key: cord-0942946-o00s8z69
authors: Caradec, Emmanuella; Mouren, Domitille; Zrounba, Mathilde; Azoulay, Levi-Dan; Blandin, Constance; Ivanoff, Sarah; Levy, Vincent; Brillet, Pierre-Yves; Nunes, Hilario; Uzunhan, Yurdagül
title: COVID-19 in a patient with idiopathic pulmonary fibrosis successfully treated with Ruxolitinib
date: 2020-11-06
journal: Respir Med Res
DOI: 10.1016/j.resmer.2020.100799
sha: e6fc84fa55eccea418ad881b9a7f85ae71bb5998
doc_id: 942946
cord_uid: o00s8z69

nan

The severe acute respiratory syndrome related to SARS-Cov-2 may be due to a huge cytokines storm, with high levels of serum mediators such as tumor necrosis factor α (TNF-α), CXCL10, Interleukin (IL)-6 (IL-6) and IL-8. (1) The Janus kinases-signal transducer and activator of transcription proteins (JAK-STAT) is a signaling pathway that plays a major role in regulation of the cytokine release. JAK inhibitors, used in inflammatory diseases and myeloproliferative syndrome, could be a therapeutic approach in Covid 19.

We report the case of a patient with essential thrombocythemia (ET) and idiopathic pulmonary fibrosis (IPF) hospitalized for severe Covid 19 who had a dramatic improvement under Ruxolitinib. At admission, patient's medication included apixaban, aspirin, atenolol, omeprazole, levocetirizine and hydroxycarbamide. The patient had a 5-day course of symptoms with fever and cough. On examination, blood pressure was 146/89 mmHg, heart rate was 77 beats/min, temperature was 39.1°C ; and oxygen saturation was 90% on room air, with a respiratory rate of 30 per minute.

Pulmonary auscultation found bibasal crackles. The results of initial blood workup were as follows:

white blood cells count 5,7 G/L, lymphocytes 2,1 G/L, hemoglobin 13.3g/dL, platelets 369G/L, C reactive protein (CRP) 62 mg/L (normal < 5 mg/L), procalcitonine 0.16ng/l (normal < 0,5 ng/L), fibrinogen 6.59g/l (normal < 4g/L), D-dimer 2 008ng/ml (normal < 500 ng/mL), and normal liver enzymes and renal function.

SARS-Cov-2 real time polymerase chain reaction test on oro-pharyngeal swab was positive. The CT scan showed bilateral ground-glass opacities and crazy paving compatible with COVID-19 with severe extension.IPF related lesions were considered stable (Figure 1-B) .

At admission in our pulmonology unit, the patient required 4L/min of oxygen (saturation 95%).

Antibiotherapy with ceftriaxone, azithromycin in addition with hydroxychloroquine were started according to the local standard of care guidelines at he time of diagnosis.

On day 2 of hospitalization, needs for oxygen increased until 6L/min to reach 95% oxygen saturation.

Blood inflammatory markers worsened, with CRP 133 mg/L, ferritinemia 950 µg/L (normal range 30 400 µg/L), LDH 612 UI/L (normal range 135-225 UI/L). Based on his ET with JAK2 mutation, and in accordance with his haematologist, we decided to switch hydroxycarbamide for ruxolitinib 10mg twice daily and we stopped all the antibiotics and hydroxychoroquine. He experienced a dramatic improvement with apyrexia on day 2 of this management and rapid decrease of oxygen flow on day 4 (sat 98% with 3L/min). Inflammatory syndrome rapidly decreased and CRP normalized at day 8. No adverse outcome was observed. The patient was discharged on April the 14 th without oxygen treatment. Figure 1 -C illustrates his CT scan 10 days after discharged with healing of Covid-19 lesions.

Ruxolitinib is a tyrosine kinase inhibitor which inhibits JAK1 and JAK2. It is approved for use in primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis, and in polycythemia vera patients who are resistant or intolerant to hydroxycarbamide. Ruxolitinib has also demonstrated efficacy as an anti-inflammatory drug in acute graft versus host disease (2) .

SARS-Cov-2 binds on ACE2 receptor, which is a cell-surface protein widely distributed in the heart, kidney, blood vessels, and especially alveolar epithelial cells. The virus may invade and enter cells through endocytosis. One of the known regulators of endocytosis is the AP2-associated protein kinase 1 (AAK1). AAK1 inhibitors can interrupt the passage of the virus into cells and may be helpful in preventing virus infection (4) . Therefore, Ruxolitinib may inhibit viral infection of cells through the inhibition of AAK1. Furthermore, JAK inhibitors act by inhibiting the activity of one or more of the JAK family of enzymes, including JAK1, JAK2, JAK3 and TYK3. The JAK-STAT pathway is central to cellular response to exogenous signals in the immune system. The JAK family of enzymes are responsible for signal transduction and JAK inhibitors play a major role in inhibiting and blocking cytokine release (including proinflammatory IL-6) that can contribute to Covid-19's related cytokine storm. Ruxolitinib is an inhibitor of JAK 1/2 and also works as an immunomodulator decreasing the cytotoxic T lymphocytes and increasing the Treg cells. Thus, Ruxolitinib may attenuate the dysregulated immune response caused by Covid-19 that generates the pneumonia and subsequent severe acute respiratory syndrome (5) .

Moreover, few studies have suggested an increased activation of the JAK-STAT pathway in IPF that may participate in lung fibrosis but no clinical data is available regarding JAK-inhibitors efficacy or tolerance in this setting (6) . We report the first case of successful Ruxolitinib treatment in an IPF patient suffering from Covid-19. Our experience with IPF patients and the natural evolution of IPF foreshadowed a pejorative issue. This case report has several limitations. First, the patient had an ET with JAK2 mutation and IPF, two rare diseases, and it is not generalizable to the general population.

Second, the patient was treated in accordance with local guidelines at the time of diagnosis including azithromycin and hydroxychloroquine. These two drugs are currently evaluated in phase 3 trials for COVID-19. Third, no causal relationship between ruxolitinib use and clinical improvement could be drawn. Indeed, spontaneous favorable outcome of COVID-19 without specific treatment is possible; therefore we cannot exclude in our case a spontaneous improvement regardless to ruxolitinib use.

Our data suggests a safe profile and possible efficacy of JAK-inhibitors in COVID-19 patients, but further well conducted studies are needed.More than 10 clinical trials evaluating the efficacy of ruxolitinib are currently ongoing (clinicaltrials.gov). Ruxolitinib has no routine clinical indication in COVID-19 outside of clinical studies. 

Overlapping and discrete aspects of the pathology and pathogenesis of the emerging human pathogenic coronaviruses SARS-CoV, MERS-CoV, and 2019-nCoV

What are the current treatment approaches for patients with polycythemia vera and essential thrombocythemia?

COVID-19: consider cytokine storm syndromes and immunosuppression. The Lancet

The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China

Associations between immune-suppressive and stimulating drugs and novel COVID-19-a systematic review of current evidence

The JAK2 pathway is activated in idiopathic pulmonary fibrosis