key: cord-325863-3t73v4ng
authors: Foss, Francine M.; Rubinowitz, Ami; Landry, Marie L.; Isufi, Iris; Gowda, Lohith; Seropian, Stuart; Perreault, Sarah; Shenoi, Sheela V.
title: Attenuated Novel SARS Coronavirus 2 Infection in an Allogeneic Hematopoietic Stem Cell Transplant patient on Ruxolitinib
date: 2020-06-25
journal: Clin Lymphoma Myeloma Leuk
DOI: 10.1016/j.clml.2020.06.014
sha: 
doc_id: 325863
cord_uid: 3t73v4ng

Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) has a high death rate in patients with comorbidities or in an immunocompromised state. We report a mild and attenuated SARS CoV-2 infection in a patient who is 17 months post stem cell transplantation and maintained on the JAK/STAT inhibitor ruxolitinib, a proposed novel therapy for SARS CoV-2 pneumonia.

SARS CoV-2 is an enveloped, positive-sense, single-stranded RNA β-coronavirus homologous to the severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) viruses [1] [2] [3] . Upon infection, SARS CoV-2 enters respiratory epithelial cells and type-2 pneumocytes and induces a secondary immune response which may be associated with cytokine storm, leading to an ARDS (Acute Respiratory Distress Syndrome) like picture [4] [5] [6] [7] [8] . Strategies to attenuate the severity of the inflammatory response have included the use of the Interleukin-6 receptor monoclonal antibody (ex. tocilizumab) [6] [7] [8] . Due to the signal transduction role that the JAK-STAT pathway plays in mediating Immune-effector cell activation, there has been interest in pursuing inhibitors of this pathway as potential therapeutic agents in mitigating COVID19-associated lung inflammation 9, 10 . We recently diagnosed COVID19 infection in a patient who was on oral ruxolitinib for management of graft-vs-host disease after allogeneic stem cell transplant and report on his presentation and the evolution of his clinical course.

A 47 y.o. male with a past medical history of allogeneic stem cell transplant was evaluated for fever and cough. His history is notable for angioimmunoblastic T Cell lymphoma treated initially with EPOCH chemotherapy resulting in a complete remission. He then underwent autologous stem cell transplant (October 2017). He relapsed in June 2018 and was treated with tipifarnib on a Phase II clinical trial. He attained a second complete clinical remission and underwent an allogeneic stem cell transplant from a 10/10 matched unrelated donor in October 2018. Five months later (March 2019) he developed chronic graft versus host disease (cGVHD) with skin and myofascial involvement and was treated with prednisone and extracorporeal photopheresis. He continued to be symptomatic, and ruxolitinib was added in October 2019. Steroids were tapered after two months and ruxolitinib 10 mg BID was continued in combination with photopheresis every other week (last session prior to admission). The most recent CD4+ cell count was 593/µl. He had recently been admitted (3 weeks prior to admission) for human metapneumovirus infection and had recovered. He denied exposure to anyone with COVID-19.

On the day of admission, he had a telehealth visit and reported five days of intermittent rigors with a temperature maximum of 102 degrees Fahrenheit at home. He reported onset of dry cough, sweats, and myalgias without shortness of breath, and denied gastrointestinal symptoms. Due to concern for COVID-19, he was brought to the hospital for evaluation. On arrival, his temperature was 99.6 degrees Fahrenheit, RR18, O2 96% on room air, he was speaking in full sentences and breathing comfortably. His lungs were clear to auscultation. A CDC-based RT-PCR assay targeting N1 and N2 of SARS CoV-2 nucleocapsid gene was negative on a nasopharyngeal (NP) swab and he was admitted for fever work up. The nasopharyngeal respiratory virus swab was negative. His chest x-ray on admission demonstrated no opacities. The following day the patient continued to have a persistent dry cough and chest CT was obtained to evaluate for possible interstitial disease or lung GVHD. Chest CT as shown in Figure  2 demonstrated new subtle patchy ground glass opacities and diffuse centrilobular ground glass nodules which are a nonspecific finding but the main differential diagnostic considerations in this clinical setting include infection (particularly viral or opportunistic) versus lung inflammation (drug toxicity or hypersensitivity pneumonitis) . As per the newly described COVID-19 pneumonia imaging classification, this would be an indeterminate appearance 11 .

Repeat SARS CoV-2 RT-PCR using the same assay was then performed on a second NP swab and was positive, with a very low viral load (cycle threshold N1 35.3/ N2 35.4). Hs-CRP was elevated at 93 mg/ml on admission, interleukin 6 was mildly elevated at 6 pg/ml (nl <5) and interleukin 10 was in the normal range at 5 pg/ml ( Figure 1 ). Fibrinogen was elevated at 655 mg/dl. His CBC showed WBC 9.4, with absolute lymphocyte count of 1200/uL, hemoglobin 12 g/dL, platelets 525,000 /uL. Chemistries were all within normal range. The patient was treated as per our institutional COVID19 protocol with hydroxychloroquine 400mg BID x 1 day followed by 200 mg BID for 4 days and he remained on ruxolitinib at a dose of 10 mg BID. His CRP declined as shown in Figure 1 and he remained afebrile without need for supplemental oxygen. He did not develop dyspnea and was discharged after 8 days of hospitalization . A week after hospital discharge, the patient remains afebrile with resolving mild cough, and clinical improvement.

This case illustrates an attenuated COVID infection in a patient who is otherwise significantly immunocompromised after allogeneic stem cell transplantation. Of interest is that the initial RT-PCR test for SARS CoV-2 RT-PCR was negative but a repeat test returned positive 24 hours later with a low viral load. False negative tests have been reported, and explanations include sampling error, poor test sensitivity, low viral load, or variable viral shedding in the upper airway, especially in patients who present with lower respiratory tract disease. Of note, sputum or BAL are more sensitive for diagnosing lower respiratory tract disease but are often not available for testing. This patient also demonstrated a moderate degree of diffuse lung involvement despite being relatively asymptomatic and without hypoxia.

We speculate that the ruxolitinib or ECP may have played a role to reduce or attenuate inflammatory response, possibly in conjunction with the early administration of hydroxychloroquine after admission. In addition, potential low viral burden of infection may have impacted the severity of cytokine release syndrome and pneumonitis.

Ruxolitinib is an orally bioavailable Janus-associated kinase (JAK) inhibitor which binds to and inhibits protein tyrosine kinases JAK 1 and 2, leading to reduction in inflammatory responses. [12] [13] [14] [15] The JAK-STAT (signal transducer and activator of transcription) pathway is involved in cellular proliferation, hematopoiesis, and the immune responses in inflammatory diseases. Cellular targets of ruxolitinib are seen in both innate and adaptive immunity. Ruxolitinib is FDA approved for the treatment of myelofibrosis and steroid refractory acute graft-vs-host disease associated with allogeneic stem cell transplantation [16] [17] [18] [19] [20] . Ruxolitinib is under study as therapy for chronic GVHD and is used commonly for this disorder due to its tolerability and anti-inflammatory effects. In a study of hepatic inflammation, ruxolitinib was shown to repress CRP by targeting the IL6/JAK/STAT signaling pathway 21 Recent data has shown that ruxolitinib may also led to infectious complications and therefore may potentially be detrimental in the setting of COVID. Sylvine et al reported infectious complications with ruxolitinib from the French Pharmacovigilance Database. 22 Of 30 infections reported in 26 patients, 20% were herpes zoster, 5 were mycobacterial, and 4 were fungal. Due to its demonstrated anti-inflammatory and immunosuppressive activities, a clinical trial of ruxolitinib along with standard of care is planned to treat patients with inflammatory pneumonia due to COVID19 (. NCT04338958). Results from the planned prospective trial should further enhance our understanding of the risks of secondary infections associated with JAK-STAT inhibitors based on their perceived myelosuppressive and immune-suppressive effects. Supplemental correlative studies will offer additional evidence on changes in host immune tolerance/effector responses and predictors of favorable outcomes with ruxolitinib in the fight against COVID associated inflammation.

The novel coronavirus SARS CoV-2 has a rising death toll especially in patients with comorbidities and those who are immunocompromised. Our patient was 17 months post stem cell transplantation and was maintained on the JAK/STAT inhibitor ruxolitinib, a proposed novel therapy for SARS CoV-2 pneumonia, throughout his clinical course with successful attenuation of symptoms. While there are a number of biomodulatory agents used for immunosuppression in the setting of organ and stem cell transplantation and autoimmune disorders, there is little available data to date on their impact on coronavirus infection and inflammatory response, nor is there data regarding underlying immunosuppressed state due to transplant or other disorders and the clinical course of COVID infection.

Recommendations on how to manage immunosuppression agents in allogeneic transplant patients who are infected with SARS CoV-2 have not been clearly established. As of June 2020, the Center for International Blood and Marrow Transplant Research reported 192 cases of SARS CoV-2 in transplant recipients, 110 of which had allogeneic transplants 23 . Of these, the majority occurred in the first 3 years after transplant and 81 patients have either resolved or improved. With agents like ruxolitinib whose mechanism of action may reduce SARS CoV-2 related complications, it may be prudent to consider continuing therapy, but alternatively in significantly immunocompromised patients, reduction of immunosuppression may be appropriate. Until data is available regarding immunosuppression agents used and T cell subset recovery from registries such as the CIBMTR, clear guidelines regarding management of COVID in post-allogeneic transplant patients on immunosuppression may remain anecdotal. As we learn more about the relevance of different pathways and host effector mechanism in COVID immune response, a rational strategy for the use of agents such as ruxolitinib can be defined. . Axial (A) and coronal (B) images from the patient's chest CT demonstrate diffuse centrilobular ground glass nodules (circles) as well as subtle, patchy ground glass opacity in the right upper lobe (arrows). These findings are nonspecific but typically seen in the setting of infectious (such as viral or opportunistic infections) or inflammatory disorders (such as drug toxicity or hypersensitivity pneumonitis) and have an indeterminate appearance for COVID-19 pneumonia.

Outbreak of a novel coronavirus

Identification of a novel coronavirus causing severe pneumonia in human: a descriptive study

A Novel Coronavirus from Patients with Pneumonia in China

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies

Recommendations for coronavirus infection in rheumatic diseases treated with biologic therapy

Why tocilizumab could be an effective treatment for severe COVID-19?

Potential therapeutic agents against COVID-19: What we know so far

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

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

Radiological Society of North America Expert Consensus Statement on Reporting Chest CT Findings Related to COVID-19. Endorsed by the Society of Thoracic Radiology, the American College of Radiology, and RSNA

Preclinical evaluation of local JAK1 and JAK2 inhibition in cutaneous inflammation

Biology and significance of the JAK/STAT signalling pathways

Ruxolitinib, a selective JAK1 and JAK2 inhibitor for the treatment of myeloproliferative neoplasms and psoriasis

Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms

Pharmacologic Inhibition of JAK1/JAK2 Signaling Reduces Experimental Murine Acute GVHD While Preserving GVT Effects

Ruxolitinib as Salvage Therapy in Steroid-Refractory Acute Graft-versus-Host Disease in Pediatric Hematopoietic Stem Cell Transplant Patients

Ruxolitinib: a steroid sparing agent in chronic graft-versus-host disease

Ruxolitinib in steroid refractory graft-vs.-host disease: a case report

Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease

Potent repression of C-reactive protein (CRP) expression by the JAK1/2 inhibitor ruxolitinib in inflammatory human hepatocytes

French Network of Regional Pharmacovigilance C. Infections associated with ruxolitinib: study in the French Pharmacovigilance database