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      Trisomy 21 and COVID-19 in Pediatric Patients

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          Abstract

          We present 4 pediatric patients with trisomy 21 (T21) and associated comorbidities who developed COVID-19 requiring hospitalization. A review of the literature revealed that co-morbidities associated with T21 may predispose patients to severe disease. Children with T21 should be considered high risk and monitored carefully if infected with SARS-CoV-2. Children with underlying health conditions, including those with respiratory conditions or who are immunocompromised, continue to be at risk of severe COVID-19. We present 4 cases of SARS-CoV-2 confirmed by PCR in patients of another possible at-risk group: children with trisomy 21 (T21) and associated co-morbidities (Table ). All four patients had COVID-19 disease requiring hospitalization, and one patient had severe disease. None has been reported previously. Of note, Cases 1, 2, and 4 are part of a COVID-19 registry managed by St. Jude Children's Research Hospital, TN. However, at the time of this submission, no data have been published from this registry. Table 1 Characteristics of patients with trisomy 21 and COVID-19 Test / Case 1 2 3 4 Co-Morbidities OSA, Obesity, CHD CHD, OSA, Dysphagia OSA, CHD, dysphagia, epilepsy, hypothyroid, recurrent aspiration pneumonia OSA, CHD, obesity Type of CHD Ventricular septal defect s/p repair Tetralogy of Fallot, s/p repair Atrial septal defect s/p repair Atrial septal defect s/p repair Pulmonary Hypertension No Yes No No Symptomatic System Respiratory, ENT Respiratory Respiratory, GI GI WB x 103 cells/μL 4.15 9.14 4.3 1.46 CRP mg/dL 1.3 1.3 6.2 1.2 Procalcitonin ng/mL 0.10 1.08 - <0.10 Ferritin ng/mL 527 - - 117 D-Dimer mcg/mL 2.26 - 3.97 - Symptomatic Days PTA 8 1 3 1 Days Hospitalized 23 7 4 2 Max Resp Support Mechanical Vent HFNC NC Baseline Support BMI 35.38 15.6 22.2 28.3 Therapy HcQ (3 days only), Toci, Rem Key OSA obstructive sleep apnea; CHD congenital heart disease; PHTN pulmonary hypertension; HFNC high flow nasal cannula; NC nasal cannula; HcQ hydroxychloroquine; Rem remdesivir; Toci tocilizumab Case 1 A 17-year-old male with T21, congenital heart disease (CHD), and obesity presented to our emergency department (ED) after five days of severe throat pain, non-productive cough, and poor oral intake secondary to pharyngitis, but without breathing difficulty. He was febrile but had a normal respiratory examination, including normal work of breathing. A rapid strep test and SARS-CoV-2 PCR were sent; both were positive. Due to overall mild symptoms, he was discharged home to receive amoxicillin for streptococcal pharyngitis. Three days later, he returned to the ED because of dehydration, fever, and concern for increasingly difficult breathing with mild supraclavicular retractions. His chest radiograph showed bilateral lower lobe reticulonodular opacities with focal airspace opacities in the left-mid-to-lower lobe and he was hospitalized for further care. On hospital day of admission (D)1, he had intermittent oxygen desaturation to 85% while asleep which resolved with re-positioning. On D2, he required 2L oxygen by nasal cannula for labored work of breathing, tachypnea, accessory muscle use, and persistent hypoxemia. Hydroxychloroquine was initiated while awaiting approval of emergency use of investigational new drug for remdesivir. On D4, he was transferred to the intensive care unit due to increasing tachypnea and need for supplemental oxygen and was started on IV remdesivir (200 mg IV loading dose on day 1, then 100 mg IV daily on days 2-10). Hydroxychloroquine was discontinued. Intubation was required on D5. On D10, he had an increase in CRP from 3.2 mg/dL at admission to 7 mg/dL and procalcitonin from 0.14 at admission to 2.43, as well as new onset of hypotension to 60s/40s mm Hg. To combat his hyperinflammatory state, tocilizumab was started. His CRP and procalcitonin decreased after a single dose to 2.7 mg/dL and 1.25, respectively. On D14, he was extubated, maintained on high-flow oxygen by nasal cannula and was no longer febrile. After extubation, he required continuous positive airway pressure (CPAP) at night time for probable obstructive sleep apnea (OSA). He was discharged to home on D23 after requiring no oxygen supplementation during the daytime Case 2 A 10-month-old male with T21, CHD, pulmonary hypertension, OSA, and dysphagia was brought to medical attention with a one day history of fever to 38.1 oC, productive cough, and increased work of breathing. On examination he was afebrile, without increased work of breathing; auscultation of his chest revealed clear breath sounds bilaterally. A chest radiograph revealed bilateral perihilar opacities with left retrocardiac opacity. Ceftriaxone was begun IV and he was admitted to the inpatient medical unit. Oxygen requirement increased from his baseline 0.75L O2 via nasal cannula at home (required overnight) to 2L due to intermittent oxygen desaturation to 85%. Symptoms progressively worsened, including increased work of breathing and decreased oxygen saturation, requiring escalation of support by high flow oxygen by nasal cannula. Vancomycin was initiated when he developed fever. On D2, positive SARS-CoV-2 was known and his antibiotics were discontinued. On D4, he was weaned to oxygen by regular flow nasal cannula in the morning and placed back on home O2 of 0.75L overnight. He tolerated being on absence of daytime supplemental O2 on D5 and was discharged tohome. Case 3 A 15-year-old male with T21, OSA, CHD, dysphagia, and recurrent aspiration pneumonia was brought to the ED after two days of cough, one day of fever, and recurrent non-bilious, non-bloody emesis following G-tube feeding. Examination revealed temperature of 38.8 oC and tachycardia, initially with normal oxygen saturation and no increased work of breathing. Oxygen desaturation to 86% ensued and requiring supplementation via nasal cannula; his chest radiograph showed no focal consolidation. During hospital D1 he required escalation of flow to a maximum of 2.5L. On D2, he was re-started on continuous G-tube feedings and subsequently was weaned to room air. On D4, feeding regimen was resumed to home bolus, and he was discharged to home. Case 4 A 14-year-old male with T21, obesity, CHD, and OSA had the acute onset of refusal to eat, abdominal pain, dry cough, and fatigue. He did not have emesis, diarrhea, increased work of breathing or fever, and remained stable on his home settings of CPAP without supplementary oxygen. Per home testing, his blood glucose was 53, and his father brought him to an outside hospital ED for further care. He was given fluids and an anti-emetic and underwent an abdominal CT for continued abdominal pain. Although the abdomen appeared normal on CT, the bases of the lungs showed ill-defined mixed airspace opacities in the lower lobes and inferior aspect of the lingula. SARS-CoV-2 PCR was sent and was positive. He was transferred to our institution for care and monitoring during which time he remained stable without fever, increased work of breathing, or need for supplementary oxygen. He was discharged after one day of hospitalization. Discussion Children with intellectual and developmental disability (IDD), including those with T21, had increased mortality rates from COVID-19 compared with peers without IDD (1). The anatomic, immunologic, and metabolic comorbidities associated with T21, as present in our cases, may increase their risk for severe COVID-19 disease. Children with T21 have abnormal upper airway phenotypic features including macroglossia, midface hypoplasia, choanal stenosis, narrow nasopharynx, enlarged tonsils and adenoids, lingual tonsils, and shortening of the palate, all of which can exacerbate patency of airways during respiratory infections (2). These abnormalities plus generalized hypotonia and increased likelihood of obesity, increase the prevalence of sleep-disordered breathing among this population, with estimated rates varying from 31-79% in children with T21 (3, 4). The onset of sleep-disordered breathing in children with T21 typically occurs at a younger age, after the second to third year of life, compared with children without T21 (3, 4). Children with T21 also have a high rate of congenital heart disease (2). Structural cardiac defects are found in about 40% of children with T21, most commonly seen are atrioventricular septal defects (5). Children with T21 and AVSD more frequently develop pulmonary vascular hypertension compared with those without trisomy (6). For children with T21, the interplay between complicated respiratory and cardiovascular anatomy and pathophysiology likely lead to increased severity and mortality of respiratory infections. Krishnan et al highlighted the interplay between congenital heart disease, pulmonary hypertension, and T21 as it relates to SARS-CoV-2 infection; 60% of patients with pulmonary hypertension and SARS-CoV-2 infection requiring hospitalization also had T21 and AVSD (7). Among our four cases, all patients had repaired congenital heart disease, though only one had pulmonary hypertension. Children with T21 may have abnormal immune function that predisposes them to more severe infections, prolonged lower respiratory tract infections, and increased incidence of acute lung injury (8, 9). Studies have found variations in immune functions in children with T21 including: mild to moderate T- and B-cell lymphopenia, with marked decrease of naive lymphocytes; impaired mitogen-induced T-cell proliferation; reduced specific antibody responses to immunizations; and defects of neutrophil chemotaxis (10). Additionally, the number of CD14/16+ pro-inflammatory monocytes is higher in patients with T21 relative to a low absolute monocyte count (11), exacerbating inflammatory morbidity during infection. Obesity has emerged as a primary risk factor for severe COVID-19 (12). Previous studies estimate an increased prevalence of obesity among children with T21 (13). A meta-analysis by Bertapelli et al found the worldwide prevalence of overweight children with T21 to be 23-70%, with obesity ranging from 0-63% (13). Current studies propose the following hypotheses: increased leptin level thought to be related to leptin resistance and decreased satiety, lower resting energy expenditure and lower physical activity compared with non-T21 youth (14, 15, 16). Increased weight can lead to upper airway obstruction and obstructive sleep apnea, which is compounded by anatomic differences in children with T21. Obesity also can lead to immune dysregulation, increasing the severity of viral disease. Obesity can result in a state of chronic meta-inflammation, which can blunt host’s antiviral response (17). During the 2009 H1N1 pandemic, obesity was associated with increased hospitalization and mortality (17). Children with T21 have hyperactivation of their interferon signaling, ultimately resulting in a hyperinflammatory state (18). For SARS-CoV-2 infection, there is increasing evidence that a hyper-inflammatory response to the virus leads to increased morbidity and mortality (18). Children with T21 may be at increased risk for further up-regulation of pro-inflammatory cytokines during COVID-19. The unique risks of upper and lower respiratory abnormalities, immune defects, increased rates of obesity and sleep disordered breathing all place those with T21 at higher risk for severe disease from respiratory pathogens. It seems prudent to take caution with children and adults with T21 infected with SARS-CoV-2.

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          Most cited references 16

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          Infections and immunodeficiency in Down syndrome.

          Down syndrome (DS) is the most common genetic disease and presents with cognitive impairment, cardiac and gastrointestinal abnormalities, in addition to other miscellaneous clinical conditions. DS individuals may have a high frequency of infections, usually of the upper respiratory tract, characterized by increased severity and prolonged course of disease, which are partially attributed to defects of the immune system. The abnormalities of the immune system associated with DS include: mild to moderate T and B cell lymphopenia, with marked decrease of naive lymphocytes, impaired mitogen-induced T cell proliferation, reduced specific antibody responses to immunizations and defects of neutrophil chemotaxis. Limited evidence of genetic abnormalities secondary to trisomy of chromosome 21 and affecting the immune system is available, such as the potential consequences of gene over-expression, most significantly SOD1 and RCAN1. Secondary immunodeficiency due to metabolic or nutritional factors in DS, particularly zinc deficiency, has been postulated. Non-immunological factors, including abnormal anatomical structures (e.g. small ear canal, tracheomalacia) and gastro-oesophageal reflux, may play a role in the increased frequency of respiratory tract infections. The molecular mechanisms leading to the immune defects observed in DS individuals and the contribution of these immunological abnormalities to the increased risk of infections require further investigation. Addressing immunological and non-immunological factors involved in the pathogenesis of infectious diseases may reduce the susceptibility to infections in DS subjects. © 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.
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            Intellectual and Developmental Disability and COVID-19 Case-Fatality Trends: TriNetX Analysis

            Background Despite possibly higher risk of severe outcomes from COVID-19 among people with intellectual and developmental disabilities (IDD), there has been limited reporting of COVID-19 trends for this population. Objective To compare COVID-19 trends among people with and without IDD, overall and stratified by age. Methods Data from the TriNetX COVID-19 Research Network platform was used to identify COVID-19 patients. Analysis focused on trends in comorbidities, number of cases, number of deaths, and case-fatality rate among patients with and without IDD who had a positive diagnosis for COVID-19 through May 14, 2020. Results People with IDD had higher prevalence of specific comorbidities associated with poorer COVID-19 outcomes. Distinct age-related differences in COVID-19 trends were present among those with IDD, with a higher concentration of COVID-19 cases at younger ages. In addition, while the overall case-fatality rate was similar for those with IDD (5.1%) and without IDD (5.4%), these rates differed by age: ages 75– IDD 21.1%, without IDD, 20.7%. Conclusions Though of concern for all individuals, COVID-19 appears to present a greater risk to people with IDD, especially at younger ages. Future research should seek to document COVID-19 trends among people with IDD, with particular attention to age related trends.
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              Prevalence of congenital heart defects and persistent pulmonary hypertension of the neonate with Down syndrome

              The aim of this study was to assess the prevalence of congenital heart defects (CHDs) and persistent pulmonary hypertension of the neonate (PPHN) in children with Down syndrome (DS) and to assess its impact on neonatal factors. It was a prospective study of a birth cohort of children with DS born between 2003 and 2006 registered by the Dutch Paediatric Surveillance Unit (DPSU). A CHD occurred in 43% of 482 children with trisomy 21. Atrioventricular septal defect was found in 54%, ventricular septal defect in 33.3% and patent ductus arteriosus in 5.8%. The incidence of PPHN in DS was 5.2%, which is significantly higher than the general population (p < 0.001). The reported mortality in newborns with DS was overall 3.3% and was still significant higher in children with a CHD versus no CHD (5.8% versus 1.5%) (p = 0.008). The presence of CHD in children with DS had no influence on their birth weight, mean gestational age and Apgar score. In neonates with DS, we found not only a 43% prevalence of CHD, but also a high incidence of PPHN at 5.2%. Early recognition of the cardiac condition of neonates with DS seems justified.
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                Author and article information

                Contributors
                Journal
                J Pediatr
                J. Pediatr
                The Journal of Pediatrics
                Elsevier Inc.
                0022-3476
                1097-6833
                27 August 2020
                27 August 2020
                Affiliations
                [1 ]Ann & Robert H. Lurie Children’s Hospital, Chicago, IL, USA
                [2 ]Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
                Author notes
                []Corresponding Author anewman@ 123456luriechildrens.org
                Article
                S0022-3476(20)31103-3
                10.1016/j.jpeds.2020.08.067
                7451004
                © 2020 Elsevier Inc. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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                Pediatrics

                trisomy 21, down syndrome, covid-19

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