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.
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 J o u r n a l P r e -p r o o f 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 highflow 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. 
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, nonbloody emesis following G-tube feeding. Examination revealed temperature of 38.8 o C 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.
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.
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 J o u r n a l P r e -p r o o f mortality (18) . Children with T21 may be at increased risk for further up-regulation of proinflammatory 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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