key: cord-0714287-wifxjik2
authors: Pain, Clare E; Felsenstein, Susanna; Cleary, Gavin; Mayell, Sarah; Conrad, Karsten; Harave, Srikrishna; Duong, Phuoc; Sinha, Ian; Porter, David; Hedrich, Christian M
title: Novel paediatric presentation of COVID-19 with ARDS and cytokine storm syndrome without respiratory symptoms
date: 2020-05-15
journal: Lancet Rheumatol
DOI: 10.1016/s2665-9913(20)30137-5
sha: 83c4f62e84bb2ba85e90fcc3cfe6824347739b12
doc_id: 714287
cord_uid: wifxjik2

nan

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen that causes COVID-19. Although early studies suggested that children and adolescents could be spared from severe disease, reports have since been published of children hospitalised or dying from COVID-19. 1, 2 We report a 14-year-old previously healthy individual who presented to our institution with a 3-day history of pyrexia, abdominal pain, nausea, and vomiting, but with out respiratory symptoms. The patient's mother reported mild respiratory symptoms 3 weeks previously but the patient had not been tested for SARS-CoV-2.

On admission (day -2), the patient was febrile (38·1°C) and cardiovascularly stable, and showed no signs of respiratory distress (figure). The abdomen was tense, with guarding in the right upper and lower quadrants. Initial investigations showed lymphopenia (0·14 × 10 9 cells per L [normal range 1·5-7·6]), a signi ficant increase in C-reactive protein (242 mg/L [normal range 0-8]), and sterile pyuria (30 cells). The patient was started on empiric piperacillin-tazobactam for sus pected acute appendicitis, and nasopharyngeal swabs were sent for SARS-CoV-2 PCR testing. Chest radiography (figure, A) and abdominal ultrasound were normal. Within 24 h of admission, the patient developed increasing dyspnoea, cough, and oxygen requirement (8 L/min), finally escalating to continuous positive airway pressure ventilation support. The patient seemed visually more unwell and inter acted less, developed a widespread maculopapular blanch ing rash (figure, B), and received fluid boluses for persistent tachycardia. Chest CT showed typical findings of SARS-CoV-2 pneumonia (figure, C). 3 A diagnosis of presumptive COVID-19 was made. Secondary multisystem inflammatory disease or cytokine storm syndrome was diagnosed based on clinical symptoms, lymphopenia, anaemia, thrombocyto penia, increased acutephase pro teins (ie, C-reactive protein and ferritin), raised serum interleukin (IL)-6 (1098 pg/mL [ . Furthermore, the patient developed mild polyarticular arthritis of the small joints of the hands. No sub stan tial cervical lymphadenopathy, conjunctivitis, or mucous mem brane changes were seen to suggest classic or com plete Kawasaki disease.

The patient was not eligible for remdesivir compassionate use because SARS-CoV-2 PCR was negative. Because the patient showed clinical features sugges tive of COVID-19-associated cytokine storm syn drome, 1,4 antiinflammatory treatment with recombinant IL-1 rec e ptor antagonist (anakinra) was initiated after multi disciplinary discussions. Anakinra was started at 4 mg/kg per day (100 mg twice a day) subcutaneously and increased to 8 mg/kg per day (200 mg twice a day) after 36 h, because the patient required inotropic support for hypotension and rising lactate (6 mmol/L). Borderline left-ventricular systolic dysfunction, enzyme leak (troponin-T 45 ng/L), aortic regurgitation, and pro gressive left coronary dilatation were noted (figure, D), and aspirin was started (2 mg/kg) for its anti thrombotic effects. Of note, Kawasaki disease-like features, including coronary aneurysms, have been rep orted in patients with COVID-19. 2 Since coronary artery dilation can occur in the context of systemic inflammatory disease, endothelial activation, or both, 5 and because the patient did not show additional clinical features of Kawasaki disease, we did not start intravenous immuno globulin or corticosteroids, after weighing the risks associated with intravenous immunoglobulin treatment (ie, thromboembolic events, aseptic meningitis, and antibody-dependent enhancement).

In temporal relation with anakinra treatment, the patient's respiratory status stabilised and clinical and laboratory variables returned to normal (figure, E), with the exception of coronary dilation that persisted at the time of discharge. Thus, anakinra was tapered and discontinued after 6 days. Subsequently, serum tested positive for SARS-CoV-2 IgG (borderline day 6, positive day 11). SARS-CoV-2 PCR on three nasopharyngeal samples (days 3, 5, and 7) and stool (day 11) were negative.

To our knowledge, this case is the first paediatric patient reported with cytokine storm syndrome during the COVID-19 pandemic presenting without respiratory symptoms on hospital admission who was successfully treated with IL-1 inhibition. Although respiratory and stool PCR testing was negative, CT chest findings and biochemical and haematological variables were highly suggestive of COVID-19, with evidence of seroconversion. Considering that PCR test sensitivity ranges around 60%, after three negative PCR results, this case could represent a post-COVID-19 inflammatory process. An alternative explanation could be viral replication at an alternative site. Although the patient developed earlystage acute respiratory distress syndrome (ARDS) in the hospital (severe oxygenation defect and bilateral pulmonary infiltrates), respiratory symptoms were not part of the initial presentation. Thus, the case resembles a previously unappreciated clinical phenotype of COVID-19 in children with rapid onset ARDS and cytokine storm syndrome after fever and abdominal pain in the absence of preceding respiratory symptoms. 1, 2 Based on our current pathophysiological under standing, SARS-CoV-2 replicates in respiratory and intes tinal epithelial cells and suppresses early type I inter feron responses. Furthermore, SARS-CoV-2 can abort ively infect innate immune cells (monocytes and macro phages), which can be facilitated by immune com plexes, accelerating viral replication and amplify ing pro inflam matory cytokine (IL-1, IL-6, tumour nec rosis factor [TNF]) release in a process termed antibody-dependent enhancement. Viral replication results in tissue damage and excessive recruitment of innate and adaptive immune cells, which mediates a dysregulated hyperinflammatory response Ferritin (ng/mL) C-reactive protein (mg/L) D-dimer (ng/mL) that contributes to cyto kine storm syndrome and organ damage, includ ing ARDS. 6 In addition to the direct cytopathic effect inflicted on target organs, pulmonary damage seen in COVID-19 is probably augmented, if not dominated, by an unopposed dysregulated immune response. ARDS can occur in patients with primary or secondary cytokine storm syndrome, including systemic juvenile idiopathic arthritis, resembling the clinical picture in the reported patient. This finding could account for the rapid onset of clinical and imaging findings. 7 Since the patient showed altered clotting (prolonged prothrombin time and activated partial thromboplastin time, and increased D-dimer) in the presence of antiphospholipid antibodies and pathologically reduced serum complement levels, immune complex generation and deposition could, in addition to endothelial activation through IL-1, have contributed to activation of the complement and clotting cascades. 8 Indeed, postinfectious antiphospholipid syn drome with thromboembolism has been reported in the context of COVID-19. 9 Furthermore, complement activa tion can take place in systemic inflammatory disorders, such as systemic juvenile idiopathic arthritis-associated macrophage activa tion syndrome. 10 Off-label treatment with anakinra was chosen to limit proinflammatory cytokine expression, which could have been triggered by antibody-dependent enhancement or invasion of yet uninfected immune cells to infected tissues. Of note, anakinra blocks IL-1 receptor signalling, which induces the expression of IL-1, IL-6, and TNF via activation of NF-κB-dependent pathways. 11 Although most clinical trials currently underway investigate IL-6 blockade, we chose anakinra based on its action upstream of IL-6 and because of less neutropenia, liver enzyme elevation, and hypertriglyceridemia, which are already present in patients with cytokine storm syndrome. Furthermore, anakinra reduces mortality in sepsis patients, 12 whereas chronic use of IL-6 blocking agents might increase the risk of secondary infections. Anakinra treatment coincided with clinical improvement and was stopped after 6 days.

During the ongoing pandemic, COVID-19 must be considered in patients with increased inflammatory vari ables and abdominal symptoms. The onset of cytokine storm syndrome and ARDS can be rapid and lifethreatening. Based on the time of testing, the site of infection, or both, PCR testing might remain negative.

Anakinra is safe and effective in other inflammatory and auto inflammatory disorders, and it could be beneficial in COVID-19-associated cytokine storm syndrome, in which disordered host responses contribute to path ology. Inflammatory endothelial activation, antiphospho lipid antibodies, and complement activation all promote a pro inflammatory and coagulopathic state. Anti thrombotic prophylaxis should be considered, particularly in the presence of coronary artery dilation or aneurysm. Pros pective controlled trials are necessary to generate evidence for stage-specific and individualised treatment options in COVID-19.

COVID-19: considerations for the paediatric rheumatologist

Hyperinflammatory shock in children during COVID-19 pandemic

Clinical and imaging features of COVID-19

On the alert for cytokine storm: immunopathology in COVID-19

Coronary artery dimensions in febrile children without Kawasaki disease

COVID-19: immunology and treatment options

Innately adaptive or truly autoimmune: is there something unique about systemic juvenile idiopathic arthritis?

Understanding inflammatory responses in the manifestation of prothrombotic phenotypes

Coagulopathy and antiphospholipid antibodies in patients with Covid-19

Hypocomplementemia associated with macrophage activation syndrome in systemic juvenile idiopathic arthritis and adult onset Still's disease: 3 cases

Current understanding of the pathophysiology of systemic juvenile idiopathic arthritis (sJIA) and target-directed therapeutic approaches

Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial

We declare no competing interests. CEP and SF, and DP and CMH, contributed equally. The patient's mother provided consent to publish this case report.