Janus Kinase-Inhibitor and Type I Interferon Ability to Produce Favorable Clinical Outcomes in COVID-19 Patients: A Systematic Review and Meta-Analysis

Lenfant²,

2020

CCJM

Section: Covid-19 Curbside Consultsmentioning

confidence: 86%

Interferon therapy for COVID-19 and emerging infections: Prospects and concerns

Lenfant²,

2020

CCJM

“… 45 , 96 Because IFN signaling is instrumental in initiating the innate immune response and in preventing viral replication, JAK-STAT inhibitors should be avoided during the very early stages of the disease. 97 Because preventing the (IFN-triggered) cytokine storm would be highly desirable, attenuating JAK-STAT signaling could very well improve disease outcome when such symptoms are occurring. Indeed, preliminary data from COVID-19 patients treated with the JAK inhibitor baricitinib in the early phases of their disease demonstrated improvements in inflammatory symptoms and in pulmonary function tests.…”

Section: Immunomodulation In Relation To Sars-cov-2mentioning

confidence: 99%

Kinase inhibitors developed for treatment of hematologic malignancies: implications for immune modulation in COVID-19

Jacobs

Eldering²,

Kater

2021

Blood Advances

Tyrosine kinase inhibitors (TKIs) are used to target dysregulated signaling pathways in virtually all hematologic malignancies. Many of the targeted signaling pathways are also essential in nonmalignant immune cells. The current coronavirus severe acute respiratory syndrome coronavirus 2 pandemic catalyzed clinical exploration of TKIs in the treatment of the various stages of COVID-19, which are characterized by distinct immune-related complications. Most of the reported effects of TKIs on immune regulation have been explored in vitro, with different class-specific drugs having nonoverlapping target affinities. Moreover, many of the reported in vivo effects are based on artificial animal models or on observations made in symptomatic patients with a hematologic malignancy who often already suffer from disturbed immune regulation. Based on in vitro and clinical observations, we attempt to decipher the impact of the main TKIs approved or in late-stage development for the treatment of hematological malignancies, including inhibitors of Bruton’s tyrosine kinase, spleen tyrosine kinase, BCR-Abl, phosphatidylinositol 3-kinase/ mammalian target of rapamycin, JAK/STAT, and FMS-like tyrosine kinase 3, to provide a rationale for how such inhibitors could modify clinical courses of diseases, such as COVID-19.

“…An analysis focused on the tractable feedbacks (e.g., target cell depletion and viral load-dependent recruitment of natural killer cells) may obscure the role of the harder to measure and perhaps undefined feedbacks. Importantly, these dynamical processes might all effectively cancel out, such that the most practical approach to probing the immune context to better understand pathology in SARS-CoV-2 and project treatment strategies is simply to identify early cytokine profiles that have been largely shown to dictate disease progression [5] and use these to guide delivery of, e.g., interferons or catch later progression into immunopathology to deliver immunosuppressants [57].…”

Section: Discussionmentioning

confidence: 99%

Disentangling the dynamical underpinnings of differences in SARS-CoV-2 pathology using within-host ecological models

2020

Health outcomes following infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are remarkably variable. The way the virus spreads inside hosts, and how this spread interacts with host immunity and physiology, is likely to determine variation in health outcomes. Decades of data and dynamical analyses of how other viruses spread and interact with host cells could shed light on SARS-CoV-2 within-host trajectories. We review how common axes of variation in within-host dynamics and emergent pathology (such as age and sex) might be combined with ecological principles to understand the case of SARS-CoV-2. We highlight pitfalls in application of existing theoretical frameworks relevant to the complexity of the within-host context and frame the discussion in terms of growing knowledge of the biology of SARS-CoV-2. Viewing health outcomes for SARS-CoV-2 through the lens of ecological models underscores the value of repeated measures on individuals, especially since many lines of evidence suggest important contingence on trajectory.