020; 174: 1-6Crossref Scopus (728) Google Scholar Worldwide, more than 1000 children who previously appeared healthy were hospitalized for MIS-C.1Dufort E.M. Koumans E.H. Chow E.J. Rosenthal E.M. Muse A. Rowlands J. et al.Multisystem inflammatory syndrome in children in New York State.N Engl J Med. 2020; 383: 347-358Crossref PubMed Scopus (986) Google Scholar,3Whittaker E. Bamford A. Kenny J. Kaforou M. Jones C. Shah P. et al.Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2.JAMA. 2020; 324: 259-269Crossref PubMed Scopus (1425) Google Scholar,4Feldstein L.R. Rose E.B. Horwitz S.M. Collins J.P. Newhams M.M. Son M.B.F. et al.Multisystem inflammatory syndrome in U.S. children and adolescents.N Engl J Med. 2020; 383: 334-346Crossref PubMed Scopus (1769) Google Scholar This child demonstrated the characteristics of MIS-C, including fever with positive SARS-CoV-2 antibodies, elevated inflammatory markers, elevated D-dimer, and multiorgan involvements.5U.S. Centers for Disease Control and PreventionMultisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19). U.S. Centers for Disease Control and Prevention, Health Advisory Network, Atlanta, GA2020Google Scholar The patient was treated with intravenous antibiotics for presumed bacterial pneumonia, and enoxaparin and intravenous immune globulin for presumed MIS-C. However, he did not respond and continued to have tachypnea, abdominal distention, and elevated inflammatory markers. Marked leukocytosis and lymphophilia were inconsistent with MIS-C. On day 14, a QuantiFERON-TB Gold Plus, which had been submitted, was reported to be positive. An abdominal ultrasound (day 16) revealed innumerable small splenic hypoechoic foci, mild hepatomegaly, and lymphadenopathy in the portal region. He was sedated and intubated to obtain a chest angiography and abdominal computerized tomography, which revealed dense consolidation of the right lower and middle lobes, hepatosplenomegaly with many hypodense splenic lesions, and portacaval adenopathy (see Figure E1 in this article's Online Repository at www.jaci-inpractice.org). Following difficult intubation and the imaging studies, he was transferred to intensive care and remained intubated for 7 additional days. Day 17 bronchoscopy revealed an endobronchial mass obstructing 80% of the bronchus. Tuberculous meningitis was excluded with cerebrospinal fluid studies. Because of positive IFN-γ release assay, splenic lesions, and lymphadenopathy, the patient was started on treatment for presumed miliary tuberculosis with rifampin, isoniazid, pyrazinamide, and ethambutol, and with corticosteroids to relieve the endobronchial obstruction on day 18. A skin test PPD was read as negative 2 days later while PCR results for tuberculosis and repeat QuantiFERRON-TB Gold Plus were also negative. Immunologic workup showed elevated immunoglobulin levels, normal lymphocyte subsets, and a normal dihydrorhodamine test result. On day 21, splenic biopsy showed acute inflammation and ill-defined minute nonnecrotizing granulomas. Bronchoalveolar lavage and gastric aspirate cultures were positive for Mycobacterium avium complex on day 33, and the treatment was optimized to cover for this with rifampin, ethambutol, and clarithromycin, in addition to moxifloxacin for latent tuberculosis infection. These new findings increased the index of suspicion for Mendelian susceptibility to mycobacterial disease (MSMD), and further investigation was conducted to identify an underlying genetic defect. Family history indicated that the parents were second-degree cousins who had no apparent family history of primary immunodeficiency disease, as shown in the family pedigree (see Figure E2 in this article's Online Repository at www.jaci-inpractice.org). MSMD was confirmed, with immunogenetic studies revealing a homozygous deletion mutation in IFN-γ receptor 2 (IFNGR2), at position c.503_504del (p.Thr168Ilefs∗33), a previously reported pathogenic mutation in a child with autosomal-recessive MSMD.6Kamoun C. Morsheimer M. Sullivan K.E. Holland S.M. Cunningham-Rundles C. Bunin N. et al.Successful unrelated cord blood transplant for complete IFN-gamma receptor 2 deficiency.J Allergy Clin Immunol. 2016; 138: 1489-1491Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar He showed clinical improvement after 3 weeks of aggressive antimycobacterial therapy. He was taken off ventilator and supplemental oxygen on day 23. Repeated bronchoscopy showed resolution of bronchoalveolar mass on day 21, and subsequent serial chest radiographs showed resolution of right-sided consolidation. Weekly ultrasounds showed decreased hepatosplenomegaly and lymphadenopathy by hospital discharge on day 55. The patient was discharged home on antimycobacterial treatment and referred for hematopoietic stem cell transplant. Mendelian susceptibility to mycobacterial disease is a rare primary immunodeficiency characteristic of severe and disseminated infections with weakly virulent mycobacteria, such as Bacillus Calmette-Guerin–BCG vaccine strain and mycobacterium avium complex, and in 50% of cases Salmonella species. MSMD can be caused by 1 of the 15 genetic mutations in the macrophage and lymphocyte loop primarily involving molecules in the IL-12/IFN-γ signaling pathways including IFNGR2.7Tangye S.G. Al-Herz W. Bousfiha A. Chatila T. Cunningham-Rundles C. Etzioni A. et al.Human inborn errors of immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee.J Clin Immunol. 2020; 40: 24-64Crossref PubMed Scopus (858) Google Scholar To date there have been fewer than 30 cases of IFNGR2 reported in the literature. More than half the cases had poor survival. Hematopoietic stem cell transplant is considered curative.8Rosain J. Kong X.F. Martinez-Barricarte R. Oleaga-Quintas C. Ramirez-Alejo N. Markle J. et al.Mendelian susceptibility to mycobacterial disease: 2014-2018 update.Immunol Cell Biol. 2019; 97: 360-367Crossref PubMed Scopus (158) Google Scholar,9Bustamante J. Boisson-Dupuis S. Abel L. Casanova J.L. Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-gamma immunity.Semin Immunol. 2014; 26: 454-470Crossref PubMed Scopus (497) Google Scholar At the time of the patient's presentation, MIS-C was increasingly recognized in New York City. He had an initial clinical picture mimicking MIS-C, which is a diagnosis of exclusion. Through microbiology, pathology, radiology, and crucial genetic studies, MSMD was discovered. This case emphasizes overlapping and distinct features of MIS-C and MSMD, which is outlined in Table II. Both diseases present with prolonged fever, cough, and elevated inflammatory markers, particularly TNF-α and IL-6. MIS-C is associated with lymphopenia, abnormal coagulation, multisystem involvement, serologic evidence of COVID-19, but unlikely to have lymphadenopathy and positive bacterial cultures. In comparison, MSMD characteristically presents with lymphophilia, disseminated multiorgan lesions, lymphadenopathy, and positive mycobacterial cultures, and is less likely to have abnormal coagulation and thrombotic events.Table IIComparing MIS-C related to COVID-19 (MIS-C) and MSMDParameterCDC MIS-C5U.S. Centers for Disease Control and PreventionMultisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19). U.S. Centers for Disease Control and Prevention, Health Advisory Network, Atlanta, GA2020Google ScholarMSMDAge<21 yEarly in childhood and rarely in adulthoodFever≥38.0°C for ≥24 h, or report of subjective fever lasting ≥24 hLikely and can occur with weight lossHospitalizationRequiredLikelyLaboratoryEvidence of inflammation:Lymphopenia, neutrophilia, elevated inflammatory markers (CRP, ESR, IL-6, procalcitonin, ferritin, LDH)Abnormal coagulation (elevated fibrinogen and D-dimer)HypoalbuminemiaLymphophiliaElevated inflammatory markers:CRP, ESR, TNF-α, IL-6Normal coagulationMay have hypoalbuminemiaSARS-CoV-2 presenceAt least 1 required:Positive by RT-PCR for RNAPositive serological assay for antibodiesPositive COVID-19 antigen by antigen assayExposure to a known case within 4 wk before onset of symptomsUnlikely except for current COVID-19 pandemicBlood and tissue culturesNegative—must exclude other diagnosesPositive blood and/or tissue culturesNontypical mycobacteria, Salmonella, Listeria, histoplasmosis, etcChest radiographyNot required for diagnosis but may include opacities (ground glass), peribronchial thickening, and/or pleural effusionsDisseminated pulmonary lesions are commonMultisystem involvementAt least 2 organ systems involved (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, or neurological)Not required but often lymphadenopathy present and multisystem involvement likely with disseminated infectionsGeneticsNot found at presentConfirmed by immunodeficiency screen for mutations in IKBKG, IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, IL12RB2, IL23R, ISG15, IRF8, TYK2, CYBB, RORC, JAK1, and SPPL2ACDC, Centers for Disease Control and Prevention; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; LDH, lactate dehydrogenase.MIS-C can be diagnosed if no other diagnosis is possible. Some patients with MIS-C may have overlapping symptoms with complete or incomplete Kawasaki disease. Open table in a new tab CDC, Centers for Disease Control and Prevention; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; LDH, lactate dehydrogenase. MIS-C can be diagnosed if no other diagnosis is possible. Some patients with MIS-C may have overlapping symptoms with complete or incomplete Kawasaki disease. We thank all frontline providers, consultants, nurses, and staff of the Kravis Children's Hospital and Mount Sinai Hospital for their care of the patient. We extend a special thanks to Samantha Ganz, MD, and Erik Sanchez, MD, for their assistance in obtaining immunogenetic testing for the patient, as well as Dr Julie Teruya-feldstein, MD, and Dr Christian Salib for the pathology study. Figure E2Pedigree chart. The mother is the daughter of one the patient's father's cousins (a second cousin to the father).View Large Image Figure ViewerDownload Hi-res image Download (PPT)
Abstract Background The impact of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection among pediatric solid organ transplant (SOT) recipients remains unclear. We sought to characterize the clinical epidemiology and outcomes following SARS-CoV-2 infection among pediatric SOT recipients in Dallas, TX. Methods Retrospective review of all SOT recipients with laboratory confirmed COVID-19 infection from March 1, 2020 –March 31, 2021. Demographic, clinical, and outcome data were stratified by transplant type and disease severity. Fischer’s exact test and Kruskall-Wallis test were used to evaluate risk factors for more severe disease among hospitalized children. Results Twenty-six SOT recipients with a median age of 14 years were included in the study. Fifteen (58%) were female, eighteen (69%) were Hispanic and thirteen (50%) were overweight/obese. Median time post-transplant was 3.6 years (1311 days, interquartile range (IQR) 394-2881). Fourteen patients were liver recipients, seven kidney, three heart, and two multiorgan. The majority of patients (65%) had a known community exposure and presented with fever (50%), cough (38%) and GI symptoms (19%). Half of all cases were hospitalized (n=13), with 2 requiring intensive care unit (ICU) admission, but no patients required positive pressure ventilation. Median hospital stay was 3 days. Five of the thirteen hospitalized patients were categorized as having moderate disease. No patients developed severe disease and there were no deaths. Older children, as well as children with multiple co-morbidities were noted on univariate analysis to be at higher risk for moderate, as compared to mild, disease. Conclusion SARS-CoV-2 infection among pediatric SOT recipients are at increased risk for hospital admission but demonstrate an overall mild /moderate disease course. Larger studies are required to elucidate the risk of morbidity between pediatric SOT recipients and immunocompetent children with SARS-CoV-2. Disclosures Amal Aqul, MD, Albireo pharma Inc. (Consultant)
Background: Although less severe than in adults, children can experience a range of COVID-19 symptoms, from asymptomatic to life-threatening, including respiratory and gastrointestinal symptoms. Medical conditions may also increase the severity of the disease in infected children. Methods: A study was performed at a single center, comparing cases and controls, and involving 253 pediatric patients who had been diagnosed with COVID-19. Two different outcomes were assessed. The first categorized symptomatic individuals who were hospitalized with COVID-19 (Hospital) from those who were not (Nonhospital). The second categorized admitted individuals who spent at least one day in the intensive care unit (ICU) from those who did not require ICU (Floor). Results: Ninety individuals (36%) had at least one underlying medical condition, with the most common being pulmonary disorders, such as asthma (12%), followed by neurodevelopmental disorders (8%), gastrointestinal disorders (6%). The Hospital group was more likely to have any comorbidity such as obstructive sleep apnea (OSA), diabetes mellitus, seizure disorder, hypertension, sickle cell disease, neurodevelopmental disorder, and immunocompromising conditions including cancer, bone marrow transplant, and other immunodeficiencies, compared to the Nonhospital group. Abdominal pain was more common in the Hospital group. shortness of breath (SOB) and diarrhea were significantly more common in the ICU group than in the Floor group. Conclusions: Early identification of pediatric patients with severe COVID-19 is important to improve outcomes. In our single center case control study, we found that the presence of G symptoms on presentation was more commonly associated with severe COVID-19 in children.
Nausea and vomiting are common sequelae of a multitude of disorders that can range from mild to severe conditions.Intracranial mass lesions can occasionally present with vomiting followed by acute neurological deterioration and sudden death, although they are usually accompanied by ongoing neurological symptoms.We aimed to report an unusual presentation of an intracranial mass resulting in death to increase awareness among pediatric emergency physicians.A previously healthy 15-month-old boy presented to the pediatric emergency department (PED) with nausea, vomiting and diarrhea.He did not have any symptom of a neurological disorder.He acutely deteriorated, developed cardiopulmonary arrest and was intubated.His cranial computed tomography showed dilatation of the third and the lateral ventricles caused by a 3x4x2 cm tumor in the posterior fossa with an evidence of hemorrhage in the tumor with minimal tonsillar herniation.An emergent extra-ventricular drainage was performed to relieve elevated intracranial pressure.He did not show any improvement and died 9 hours after admission.Common symptoms in PED like nausea and vomiting are mostly due to benign etiologies such as gastroenteritis.One should always keep in mind that there may be an underlying intracranial pathology and further investigation should not be delayed.
Abstract Background Human parechovirus (HPeV) infection can result in severe disease in infants, including sepsis, seizures, brain injury, and death. In 2022, a resurgence of HPeV was noted in young infants. The spectrum of illness and outcomes remain to be fully described. Methods A multistate retrospective cohort study was conducted to evaluate hospitalizations and outcomes of infants aged ≤6 months admitted in 2022 with laboratory-confirmed HPeV infection. Infants with severe disease were defined as having clinical seizures, or abnormalities on magnetic resonance imaging or electroencephalogram during admission. Infants with severe versus nonsevere disease were compared using descriptive statistics. Results A total of 124 U.S. infants were identified with HPeV in 11 states. Cases of HPeV peaked in May and presented at a median of 25.8 days of life (0–194 d) with fever, fussiness, and poor feeding. Bacterial and other viral co-infections were rare. Thirty-three (27%) of infants had severe neurologic disease, were more likely to present at an earlier age (13.9 vs 30 days of life, P < .01), have preterm gestation (12% vs 1%, P = .02), and present with respiratory symptoms (26% vs 8%, P = .01) or apnea (41% vs 1%, P < .001). Subcortical white matter cytoxic cerebral edema was common in severe cases. Two infants with HPeV died during admission with severe neurologic HPeV disease; no infant with mild HPeV disease died. Conclusions This is the largest, geographically diverse U.S. study to describe the 2022 HPeV outbreak among infants. Longitudinal follow up of infants is needed to define predictors and outcomes of severe HPeV disease.
Although less severe than in adults, children can experience a range of COVID-19 symptoms, from asymptomatic to life-threatening, including respiratory and gastrointestinal symptoms. Medical conditions may also increase the severity of the disease in infected children.
Asthma outcomes are influenced by factors at multiple ecological levels: the individual and his/her family, home, medical care, and community. This systematic review describes recently published single-level and multilevel behavioral interventions to improve asthma outcomes.Of the 23 total title/abstracts reviewed in the original systematic search of PubMed, Ovid, Scopus, PsychINFO, and CIHAHL reference review databases, six met inclusion criteria. Five of the studies focused on low-income and/or minority populations. Promising interventions include culturally tailored online asthma self-management programs and family-centered asthma education delivered at the bedside during hospitalization for an acute asthma exacerbation.Culturally, tailored online self-management programs offer difficult-to-reach populations asthma support that can be completed at the time and pace most convenient for the individual user. Family-focused asthma education, delivered at the bedside during an acute asthma hospitalization by highly motivated lay volunteers, is an efficacious and low-cost approach to improving pediatric asthma self-management.
