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
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
Characteristics of patients with trisomy 21 and COVID-19
Test / Case
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
WB x 103 cells/μL
Symptomatic Days PTA
Max Resp Support
HcQ (3 days only), Toci, Rem
OSA obstructive sleep apnea; CHD congenital heart disease; PHTN pulmonary hypertension;
HFNC high flow nasal cannula; NC nasal cannula; HcQ hydroxychloroquine; Rem remdesivir;
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
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.
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.
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 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
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
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.