key: cord-0899818-g30eoo8l
authors: Vita, Serena; Di Bari, Virginia; Corpolongo, Angela; Goletti, Delia; Espinosa, Joaquin; Petracca, Sebastiano; Palmieri, Fabrizio; Nicastri, Emanuele
title: Down Syndrome patients with COVID-19 pneumonia: a high-risk category for unfavourable outcome
date: 2020-11-30
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.11.188
sha: 8d9b9869a603f897aa53945dc72fdbcc809c58b0
doc_id: 899818
cord_uid: g30eoo8l

We report two cases of COronaVIrus Disease-19 in patients with Down Syndrome and describe the identification, diagnosis, clinical course, and management of the infection. Down Syndrome, which is caused by trisomy 21, is characterized by immune dysregulation, anatomical differences in the upper respiratory tract, and higher rate of comorbidities. All these risk factors can contribute to more severe clinical presentations of COVID-19. It is essential to raise awareness of the clinical relevance of SARS-COV-2 infection in DS patients, as well in other most vulnerable patients in order to improve their management and treatment and to candidate these individuals for vaccination, once available.

In December 2019 the novel coronavirus SARS-CoV-2 was identified as the etiologic agent of the COronaVIrus Disease-19 (COVID-19) outbreak occurring in Wuhan, China [Zhu N et al, 2020] . The clinical spectrum of COVID-19 is wide, ranging from asymptomatic infection to severe disease and death. Pro-inflammatory factors play a central role in COVID-19 severity and mortality, inducing an excessive inflammatory and immune response, leading to acute respiratory distress (ARDS) and multi-organ failure (MOF) [Zhou F et al, 2020] .

Down Syndrome (DS) is the most common chromosomal abnormality in humans. It's caused by trisomy 21 (T21) and it is characterized by an immune dysregulation, that predispose to autoimmune disorders [Nisihara et al, 2007] , and to anatomical differences in the upper respiratory tract (such as a smaller trachea enlarged adenoids/tonsils, glossoptosis, upper airway narrowing and tracheal bronchus airway malacia), that predispose to a high frequency of respiratory disease, the leading cause of mortality in persons with DS [Colvin et al, 2017 ; Byard RW. Forensic issues in Down syndrome fatalities. J Forensic Leg Med. 2007 Nov; 14(8):475-81; Englund et al, 2013] . In particular, lower respiratory tract infection (LRTIs) accounts for 43-78% of intensive care unit (ICU) admissions, and 50% of those required ventilation support [Watts et al, 2013] .

Respiratory syncytial virus is the most common cause of LRTIs in DS, leading to severe bronchiolitis.

Moreover, during the H1N1 pandemic higher risk of hospitalization, endotracheal intubation (EI), and death has been reported in DS patients [Perez-Padilla et al, 2010] . Despite the increased rate of respiratory infections, no increased risk of SARS-CoV-2 infection in DS individuals has been described.

We report two COVID-19 cases in Caucasian patients with DS with a nasopharyngeal swab (NFS) positive for SARS-CoV-2 without other respiratory coinfections, with a chest computer tomography (CT) scan showing a bilateral interstitial pneumonia.

A 59 years-old DS woman with previous history of congenital hydrocephalus, epilepsy and hypothyroidism, coming from a rehabilitation facility, was admitted on March 4th, 2020, to the Emergency Department (ED) because of acute dyspnoea. Physical examination showed: Glasgow Coma Scale 12, body temperature (BT) 37.0°C, blood pressure (BP) 80/50 mmHg, Hearth Rate (HR) 90 bpm, and peripheral oxygen saturation (SpO2) on ambient air (AA) 93% with a PaO2/FiO2 (P/F) ratio of 262 mmHg. Blood tests revealed severe lymphopenia (230 cells/μl), thrombocytopenia (60.000/μl), high C-reactive protein levels (CRP) (14.85 mg/dL, normal range <1) and mild hypokalaemia (2.81 mmol/L, normal range 3.5-5 mmol/L) (Table 1) . D-dimer (370 ng/ml) were slightly above the normal value (<250 ng/ml). In the ED the patient had multiple generalized seizure episodes, and P/F ratio fell to 162 mmHg. A cranial CT scan did not reveal CNS abnormalities, except for her tetraventricular hydrocephalus. Oxygen supplementation with O2 at 10L/min, sub-cutaneous enoxaparin (4000 UI/daily) and intravenous (iv) sodium valproate (800mg/daily), methylprednisolone (1 mg/Kg/daily), piperacillin-tazobactam (13.5 mg/daily), and noradrenaline (2ml/h) were started.

From day 1-5, she was in serious clinical but stable conditions, with a stable 200 mmHg P/F ratio. At day 3 lopinavir/ritonavir therapy (400 mg/100 mg/daily) was started. At day 6, patient's conditions became critical, with a P/F ratio persistently below 200 mmHg. From day 6-9, O2 supplementation was increased to 12 L/min, without improvement. Blood tests revealed severe hypokalaemia (1.7 mmol/L), hypocalcaemia (6.2 mg/dl; normal range: 8.6 -10.4) and mild hypernatremia, and an A 42-year-old DS woman with hypothyroidism was admitted on March 24 th 2020 to ED because of fever in the 6 previous days. She lived in a home setting where her brother had been diagnosed with COVID-19 pneumonia. Physical examination showed: BT 37 °C, BP 130/80 mmHg, HR 100 bpm, SpO2 95% on AA, with a P/F ratio of 538 mmHg. Blood tests showed lymphopenia (500 cells/μl), thrombocytopenia (99,000/μl), increased CRP level: 4.63 mg/dl (Table 1) . Hydroxycloroquine (400 mg/daily), lopinavir/ritonavir (400/100 gr/daily) and iv ceftriaxone (2 grams/daily) therapy was started. From day 2-5 increased, LDH (293 U/L), CRP (7.82), ferritin (1.633 ng/ml), and d-Dimer

(1.266 ng/ml), levels, thrombocytopenia (79,000/μl) and lymphopenia (600/μl), aspartate transaminase (AST) 71 UI/l, were recorded and a gradual reduction of P/F ratio to 140 mmHg was observed. Iv methylprednisolone (1 mg/Kg/daily) and increased oxygen supplementation until continuous positive airway pressure (CPAP) supplementation were prescribed.. On day 6 considering a P/F ratio of 100 mmHg during CPAP, the patient received iv 400 mg sarilumab therapy, underwent endotracheal intubation, and was transferred to ICU. She was mechanically ventilated for 5 days with a progressive improvement and on day 29, she was discharged, with two consecutive NFS resulted negative for SARS-CoV-2.

We described two patients with Down Syndrome affected by COVID-19: one of them with unfavourable clinical outcome. DS presents with a complex clinical spectrum of variable features affecting most organ systems. Various genetic mechanisms may be contributors to the phenotype of DS, and more than 80 clinical features with variation in number and in severity are reported in DS [Epstein et al 2007; Patterson 2007 ]. Our two patients had a different features of DS, the case 1 presenting a more complexed clinical DS with congenital hydrocephalus and epilepsy.

The two individuals had a different age: the first patient was close the maximum life span for DS and elderly is commonly considered an independent risk factor for unfavourable outcome in patients with COVID-19 [Zhou F and al, 2020] .

Both individuals presented lymphopenia at admission. The first patient had a stable course of disease for 10 days, requiring low-flow oxygen supplemental therapy and without major inflammatory index alterations, until precipitated. The second patient showed a progressive increase in both inflammation indexes and need of oxygen supplementation until CPAP support and mechanical ventilation by EI was required. As for SARS-CoV-1 and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infections, severe respiratory deterioration in COVID-19 is usually related to an exacerbated immune response to the virus, leading to the cytokine release syndrome [Picchianti Diamanti et al, 2020; Channappanavar et al, 2017] . Patients with severe COVID-19 had lymphopenia along with high levels of circulating pro-inflammatory cytokines compared to patients with mild COVID-19 illness. SARS-CoV-2 cytokine production appears related to Type I and III interferons (IFNs), followed by infiltration and activation of different immune cells and following by hyperproduction of cytokines, exacerbated immune activation, and progressive decline of respiratory function [Tisoncik et al, 2012] . Studies have showed in DS the occurrence of an interferonopathyc signature with a dysregulation of IFN-inducible cytokines causing a chronic inflammation state [Sullivan et al, 2016 , Sullivan et al. 2017 , and a widespread hypersensitivity to IFN stimulation across the human immune system [Araya et al, 2019] . Recently, in an animal model carrying triplication of these IFN receptors, activation of toll-like receptors and consequent induction of the IFN antiviral response, lead to a cytokine storm with a worsening of liver pathology and rapid death [Tuttle et al, 2020] (Figure 1 ).

The first patient did not received immunomodulating therapy, as it was not yet available at the time of admission, while at the second one was administered the anti-IL-6 agent sarilumab and in the following days she had a progressive improvement of respiratory function until recovered.

Retrospective studies indicated that an elevated level of IL-6, an inflammatory cytokine, was J o u r n a l P r e -p r o o f associated with a risk of mortality in COVID-19, suggesting that it may act as a critical mediator for respiratory failure, shock, and MOF [Ruan et al, 2020] . Immunomodulatory agents targeting directly the key cytokines may also help to alleviate hyperinflammation symptoms in severe cases [Cantini et al, 2020a; Cantini et al, 2020b; . Nevertheless, a phase 2/3 double blind randomized clinical trial evaluating the clinical efficacy of sarilumab relative to the control arm in adult patients hospitalized with COVID-19 receiving mechanical ventilation at baseline was terminated prematurely because the trial did not meet its primary and key secondary endpoints (clinicaltrial.gov).

In the light of such considerations, the different course of the two patients can be ascribed to i) different expression and feature of the DS, ii) different age and life expectancy of the two cases, iii) different host-virus interaction leading to a different immunological response, that in the second patient resulted in a cytokine storm, iv) different outbreak period in which the infection was contracted. Case 1 was admitted at the beginning of the epidemic, when there was a limited knowledge of the clinical management of COVID-19. Differently, the second case occurred about 20 days later when pathogenic mechanisms, drug protocols, and indications to invasive respiratory support were more clearly defined.

In conclusion, individuals with DS, due to the high rate of comorbidities, anatomical differences in the upper respiratory tract and immune dysregulation, manifest several risk factors for respiratory infections and unfavourable outcome. Recognition of the clinical relevance of DS in the management of COVID-19 is crucial and people with DS are among the priority candidates for early immunosuppression therapy, for available antiviral therapies and, finally, for SARS-CoV-2 vaccination, once available.

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