Introduction
SARS-CoV-2 is a positive-sense, single stranded RNA in theCoronaviridae family of viruses1.2. Most cases
of infection present with mild disease phenotype with self-limiting
symptoms largely consisting of fever, fatigue, dry cough, headache, and
diarrhea1,2. However, roughly 14% of patients develop
a severe disease phenotype requiring hospitalization, most commonly due
to dyspnea and hypoxia3,4. Characteristic laboratory
features of this virus are leukopenia, prolonged prothrombin time, and
elevated serum concentrations of D-dimer, lactate dehydrogenase (LDH),
ferritin, and c-reactive protein (CRP)5. Chest
computed tomography classically demonstrates bilateral ground glass
opacities1. A critical component of the pathogenesis
of SARS-CoV-2 consists of a hyperactive immune response to the virus
resulting in a sudden, acute increase in pro-inflammatory cytokines,
termed “the cytokine storm”6. Key pro-inflammatory
cytokines upregulated in this process include interleukin 6 (IL-6), and
tumor necrosis factor-alpha (TNF-α)6. IL-6 is one of
the most highly expressed cytokines in SARS-CoV-2 infection and elevated
serum levels of IL-6 are associated with a poor
prognosis7-9. Elevated cytokine levels prompt an
influx of various immune cells into the site of infection, leading to
tissue destruction and multiorgan damage10. Immune
mediated tissue destruction is thought to be a contributing factor to
the development of several life-threatening complications, such as acute
respiratory distress syndrome, septic shock, and multiorgan
failure11.
Primary myelofibrosis (PMF) is an acquired stem cell neoplasm with
ineffective hematopoiesis, bone marrow fibrosis and splenomegaly. Clonal
populations of dysplastic megakaryocytes and myeloid cells release
inflammatory cytokines that are responsible for clonal evolution,
symptom burden, progressive myelofibrosis and extramedullary splenic
hematopoiesis12. Risk factors for acquired PMF include
smoking, excessive alcohol intake, exposure to radiation, or exposure to
industrial solvents13. Common gene mutations found in
patients with PMF include Janus kinase 2 (JAK2V617F), calreticulin
(CALR), thrombopoietin receptor (MPL515L/K), and ten-eleven
translocation 2 (TET2). The early phase of PMF is termed the
pre-fibrotic phase when patients have traditionally been thought to be
asymptomatic. This phase is characterized by a hypercellular marrow with
megakaryocytic hyperplasia and minimal fibrosis12.
However, recent studies by Mesa have shown that most patients with
myeloproliferative neoplasms, and particularly myelofibrosis, are
symptomatic at onset.14 At later stages of disease
progression, myelofibrosis develops due to the release of excessive
amounts of growth factors from megakaryocytes and monocytes resulting in
fibroblast proliferation, collagen synthesis and an increasing degree of
fibrosis12. Patients may express cytokine related
hypercatabolic symptoms such as fatigue, weight loss, fever, and chills,
together with abdominal discomfort from splenomegaly. Splenomegaly is
primarily due to extramedullary hematopoiesis but can also be due to
splanchnic vein thrombosis12. Treatment largely
depends on disease burden; while many patients are observed without
treatment, young, high risk patients may receive allogenic stem cell
transplant15. For other patients, therapies are
designed to dampen the excessive inflammatory marrow
milieu16. On the molecular level, Janus kinases (JAKs)
mediate cytokine production through various downstream signaling
pathways, such as the signal
transducer and activator of transcription (STAT)
pathway17. The JAKs consists of four tyrosine kinases
that consists of JAK1, JAK2, JAK3, and tyrosine kinase 2
(TYK2). They transmit
extracellular signals, such as proinflammatory cytokines, to the nucleus
by activating STAT. Ultimately, these extracellular signals result in a
transcriptional response of target genes from cellular
DNA18. In this pathway, receptors bind to various
cytokines that, in turn, trigger and orchestrate innate immune
responses19. Additionally, interferon acts through the
JAK-STAT pathway to target genes responsible for antiviral and adaptive
immune responses20. The JAK2V617F variant, a
gain-of-function mutation, causes constitutive activation of tyrosine
kinase domain of JAK2 leading to dysregulated immune
response21. This mutation is present in majority of
patients with myeloproliferative neoplasms. JAK inhibitors ruxolitinib
and fedratinib are FDA approved for the treatment of
PMF22. The immunosuppressive effects of JAK inhibition
vary based on the specificity and dosage of each drug, which also
accounts for the range in toxicology profiles. Ruxolitinib is a JAK 1-2
inhibitor that causes a reduction in cytokine production. This drug was
shown to decrease spleen size and disease-related symptoms compared to
placebo in the double-blind COMFORT-I trial consisting of 309 patients
with intermediate-2 or high-risk myelofibrosis. Ruxolitinib is primarily
utilized in the treatment of myelofibrosis, but it is also licensed for
patients with polycythemia vera intolerant or refractory to hydroxyurea.
However, ruxolitinib is also utilized off label for diseases involving
cytokine release as the primary pathogenesis, including graft versus
host disease and hemophagocytic
lymphohistiocytosis23,24. Fedratinib is a selective
oral JAK 2 inhibitor that has demonstrated similar results as
ruxolitinib in placebo-controlled, randomized phase II and III clinical
trials22.
However, four patients developed neurological symptoms during clinical
trials and fedratinib now carries a black block warning for serious and
fatal encephalopathy, including Wernicke
encephalopathy25. Prior to administering fedratinib,
thiamine levels must be measured and replenished. Multiple small
molecule JAK inhibitors are also utilized in the treatment of many
inflammation-driven pathologies, such as inflammatory bowel disease,
rheumatoid arthritis, and psoriasis26. Another
molecular component in inflammation regulation is interferon which for
decades has been used successfully in the treatment of patients with
myeloproliferative neoplasms. Interferon normalizes cell counts in the
majority of patients within a few months. Interferon also improves
megakaryocytic dysfunction in part through induction of
IFITM327. This led to treatment of early phase PMF
with interferon28-30. Eighty percent stabilization,
partial response or remission were observed in phase 2 studies.
Architectural reversion of the marrow fibrosis after treatment was
noted. Recent studies have demonstrated efficacy of ruxolitinib and
interferon α2 combination PMF treatment with an acceptable toxicity
profile31. Combination therapy was shown to elicit
complete remissions in 3 out of 18 patients and complete hematologic
response in 11 out of 12 patients32.
JAK/STAT pathway inhibitors have been proposed as a therapy to target
the hyperinflammation associated with SARS-CoV-217.
This hyperinflammation seen in SARS-CoV-2 is similarly observed in
cytokine release syndrome (CRS), characterized by elevated IL-6, IL-2,
IL-7, IL-10, and more1,33. Elevations in serum
cytokine and chemokine levels correlate with disease severity and
adverse clinical outcome1. Specifically, increased
levels of IL-6 have been reported in patients with severe SARS-CoV-2 and
have been associated with increased mortality7-9. IL-6
plays pivotal role in CRS through JAK-STAT signaling that results in
altered immune regulation and oxidative stress18.
Therefore, many treatments are aimed at ameliorating the cytokine storm
by inhibiting the JAK-STAT pathway. Ruxolitinib has been shown to
significantly reduce IL-6 and CRP levels in patients with myelofibrosis,
with a relatively mild side effect profile and is therefore being
considered as a treatment option for SARS-CoV-234. Of
note, there is concern for increased risk of infection in patients
treated with JAK inhibitors, as JAK-STAT signaling is responsible for
the signal transduction of type I interferon18.
Interferons are crucial for preventing viral replication in the early
stage of infection in addition to enhancing antibacterial
immunity35. This was evidenced by previous studies
reporting increased incidence of bacterial infections, particularly
urinary tract infections in patients treated with JAK
inhibitors36. Interferons may be protective early in
SARS-CoV-2 infection and damaging later in the infection. Thus, the
effects of interferon in COVID-19 patients is likely complex and time
dependent.
We present the case of an 83-year-old woman found to be SARS-CoV-2
positive who was asymptomatic while taking ruxolitinib for co-existing
PMF but displayed a prolonged period of nasal swab PCR positivity.
Culture failed to reveal infectious virions. Administration of pegylated
interferon was followed by rapid clearance of viral RNA by PCR. We
hypothesize that the combination of ruxolitinib with interferon may be
useful in the acute COVID-19 setting to induce viral clearance with
reduced risk of cytokine storm.