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Pharmaco-Immunomodulatory Therapy in COVID-19

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Pharmaco-Immunomodulatory Therapy in COVID-19 UC Irvine UC Irvine Previously Published Works Title Pharmaco-Immunomodulatory Therapy in COVID-19. Permalink https://escholarship.org/uc/item/9r8859hb Journal Drugs, 80(13) ISSN 0012-6667 Authors Rizk, John G Kalantar-Zadeh, Kamyar Mehra, Mandeep R et al. Publication Date 2020-09-01 DOI 10.1007/s40265-020-01367-z Peer reviewed eScholarship.org Powered by the California Digital Library University of California Drugs https://doi.org/10.1007/s40265-020-01367-z LEADING ARTICLE Pharmaco‑Immunomodulatory Therapy in COVID‑19 John G. Rizk1 · Kamyar Kalantar‑Zadeh2,3,4 · Mandeep R. Mehra5 · Carl J. Lavie6 · Youssef Rizk7 · Donald N. Forthal8,9 © Springer Nature Switzerland AG 2020 Abstract The severe acute respiratory syndrome coronavirus 2 associated coronavirus disease 2019 (COVID-19) illness is a syndrome of viral replication in concert with a host infammatory response. The cytokine storm and viral evasion of cellular immune responses may play an equally important role in the pathogenesis, clinical manifestation, and outcomes of COVID-19. Sys- temic proinfammatory cytokines and biomarkers are elevated as the disease progresses towards its advanced stages, and correlate with worse chances of survival. Immune modulators have the potential to inhibit cytokines and treat the cytokine storm. A literature search using PubMed, Google Scholar, and ClinicalTrials.gov was conducted through 8 July 2020 using the search terms ‘coronavirus’, ‘immunology’, ‘cytokine storm’, ‘immunomodulators’, ‘pharmacology’, ‘severe acute respira- tory syndrome 2’, ‘SARS-CoV-2’, and ‘COVID-19’. Specifc immune modulators include anti-cytokines such as interleukin (IL)-1 and IL-6 receptor antagonists (e.g. anakinra, tocilizumab, sarilumab, siltuximab), Janus kinase (JAK) inhibitors (e.g. baricitinib, ruxolitinib), anti-tumor necrosis factor-α (e.g. adalimumab, infiximab), granulocyte–macrophage colony- stimulating factors (e.g. gimsilumab, lenzilumab, namilumab), and convalescent plasma, with promising to negative trials and other data. Non-specifc immune modulators include human immunoglobulin, corticosteroids such as dexamethasone, interferons, statins, angiotensin pathway modulators, macrolides (e.g. azithromycin, clarithromycin), hydroxychloroquine and chloroquine, colchicine, and prostaglandin D2 modulators such as ramatroban. Dexamethasone 6 mg once daily (either by mouth or by intravenous injection) for 10 days may result in a reduction in mortality in COVID-19 patients by one-third for patients on ventilators, and by one-ffth for those receiving oxygen. Research eforts should focus not only on the most rel- evant immunomodulatory strategies but also on the optimal timing of such interventions to maximize therapeutic outcomes. In this review, we discuss the potential role and safety of these agents in the management of severe COVID-19, and their impact on survival and clinical symptoms. Key Points 1 Introduction COVID-19 is a syndrome of viral replication and a host Although the pathogenesis of COVID-19, the result of infec- infammatory response. tion with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is still not completely understood, a pro- Tackling the immune response may be as important as posed four-stage classifcation system of escalating phases addressing viral replication. represents a useful construct for a structured approach to Specifc and non-specifc immune modulators have the clinical phenotyping, choice of therapy, and clinical outcome potential to inhibit cytokines and quell the cytokine [1, 2]. Stage I (early infection) begins at the time of viral storm. inoculation and establishment of infection. Patients may or may not manifest non-specifc symptoms (i.e. malaise, fever, sore throat, dry cough), and treatment is often symp- tomatic. Stage II is characterized by hyperresponsiveness of the immune system. Patients develop viral pneumonia and possibly hypoxia, and markers of systemic infammation are elevated. The third stage is characterized by a hypercoagula- * John G. Rizk [email protected] ble state. Patients with hypoxia are likely to progress to stage IV, the most severe stage, where multiorgan failure occurs. Extended author information available on the last page of the article Vol.:(0123456789) J. G. Rizk et al. Most patients also develop lymphopenia and pneumonia 3 Immunomodulatory Agents with bilateral infltrations on chest computed tomography (CT) scan [3–5]. Systemic proinfammatory cytokines and Once a pathogen enters the body, it is addressed by two biomarkers such as interleukin (IL)-1, IL-2, IL-6, and IL-7, lines of defense: innate immunity and adaptive immu- tumor necrosis factor (TNF)-α, granulocyte–macrophage nity (Fig. 2) [13]. Innate immunity encompasses a num- colony-stimulating factor (GM-CSF), macrophage infam- ber of soluble and cell-based antimicrobial factors and is matory protein 1-α, C-reactive protein (CRP), ferritin, and triggered very early after infection. Adaptive immunity, D-dimer are signifcantly high in this stage [4, 6]. which consists of pathogen-specifc antibody and T cells, The presence of elevated proinfammatory cytokines in develops later and contributes to both clearing of infec- advanced stages of disease was also observed in prior epi- tion and immunity against subsequent infection. Innate demics, such as those caused by SARS-CoV and MERS- and adaptive immunity work together to detect and elimi- CoV, suggesting a cytokine release syndrome (CRS) or nate pathogens. Immunomodulatory drugs can stimulate ‘cytokine storm’-mediated immunopathology [7–9]. The (immunostimulants), suppress (immunosuppressants) or cytokine dysregulation and infux of infammatory myeloid modulate various aspects of the immune system, including cells can lead to lung infltration and critical symptoms, both adaptive and innate immune systems [14]. Immu- including sepsis, shock, respiratory failure, acute respiratory nostimulators are often prescribed to enhance the immune distress syndrome (ARDS), multiorgan system dysfunction, response against infectious diseases, however, morbidity and death [10]. Since lymphopenia is often observed in early and mortality in severe COVID-19 is associated with and late stages of COVID-19 patients, the CRS may likely be hyperinfammation [15], and interfering with cytokine mediated by leukocytes other than T cells [9]. The cytokine signaling using immunomodulatory strategies may sig- storm is thought to resemble secondary hemophagocytic nifcantly reduce hyperinfammation in these patients. lymph histiocytosis (sHLH) [11]. The macrophage activa- The action of immunomodulators can be specifc or non- tion syndrome (MAS)-like pulmonary immunopathology specifc [13, 14]. characteristic of COVID-19, above and beyond the direct endothelial damage from SARS-CoV-2, may explain the high degree of micro- and macrothrombotic fndings in this patient population [12]. 4 Specifc Immune Modulators Cytokine storm, along with viral evasion of cellular immune responses, may play an equally important role in 4.1 Anti‑cytokines disease progression. Thus, tackling the immune response with immunomodulatory agents may be as important as 4.1.1 Interleukin (IL)‑1 Receptor Antagonists addressing viral replication to prevent the progression to multiorgan dysfunction (Fig. 1). Herein, we discuss the role Anakinra is a recombinant human IL-1 receptor antago- of specifc and non-specifc immunomodulating agents, nist indicated for rheumatoid arthritis (RA) and cryopyrin- including neutralizing monoclonal antibodies, corticos- associated periodic syndromes [16]. It works by inhibiting teroids, and other molecules in the management of severe the proinfammatory cytokines IL-1α and IL-1β [17]. In COVID-19, and their impact on survival and clinical earlier studies, anakinra was shown to be efective in treat- symptoms. ing MAS, which presents as a fulminant cytokine storm [18]. This may suggest a role for anakinra in combating CRS symptoms in COVID-19 patients. Re-analysis of 2 Methods of Literature Review data from a phase III randomized controlled trial revealed that IL-1 receptor blockade with anakinra was associated An English-language literature search was performed using with signifcant improvement in survival of patients with PubMed and Google Scholar to identify relevant articles sepsis [19]. There are currently no published controlled published through 8 July 2020. Search terms included ‘coro- clinical trials supporting the efcacy or safety of anak- navirus’, ‘immunology’, ‘cytokine storm’, ‘immunomodula- inra in treating COVID-19. In a small case-series of nine tors’, ‘pharmacology’, ‘severe acute respiratory syndrome patients with moderate to severe COVID-19 pneumonia, 2’, ‘SARS-CoV-2’, and ‘COVID-19’. The authors of this the use of anakinra was well-tolerated and efective in current review included case reports, case series, review arti- improving clinical and biological markers [20]. In a dif- cles, and randomized controlled trials. Ongoing and planned ferent cohort study on patients with severe COVID-19, clinical trials were identifed using the search term ‘COVID- anakinra decreased both the need for invasive mechanical 19′ on the ClinicalTrials.gov website. ventilation in the intensive care unit, and mortality [25% Pharmaco-Immunomodulatory Therapy in COVID-19 Fig. 1 Schematic representation of the immunomodulators’ site of stimulating factor, IFN interferon, IL interleukin, IL-6R interleukin-6 action. Hydroxychloroquine, azithromycin, statins, RAASi and their receptor, IVIG intravenous immunoglobulin,
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