key: cord-0851120-klcw6k9u
authors: Kim-Hellmuth, Sarah; Hermann, Matthias; Eilenberger, Julia; Ley-Zaporozhan, Julia; Fischer, Marcus; Hauck, Fabian; Klein, Christoph; Haas, Nikolaus; Kappler, Matthias; Huebner, Johannes; Jakob, André; von Both, Ulrich
title: SARS-CoV-2 triggering severe ARDS and secondary HLH in a 3-year-old child with Down syndrome
date: 2020-11-14
journal: J Pediatric Infect Dis Soc
DOI: 10.1093/jpids/piaa148
sha: 7a4520cfc38c5d0430c1d19ade95fd14e90e4006
doc_id: 851120
cord_uid: klcw6k9u

Down syndrome (DS) predisposes to severe immunologic reaction secondary to infectious triggers. Here we report a paediatric DS patient with COVID-19 who developed a hyperinflammatory syndrome, severe ARDS and secondary HLH requiring PICU admission and treatment with steroids, IVIG and Remdesivir. Investigations into genetic susceptibilities for COVID-19 and SARS-CoV-2-associated complications warrants systematic clinical and scientific studies.

M a n u s c r i p t [2] with some features resembling Kawasaki disease or toxic shock syndrome [3] . In this context, the Royal College of Paediatrics and Child Health (RCPCH) has published a case definition and guidance for clinicians in the UK and worldwide [2] .

Patients with Down syndrome (DS) and DS-associated comorbidities are at higher risk for severe clinical manifestations of respiratory infections. While a few recent case reports have detailed COVID-19 in paediatric DS patient [4, 5] none have focused on the immunological features associated with COVID-19 in DS patients. Here we present a case of COVID-19triggered secondary haemophagocytic lymphohistiocytosis (sHLH) in a child with DS.

End of March 2020, a 3-year-old boy of central African descent with DS, previously repaired atrioventricular septal defect (AVSD), pulmonary hypertension, and a history of recurrent episodes of bronchitis presented to our paediatric accident & emergency department (A&E).

His AVSD had been corrected at 9 months of age and he was subsequently treated for residual pulmonary hypertension for a period of 8 months; following treatment he had no further cardiac issues. Immunisations were all up to date. The child presented with a three- A c c e p t e d M a n u s c r i p t 5 sick thyroid syndrome (fT4 0.8ng/dl, fT3 1.3 pg/ml, normal TSH) and signs of sHLH characteristic of a cytokine storm (Hb 7.8 g/dl, platelets 84,000/mm 3 , WBC 9,220/mm 3 , triglycerides 151 mg/dl, AST 108 U/l, soluble IL-2 receptor 2702 kU/l, fibrinogen 454 mg/dl, ferritin 7499 ng/ml). The latter can be summarised in the HScore, a score for the diagnosis of reactive hemophagocytic syndrome [6] (Table 1 ). In contrast, patient and clinical features characteristic for MIS-C such as older age, gastrointestinal symptoms, rash or conjunctivitis were missing. There were no signs of cardiac or coronary involvement on repeated echocardiography while the child was treated on PICU; however, a tricuspid regurgitation with a peak pressure of 60-70 mmHg was observed on day 4 of the illness indicating development of a novel moderate pulmonary hypertension during his stay on PICU.

Ampicillin was escalated to piperacillin/tazobactam (1.3 g q8H) in view of rapid clinical deterioration and the boy was started on remdesivir (5 mg/kg loading dose, followed by 2.5 mg/kg OD) via a compassionate use program. Upon diagnosis of sHLH according to HScore, immunosuppressive / immunomodulatory therapy was initiated with prednisolone (2mg/kg OD) and the boy received a single dose of intravenous immunoglobulin (IVIG) (1g/kg). Evaluation of the gene expression pattern of interferon-stimulated genes on day 8 demonstrated a profound activation of the type-I-IFN response. Over the next few days, the clinical condition gradually improved allowing weaning from invasive CMV on day 12.

Remdesivir was continued for a total of 9 days; steroids were also weaned and eventually discontinued on day 17. He had normal oxygen saturation on room air on day 16 and displayed gradual normalisation of pulmonary arterial pressure from day 9 onwards. While Our patient illustrates a case of severe pulmonary COVID-19 triggering sHLH. Patients with Down syndrome show a consistently activated signalling cascade in the IFN pathway [7] , which may have predisposed our patient to progress to sHLH. Trisomy 21 has been demonstrated to activate the IFN transcriptional response in a number of human cell lines, including monocytes and T cells [7] . Hence, children with Down syndrome might be at increased risk for developing sHLH in the context of various infectious triggers as documented in a few case reports [8, 9] , including viruses such as SARS-CoV-2. Secondary HLH is a life-threatening condition that has some features in common with MIS-C such as persistent fevers, abnormal blood cell counts and inflammatory markers. However, it is important to note that inflammatory markers such as ferritin, fibrinogen, and AST do not reach the levels of sHLH patients [10] . In addition, MIS-C commonly affects older children 

COVID-19 Disease Severity Risk Factors for Pediatric Patients in Italy

Guidance: Paediatric multisystem inflammatory syndrome temporally associated with COVID-19

Hyperinflammatory shock in children during COVID-19 pandemic

Trisomy 21 and Coronavirus Disease 2019 in Pediatric Patients

SARS-CoV-2 Infection in Patients with Down Syndrome, Congenital Heart Disease, and Pulmonary Hypertension: Is Down Syndrome a Risk Factor?

Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome

Trisomy 21 consistently activates the interferon response

Hemophagocytic Lymphohistiocytosis Secondary to Mycoplasma Pneumoniae Infection in a Trisomy 21 girl

Hemophagocytic lymphohistiocytosis in adults

Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2

Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Metaanalysis

We thank clinical and nursing staff for excellent care and colleagues at the university hospital Dresden for performing RNA profiling of IFN-stimulated genes.

A c c e p t e d M a n u s c r i p t 8 M a n u s c r i p t 11 A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 13 Figure 1