key: cord-0975808-kacg9sf4 authors: Chamilos, Georgios; Lionakis, Michail S; Kontoyiannis, Dimitrios P title: Are all patients with cancer at heightened risk for severe Coronavirus Disease 2019 (COVID-19)? date: 2020-08-07 journal: Clin Infect Dis DOI: 10.1093/cid/ciaa1079 sha: 0617015dd65f0f677bc69ac21bf5a7ab58e84e23 doc_id: 975808 cord_uid: kacg9sf4 Cancer patients are traditionally considered at high-risk for complicated respiratory viral infections, due to their underlying immunosuppression. In line with this notion, early case series reported high mortality rates of SARS-CoV-2 infection in patients with malignancy. However, subsequent large prospective epidemiological surveys indicate that the risk for severe COVID-19 may be largely attributed to the multiple confounders operating in this highly heterogeneous population of patients rather than the cancer or its treatment per se. In this viewpoint, we critically discuss the conundrums of SARS-CoV-2 infection in cancer patients and underscore mechanistic insights on the outcome of COVID-19 as it relates to cancer therapy and the type and status of the underlying malignancy. We emphasize the concept that not all cancer patients are at similarly high-risk for a complicated COVID-19 course and the need to develop a roadmap of translational and clinical research on COVID-19 in this challenging group of patients. Furthermore, advanced metastatic malignancy and poor performance status are implicated as drivers of severe COVID-19 in cancer patients ( Table 1) . The etiology is likely multifactorial. The high levels of expression of the newly identified SARS-CoV-2 entry receptor neuropilin-1 in epithelia and endothelia of patients with advanced cancer could facilitate viral proliferation [17, 18] . Malignancy-or drug-induced hyper-coagulability states could also instigate thrombotic complications in patients with certain types of advanced malignancies, further aggravated by the prothrombotic state of severe COVID-19 [19] [20] [21] [22] [23] . Moreover, immunometabolic deregulation related to myeloid cell dysfunction, T-cell exhaustion, and cancer cachexia, all prominent in advanced cancers, might have a negative impact on antiviral immunity [24, 25] . Hence, delays in initiation of curative chemotherapy or surgery to control the underlying malignancy and limited access to supportive care could negatively affect the course of COVID-19 in these cancer patients. Importantly, bacterial or fungal super-infections have been diagnosed in up to 50% of severely ill COVID-19 patients in intensive care units [26, 27] . Given the challenges in A c c e p t e d M a n u s c r i p t 5 performing bronchoscopy to diagnose pneumonia in COVID-19 patients, the low autopsy rates, relative short-term follow up, and limited patient-level information in most epidemiological studies thus far, the exact cause of death and the relative contribution of secondary infections on morbidity and mortality remain elusive and could be underestimated, a concern especially relevant in cancer patients who have excess risk for nosocomial and opportunistic infections [28] . Lymphopenia and COVID 19. Lymphopenia compromises cytotoxic T-cell-and NK-celldependent antiviral responses and is consistently associated with an increased risk of poor outcomes in COVID-19 patients [29] (Table-2 ). Lymphopenia and lymphocyte dysfunction are prominent intrinsic features of lymphoid malignancies and conventional chemotherapeutic agents (e.g., corticosteroids, purine analogs, cyclophosphamide/fludarabine prior to CAR T-cell therapy). In addition, targeted biologics (e.g., alemtuzumab, rituximab, CD38-targeting monoclonal antibodies) given for lymphoid malignancies can induce profound and persistent lymphocytopenia and/or lymphocyte dysfunction. Therefore, the quantitative and qualitative defects of T-cells and B-cells in certain hematological malignancy patients may contribute to poor COVID-19 outcomes due to unabated SARS-CoV-2 proliferation or impaired development of protective anti-SARS-CoV-2 antibodies [30, 31] . Emerging evidence implicates hyperinflammatory responses derived from monocytes/macrophages [30] [31] [32] and neutrophils [20] [21] [22] [23] as a driver of immunopathology and poor outcomes in the late phase of severe COVID-19 infection. Accordingly, preclinical studies suggest that chemotherapy-induced leukocytopenia improved outcomes of SARS infection [33] [34] . In that light, it is plausible that cancer patients with chemotherapy-induced neutropenia and monocytopenia might have attenuated hyper-inflammatory innate responses and abrogated tissue damage during A c c e p t e d M a n u s c r i p t 6 COVID-19. This hypothesis is in line with the use of myeloablative regimens as front-line therapy for other, often virus-driven, conditions associated with cytokine storm and/or macrophage activation, such is hemophagocytic lymphohistiocytosis, and is supported by preliminary reports demonstrating no clear association between recent receipt of cytotoxic chemotherapy and severe COVID-19 in cancer patients [2, [8] [9] [10] [11] (Table 1 ). In addition, cancer patients with chemotherapy-induced neutropenia and accompanying thrombocytopenia might be less susceptible to developing thrombotic complications due to endothelial dysfunction, a hallmark histopathological feature of COVID-19 [20] [21] [22] [23] , which is thought to be driven by platelet activation and neutrophil extracellular trap formation ( Table 2 ). On the other hand, cancer patients might be at higher risk for COVID-19-associated hyper-inflammatory and/or thrombotic complications during neutrophil recovery from chemotherapy-induced myelosuppression due to Immune Reconstitution Inflammatory Syndrome-like effects [35] . Therefore, future studies will be needed to define how the kinetics of chemotherapy-induced myelosuppression and recovery might affect the hyperinflammatory and thrombotic complications of COVID-19 in cancer patients. inhibitors that are increasingly used in certain cancer types and target signaling pathways in immune cells (e.g., JAKs, BTK) or the vascular endothelium (e.g., VEGF) are under evaluation in randomized placebo-controlled trials in patients with severe COVID-19 with the goal to ameliorate hyper-inflammatory and/or thrombotic complications [36] . Thus, cancer patients already receiving such therapies might be protected from hyper-inflammatory immunopathology, and conversely, discontinuation of such therapies in cancer patients infected with SARS-CoV-2 could instigate hyper-inflammation as recently suggested with BTK inhibition [37, 38] , and also adversely affect the control and long-term outcome of the underlying malignancy (Table-2 A c c e p t e d M a n u s c r i p t 7 impact the balance between host control of viral replication and hyper-inflammatory responses in COVID-19, and because selective epigenetic inhibitors (e.g., BET inhibitors) are promising therapies for inflammatory diseases [39] (Table-2 Table 1) . In conclusion, COVID-19 is a novel viral disease with unique clinical, epidemiological, and pathogenetic features, many of which remain poorly-understood (Table-2 A c c e p t e d M a n u s c r i p t 15 Bacterial translocation due to chemotherapy-induced mucositis, changes in lung and/or gut microbiota due to cancer-induced dysbiosis, may result in increased rates of secondary infections. 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How safe is IL-6 blockage and or/corticosteroids as it relates to risk for superinfections and downstream OIs?Would vaccination against COVID-19 be suboptimal or contraindicated in cancer patients?Could trained immunity (innate immune memory) approaches (e.g., BCG vaccines) induce beneficial or detrimental inflammatory responses in cancer patients with COVID-19? As outcome determinants are multifactorial, how to develop and validate clinical prediction models to inform/triage level of care (e.g. active chemotherapy, delayed or attenuated chemotherapy, ICU utilization, hospice care) and assess the impact of various antiviral and immunomodulatory therapies in cancer patients with COVID-19?