key: cord-0913898-a54zhzpx
authors: Innes, Andrew J; Cook, Lucy B; Marks, Sasha; Bataillard, Edward; Crossette‐Thambiah, Christina; Sivasubramaniam, Gayathiri; Apperley, Jane; Milojkovic, Dragana
title: Ruxolitinib for tocilizumab‐refractory severe COVID‐19 infection
date: 2020-06-27
journal: Br J Haematol
DOI: 10.1111/bjh.16979
sha: 19f8f179738374cc0757ac0555f15d4cf8ea33ed
doc_id: 913898
cord_uid: a54zhzpx

Whilst the majority of patients with COVID‐19 infection have mild self‐limiting symptoms, for some the SARS‐CoV2 virus can trigger a severe hyperinflammatory syndrome which is life threatening. Anti‐IL6 therapy has shown promise in restraining the hyperinflammatory syndrome and while IL‐6 is a pleiotropic mediatory of the inflammatory response, redundancy within inflammatory pathways means that the use of such targeted monoclonal therapy may have too restricted a repertoire in some patients. We present the case of a 53‐year‐old haematopoetic stem cell transplant recipient who developed a severe COVID‐19 that was refractory to anti‐IL6 therapy, but responded to Jak‐Stat inhibition with ruxolitinib, demonstrating its safety and efficacy in this setting.

of such targeted monoclonal therapy may have too restricted a repertoire in some patients. We present the case of a 53-year-old haematopoetic stem cell transplant recipient who developed a severe COVID-19 that was refractory to anti-IL6 therapy, but responded to Jak-Stat inhibition with ruxolitinib, demonstrating its safety and efficacy in this setting.

For the majority of patients, the natural course of COVID-19 infection is mild and self-limiting, but for some, the disease is severe and can be catastrophic (1) . There is mounting evidence that a viral-induced cytokine storm can drive a hyperinflammatory syndrome, and raised serum ferritin and IL-6 levels are associated with a worse outcome (2) . Whilst this phenomenon is not unique to the SARS-CoV2 virus, a striking feature in this setting is the hypoxia and lung injury associated with it. Patients who develop respiratory failure and require ventilatory support have higher plasma levels of an array of inflammatory cytokines including LIL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα, and their presence is associated with an inferior outcome (3) . The manifestation of the COVID19-hyperinflammatory syndrome are reminiscent of the cytokine release syndrome seen with chimeric antigen receptor (CAR) T-cell therapy, and this has provoked the use of anti-IL6 therapy with promising results (4, 5) . However, this approach directs therapy again a single facet of the immune response, and whilst IL-6 is a pleiotropic mediator of inflammatory signalling, this strategy may be too targeted. There is considerable redundancy in cytokine and inflammatory pathways, so inhibiting a single molecule may permit collateral pathways to continue to drive the hyperinflammatory response.

Ruxolitinib is a JAK1/JAK2 inhibitor indicated for the treatment of disease-related splenomegaly or constitutional symptoms in patients with myelofibrosis or polycythaemia vera. While ruxolitininb also significantly reduces serum IL-6 levels and c-reactive protein (CRP) in patients with myelofibrosis (6) Our report suggests that patients with evidence of a hyperinflammatory response in severe COVID19 resulting in respiratory failure that does not respond to IL-6 blockade may respond to biological agents targeting alternative components of the inflammatory cascade. Interesting, despite clear evidence of an inflammatory response to SARS-CoV2 this patient had a disproportionately raised ferritin to CRP, which may be accounted for by his existing immunosuppression, and may also identify a group of patients in whom more promiscuous immunosuppression is necessary rather than targeted IL-6 blockade.

AJI, LBC, SM, EB, CCT, GS, JFA and DM were involved in the care of the patient and contributed to data collection and analysis. AJI and DM wrote the manuscript, and all authors reviewed, edited and approved the final draft.

EB is an employee of F. Hoffmann-La Roche Ltd. The other authors have no conflicts of interest to disclosed. 

Clinical characteristics of coronavirus disease 2019 in China

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Effective treatment of severe COVID-19 patients with tocilizumab

Interleukin 6-blockade treatment for severe COVID-19 in two patients with multiple myeloma

We thank the nurses, doctors and allied healthcare professionals in the haematology and CPAP unit at Hammersmith Hospital. AJI and JFA acknowledge support from the NIHR and Imperial BiomedicalResearch Centre (BRC).