key: cord-0909280-i6r419kp
authors: Akinosoglou, K.; Velissaris, D.; Ziazias, D.; Davoulos, C.; Tousis, A.; Tsiotsios, K.; Kalogeropoulou, C.; Spyridonidis, A.; Marangos, M.; Fligkou, F.; Gogos, C.
title: Remdesivir and Tocilizumab: Mix or Match
date: 2020-06-03
journal: J Med Virol
DOI: 10.1002/jmv.26117
sha: 6ae1be8fc6a2bc7147f21ea56db72ff8b72662ef
doc_id: 909280
cord_uid: i6r419kp

To date, no therapy has demonstrated definite efficacy for patients with COVID‐19. Antiviral, as well as, anti‐inflammatory approaches, as these represented by remdesivir (RDV) and tocilizumab (TCZ) use, have been recently put forward. However, data upon optimal choice of one over the other, or potential need for regimen combination, remains an open question. We hereby report two well‐matched cases of SARS‐CoV‐2 (+) patients, developing respiratory failure, both receiving TCZ following severe inflammatory response, with or without RDV. We argue that, RDV administration is pivotal early in the course of the disease, since TCZ use alone cannot ensure inflammation control. This article is protected by copyright. All rights reserved.

We read with great interest the recently published article by Chakraborty et al 1 in response to IL-6 antagonist use, for the management of COVID-19 -related cytokine storm. We agree that to date, no therapy has demonstrated definite efficacy for patients with COVID-19, hence in this context antiviral e.g remdesivir (RDV) 2 , as well as, antiinflammatory approaches (TCZ) 3 , have been recently put forward. However, data upon optimal choice of one over the other, or potential need for regimen combination, remains an open question. We hereby report our experience with two identical cases of SARS-CoV-2 (+) patients, developing respiratory failure, both receiving TCZ following severe inflammatory response, with or without RDV, and we argue that, even though, TCZ administration may dump underlying inflammatory response mediated by IL-6, cytokine storm cannot be totally diminished by this blockade, since other distal pathways remain active.

Two SARS-CoV-2 (+) patients 59 (Patient 1) and 49-year-old (Patient 2) respectively, both with medical history of dyslipidaemia, otherwise unremarkable, presented in our department with low grade fever and dyspnoea, on 5 th day of symptoms.

Both patients had received hydroxychloroquine (800mg LD followed by 400mg qd) and azithromycin (500mg LD, followed by 250mg qd) for 4 days prior to admission, with no response. Upon presentation, they were both in good condition, showing signs or incipient lower respiratory tract infection and mild hypoxia of 94 and 93% oxygen saturation on room air, respectively. On third day of admission, their clinical condition deteriorated, both presenting high grade fever up to 39.5°C and respiratory failure (pO2/fiO2<200), on air entrainment-masks. In line with increased inflammatory markers, we administrated TCZ in both patients. Patient 2 was also approved to receive RDV, in the context of compassionate use. Defervescence and drop in CRP occurred within the next 24 hours of TCZ infusion, in both patients. However, during the same time, both required non-invasive positive pressure and invasive mechanical ventilatory support respectively, exhibiting laboratory markers and imaging as shown in Fig 1. Interestingly, at this time, patient 1 showed signs of ongoing hemophagocytic syndrome (HLH) (HScore:193, absent NK cell activity), contrary to patient 2 (HScore: 63, mildly increased NK cell activity). On day five following administration, both patients presented significant respiratory and radiologic improvement, and were eventually transferred from ICU to medical ward, with low flow oxygen supply, where they continued an uncomplicated course until discharge.

A unique pattern of immune dysregulation, associated with sustained cytokine production and hyper-inflammation has been recently identified in severe COVID-19 cases 4 . The primary source and kinetics of the cytokine storm however, remain elusive.

On one hand, there is defective antigen presentation driven by IL-6, and on the other, an HLH like syndrome mediated by IL-1β 4 . Exact timing of these processes need to be addressed, while simultaneous progression of both syndromes, similar to bacterial sepsis is possible. It seems that blockade of IL-6, by TCZ in COVID-19 patients partially rescues immune dysregulation 4, 5 . Even though, both of our patients received TCZ and presented prompt decrease in inflammatory markers similar to others 3,5 , patient one was consequently driven to HLH. It is possible, that even though, hyper-inflammatory response is mainly driven by IL-6, its blockade can leave alternative pathways intact, pushing response to the other end; that of HLH. Previous authors have noted the need to screen those patients for secondary HLH, as this reflected in HScore >169, where respective immunomodulatory therapy could prove beneficial 6 .

Whether, systemic cytokine storm or actually direct virus-induced tissue damage, or development of both, contributes to poor outcomes remains to be seen. In the latter case, we should expect a combination of approaches, rather than a magic bullet to target SARS-CoV-2. Nonetheless, the earlier in the cascade we target, the best chances we have to get optimal results. We argue that, RDV can blunt inflammatory response, by hampering viral replication, thus; preventing inflammatory mediator release to any direction, at its very beginning.

Even though, well-matched, our cases are far from a randomised clinical trial of that sort. Recently initiated REMDACTA trial could elucidate RDV and TCZ potential combination use. In line with previous authors 1 we stress the complexity and variety of pathways underlying inflammatory response, that can drive diverse outcomes. We suggest administration of RDV, early before secondary uncontrolled inflammatory response takes place. If the latter does occur, immunomodulation e.g via TCZ use is an option, but does not solely seem to drive outcomes. Managing hyperinflammation with immunomodulation is important, but source control, with proper and timely antiviral therapy remains critical. 

COVID-19: Consider IL6 receptor antagonist for the therapy of cytokine storm syndrome in SARS-CoV-2 infected patients

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial

Effective Treatment of Severe COVID-19 Patients with Tocilizumab. 2020

Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure

Tocilizumab treatment in COVID-19: A single center experience

COVID-19: consider cytokine storm syndromes and immunosuppression