Abstract
The clinical spectrum of COVID-19 ranges from asymptomatic disease to viral pneumonia leading to acute respiratory distress syndrome (ARDS), multiorgan failure, and death. In addition to these risk factors, COVID-19 patients with cancer were shown to have poor outcomes in multiple studies. Hyperinflammatory response (cytokine storm) is one of the main features of severe disease and is also associated with poor outcomes including intensive care unit (ICU) and mortality in patients with COVID-19. Several potential factors might be associated to poor prognosis in patients with COVID-19 accompanying cancer. Higher development of cytokine storm, receiving chemotherapeutics and/or immunosuppressants, higher susceptibility to infections as well as other potential metabolic complications could be counted among these factors. Inflammatory cytokines are essential for the development and progression in cancer. Patients with malignancy and/
or receiving immunosuppressants are at high risk for complications, development of cytokine storm, and poor outcomes associated with COVID-19. Furthermore, recurrent/prolonged cytokine storm is an emerging potential life-threatening condition in patients with cancer or immunosuppressants beyond prolonged PCR positivity.
Keywords
COVID-19, SARS-Cov-2, Cytokine storm, Hyperinflammation, Cancer, IL-6
Introduction
At the end of 2019, the world faced a new disease, COVID-19 caused by SARS-Cov-2 and became a pandemic within few weeks. The fact that COVID-19 spreads very quickly and has significant morbidity and mortality had devastating effects all over the world. The clinical spectrum of COVID-19 ranges from asymptomatic disease to viral pneumonia leading to acute respiratory distress syndrome (ARDS), multiorgan failure, and death. Several clinical characteristics and comorbidities such as older age, male gender, and presence of diabetes mellitus were found to be associated with higher mortality in patients with COVID-19 so far [1]. In addition to these risk factors, COVID-19 patients with cancer were shown to have poor outcomes in multiple studies [2,3].
Hyperinflammatory response (cytokine storm) is one of the main features of severe disease, and also associated with poor outcomes including intensive care unit (ICU) requirement and mortality in patients with COVID-19 [4]. The cytokine storm is a condition of uncontrolled systemic hyperinflammation caused by the release of a large amount of pro-inflammatory cytokines, such as interleukin (IL)-1, IL-6, IL-18, interferon (IFN)-γ and tumor necrosis factor-alpha (TNF-α), leading to multi-organ failure and even death [5-7].
In this paper, we aimed to evaluate the course of COVID-19 in patients with cancer, the pathogenesis and treatment of COVID-19-associated cytokine storm in patients with cancer.
Immune Mechanism of Severe COVID-19 and COVID-19-Associated Cytokine Storm
In COVID-19, SARS-Cov-2 binds to angiotensin-converting enzyme type 2 (ACE2) receptor which is particularly expressed along with the virus S protein priming protease TMPRSS2 [8], leads to the release of viral ssRNA and binding to pattern recognition receptors (PRRs). Among the PRRs, three major receptors are involved in viral infections; Toll-like receptors (TLRs), retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) [9]. Binding of SARS-Cov-2 viral ssRNA to TLR 7-8 stimulates nuclear factor-kappa B (NF-κB) with activation of the JAK-STAT pathway and production of several proinflammatory cytokines such as type 1 IFN (alpha and beta), IL-6, TNF-α and others [10]. IFN pathway is essential to eliminate viral RNA thereby termination of viral infection. Insufficient or delayed type 1 IFN response, especially in some circumstances such as immunosuppression, presence of cancer, or some genetic alterations (such as TLR 7 polymorphisms) causes defective clearance of viral RNA and leads to cytokine storm in patients with COVID-19. Low levels of type 1 IFN but higher levels of TNF-α and IL-6 produced by dendritic cells (DCs) infected with SARS-CoV have been revealed in one study and support this hypothesis [11]. Delayed type 1 IFN signaling was shown in mice with lethal SARS-CoV infection with the increase in viral titers and excessive inflammatory response [12]. This mechanism may explain higher frequency of cytokine storm s as well as poor outcomes in such patient groups.
Inflammasome and COVID-19-Associated Cytokine Storm
There is also another important pathway in the pathogenesis of COVID-19-associated cytokine storm. Recent evidences showed that SARS-CoV-2 also activates an intracellular multiprotein complex which is called ‘inflammasome’ after binding TLRs. Inflammasomes present in innate immune cells such as neutrophils, macrophages, and DCs and have an essential role in the host defense against microorganisms including viruses. The inflammasome is coordinated by the NLRP3 sensor (Nucleotide-binding oligomerization domain [NOD], Leucin e-rich Repeat, Pyrin domain, adaptor protein ASC, as well as the effector protein caspase 1) and also drives cleavage of pro-IL-1β by caspase-1, followed by the production of active IL-1β [13]. There are several rheumatologic conditions associated with inflammasome activation and higher IL-1β production such as Familial Mediterranean Fever (FMF), gout, adult-onset still disease (AOSD) [14] as well as hyperinflammatory circumstances such as macrophage activation syndrome (MAS), hemophagocytic lymphohistiocytosis (HLH) [15].
Viral genomic material and virus-induced Type I IFNs activates inflammasome and pyroptosis in many RNA virus infections [16]. Higher levels of IL-1α and IL-1β were shown in patients with COVID-19 compared to healthy controls [17]. Additionally, activation of NLRP3 inflammasome was observed in patients with severe COVID-19 with higher levels of inflammasome products such as caspase 1, IL-1β, and ILRIG 18 [18,19]. Considering the resemblance of inflammatory phenotype in HLH and MAS with COVID-19-associated cytokine storm, inflammasome and relevant cytokines are thought to have an important role in severe COVID-19. Immunopathogenesis and development of cytokine storm in COVID-19 was summarized in the Figure.
Figure: TLR: Toll-like Receptor, IFN: Interferon, IL-1β: Interleukin 1 Beta, IL-6: Interleukin 6, TNF-α: Tumor Necrosis Factor Alpha, ACE-2:Angiotensin Converting Enzyme 2, RIG-1: Retinoic acid-Inducible Gene I, ISG: Interferon-Stimulated Genes, NF?B: Nuclear Factor kappa B.
Cancer and COVID-19
Several potential factors might be associated to poor prognosis in patients with COVID-19 accompanying cancer. Higher development of cytokine storm, receiving chemotherapeutics and/or immunosuppressants, higher susceptibility to infections as well as other potential metabolic complications could be counted among these factors. In Mengyuan Dai et al. study in 2020, higher COVID-19 disease severity, higher secondary infection rate, and higher mechanical ventilation, as well as mortality rate, were observed in patients with COVID-19 accompanying cancer compared to the others [20]. In this study, higher mortality was also established among cancer patients, especially in patients with hematological cancer and receiving chemotherapeutics. Additionally, a higher mortality rate in patients who received immunotherapy compared to chemotherapeutics was a remarkable finding in the former study emphasize the crucial role of the underlying immune pathogenesis in COVID-19-associated cytokine storm. Beside the other risk factors such as genetic and demographic features, the level of immunosuppression may have important role in the development of COVID-19-associated cytokine storm in patients with cancer. Higher frequency of COVID- 19-associated cytokine storm in patients with hematological cancer compared to other malignancies as well as in patients with receiving chemotherapies compared to those had not, support this hypothesis. In another observational study from China mortality was two times higher in patients with cancer [21]. In this study, receiving anti-tumor treatment within 14 days had an increased risk of developing severe events (Hazard ratio [HR] = 4.079, 95% Confidence interval [CI]: 1.086– 15.322, p=0.037) [21]. Poor outcome in patients with COVID- 19-accompanying cancer compared to those had not was (39 % vs 8 %; p=0.0003, respectively) also established in Liang et al. study in 2020 [22]. Furthermore, anti-tumor treatment was also associated with severe disease course in this study (odds ratio [OR] 5·34, 95 % CI 1·80–16·18; p=0·0026).
Inflammatory cytokines are essential for the development and progression in cancer. High cytokine levels produced by tumor or stromal cells (IL-1β, IL-6, TNF, IL-8, IL-17 ) are associated with advanced stages of breast, prostate, and colon cancer [23,24]. Among these cytokines, IL-6 is important with its role in immune regulation and autoimmunity as well as cancer development. Blocking IL-6 is effective in several immunemediated diseases such as rheumatoid arthritis, AOSD, and large vessel vasculitis [25-27]. The mechanisms of IL-6 in tumorigenesis are promoting enhanced survival of cancer cells, increased angiogenesis, and inhibition of CD-8 T and NK cell functions [28-30]. The close association between IL-6 and cancer development was established in several cancers such as lymphomas, multiple myeloma, and solid tumors [31-33]. Moreover, promising results exist in several cancers such as myeloma and Castleman’s disease with IL-6 inhibitors such as tocilizumab [34,35]. Furthermore, the efficacy of IL-6 blocking was established in cytokine release syndrome (CRS) secondary to chimeric antigen receptor T cell (CAR-T cell) treatment in patients with hematological cancer [36]. These results emphasize the crucial role of IL-6 for the development of cancer, especially in hematological malignancies such as myeloma, lymphoma, and Castleman’s disease. IL-6 is also the main stimulator of STAT3, which has an important role in inflammation and oncogenesis together with NF-κB, which can activate the IL-6 amplifier [37]. This positive feedback loop is related to an increase in various proinflammatory cytokines and could be one of the main targets in the treatment of COVID-19 induced hyperinflammatory state. Higher cytokine levels are also shown during chemotherapy and radiotherapy in patients with cancer [38]. Additionally, it was shown that higher IL-6 and TNF-α levels secondary to cytostatic or targeted treatment were associated with higher mortality among hospitalized non-COVID-19 cancer patients [39]. The immune response triggered by antigens resulting from lysis of tumor tissue after cytotoxic therapy may explain the hyperinflammation as well as poor prognosis of COVID-19 in these patients. On the other hand, further studies are needed to clarify this issue.
Immunosuppression and COVID-19
At the beginning of the pandemic , the prognosis and course of the COVID-19 in patients receiving immunosuppressants was one of the major concerns among immunocompromised patients. After this uncertainty, there has been growing evidence of poor outcomes including higher hospitalization, the need for ICU admission, and mortality in patients receiving immunosuppressants such as corticosteroids, azathioprine, and mycophenolate mofetil as well as several biologic therapies [40,41] . In Akama-Garren et al. study in 2021, prior immunosuppressive therapy (30 % vs 17 %; p=0.036) was associated with higher mortality in patients with COVID-19 [42]. Among biological drugs, rituximab has the highest risk for poor outcomes in COVID-19 both in patients with immunemediated diseases and hematological cancer [43]. Impaired antibody response and defective clearance of SARS-Cov-2 with immunosuppressants, especially rituximab are the main possible mechanisms of poor outcomes in these patients. In a large study of 1090 patients with inflammatory rheumatic diseases who were evaluated for COVID-19, those who received rituximab therapy developed more severe infections and needed longer hospitalization [43]. Chronic immune stimulation by prolonged SARS-Cov-2 RNA leads to higher production of proinflammatory cytokines and therefore development of severe disease course as well as cytokine storm in immunocompromised patients. Several case reports revealing poor outcome in patients receiving rituximab supported this hypothesis [44,45]. Although prolonged PCR positivity is well known among immunocompromised patients [46] there are few cases of symptomatic COVID-19 recurrence [47-51]. On the other hand, relapsing or prolonged cytokine storm in these patients is unclear. Recently we published a case of chronic lymphocytic leukemia patient receiving rituximab together chemotherapies who developed recurrent/prolonged cytokine storm after a dramatic response to steroid and tocilizumab [52]. While the patient had a good response to tocilizumab initially, after recurrence of cytokine storm high dose intravenous anakinra was not effective. These findings emphasize that recurrent/prolonged cytokine storm in patients with COVID-19 may occur especially in patients with cancer or on immunosuppression. Ye et al. study in 2020 also revealed a possible viral reactivation in 5/55 (9.1%) discharged patients previously diagnosed with COVID-19 [53]. Four of these five patients were symptomatic and also COVID-19 recurrence was associated with immunosuppression in this study. Moreover, recurrent COVID-19-associated cytokine storms in immunosuppressive patients was also described in other case reports [54,55]. In light of these results, close followup of immunocompromised patients, especially receiving rituximab and/or chemotherapeutics should be considered in patients with COVID-19.
Treatment of Cytokine Storm
Glucocorticoids
Glucocorticoids (GC) are nonselective immunosuppressive agents and effective against cytokine storms by inhibiting multiple inflammatory pathways including the expression of several proinflammatory cytokines and leukocyte migration [56]. These drugs are used in the first-line for the treatment of various hyperinflammatory conditions in resemblance to COVID-19-associated cytokine storm; such as HLH, MAS, and CRS associated with CAR-T cell therapy [57,58]. Initial data on the use of GCs from studies performed in China was conflicting and led to recommendations against the routine use of corticosteroids in World Health Organization guidelines due to results pointing to prolonged viral shedding and increased mortality in severe patients [59-61]. After the UK-based Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial reported its findings in favor of dexamethasone therapy among patients who required mechanical ventilation, further evidence supporting these conclusions has emerged. A metaanalysis of 7 randomized controlled trials (RCT) suggested that GCs decrease 28-day all-cause mortality in severe COVID-19 patients. These data had led the GCs to become the standard of care in patients who require hospitalization and/or need oxygen therapy.
However, GC therapy should always be used with caution due to possible side effects including secondary infection risk. Uncontrolled and prolonged GC use in patients with rheumatic and inflammatory diseases has shown to be associated with poor outcomes in some studies [62], most probably due to delayed immune response and prolonged viral shedding. Finally, there are no positive data on GC use in mild COVID-19 disease.
Anti-IL-6 therapy
IL-6 is a pleiotropic cytokine that is essential for inflammation and hematopoiesis and plays a central role in the immune response by the stimulation of acute-phase response; however, as mentioned above, it is one on the major contributors of chronic inflammation and cytokine storm. Tocilizumab, a humanized monoclonal antibody against IL-6 receptor (IL- 6R), has been shown to be effective in several conditions with excessive production of IL-6 such as systemic juvenile idiopathic arthritis and CRS. Several open-label or randomized controlled studies were initiated with tocilizumab and other biologic agents blocking IL-6 activity. One of the largest trials on tocilizumab, the RECOVERY trial (which included 4116 patients receiving respiratory support or invasive mechanical ventilation (IMV)) found that patients treated with tocilizumab (400 to 800 mg) have higher rates of discharge within 28-day (54% vs. 47%) and less likely to need IMV or die (38% vs. 33%) [63]. Although conflicting results were reported possibly due to inadequate methodology in several studies [64], the efficacy of tocilizumab on clinical improvement (31 more with improvement per 1000 patients) and death (32 fewer deaths per 1000 patients on 28-day) in severe COVID-19 were shown in a Cochrane meta-analysis which included 10 RCTs and a total of 7308 patients [65].
Tocilizumab treatment was also reported to be efficient for patients with malignancy and severe COVID-19 in several cases. In the Table, we summarized the available reports of patients with malignancy and severe COVID-19 treated with tocilizumab and/or anakinra [52,66-72]. These findings were not surprising considering the role of IL-6 both in oncogenesis and COVID-19-associated cytokine storm and could be interpreted as the dominance of IL-6 in the inflammatory milieu of these patients. On the other hand, there are few data to evaluate the efficacy and safety of tocilizumab as well as other biological treatments since the patients with cancer were excluded from RCTs. Thus, only small observational studies and case reports exist in patients with cancer receiving biological treatments. This issue might be a research topic in future studies.
| Author | Age/Sex | Malignancy | Treatment for malignancy | Last treatment | COVID-19 associated cytokine storm treatment | |||
|---|---|---|---|---|---|---|---|---|
| Glucocorticoids | First line | Second line (in case of resistance) | Last reported status | |||||
| Bouchlarhem et al. [66] | 41/M | CML blast phase | HyperCVAD Nilotinib |
2 months ago | DXM 6 mg | Tocilizumab | discharge | |
| Lanceta et al. [67] | 65/M | Metastatic merkel cell carcinoma | None | none | Applied- dose not specified | Tocilizumab | discharge | |
| Bektas et al. [52] | 52/M | CLL | FCR | 30 days ago | MP 40 mg/day | Tocilizumab | Anakinra high dose iv. |
exitus |
| Innes et al. [91] | 53/M | CML blast phase - HSCT - GVHD | Glucocorticoids Cyclosporin A MMF |
ongoing | None | Tocilizumab | Ruxolitinib | discharge |
| Di Lorenzo et al. [68] | 69/M | Stage IV prostate cancer | LHRH agonism | ongoing | None | Tocilizumab | discharge | |
| Bonomi et al. [69] | 65/M | Metastatic lung adenocarcinoma | Carboplatin Pemetrexed Pembrolizumab |
ongoing | None | Tocilizumab | discharge | |
| Ranger et al. [70] | 52/M | CML | Imatinib | ongoing | None | Tocilizumab | discharge | |
| Zhang et al. [71] | 60/M | Myeloma | Thalidomide | ongoing | None | Tocilizumab | discharge | |
| Chaidos et al. [92] | 66/M | Myeloma | Lenalidomide | ongoing | None | tocilizumab | discharge | |
| 59/M | Myeloma | Bortezomib and panobinostat | ongoing | None | Tocilizumab | Tracheostomy in ICU | ||
| Villegas et al. [72] | 62/M | Diffuse large B cell lymphoma | 2nd line chemotherapy Not specified | ongoing | Applied- dose not specified | Tocilizumab | Anakinra low-dose sc. |
exitus |
| 50/F | Rosai-Dorfman syndrome | 3rd line chemotherapy - Not specified | ongoing | Applied- dose not specified | Tocilizumab | Anakinra low-dose sc. |
exitus | |
| 72/M | CLL | 1st line chemotherapy - Not specified | ongoing | Applied- dose not specified | Tocilizumab | Anakinra low-dose sc. |
exitus | |
| 82/M | Waldenstrom's macroglobulinemia | 2nd line chemotherapy Not specified | ongoing | Applied- dose not specified | Tocilizumab | Anakinra low-dose sc. |
exitus | |
| 56/F | Diffuse large B cell lymphoma | 1st line chemotherapy - Not specified | ongoing | Applied- dose not specified | Tocilizumab | Anakinra low-dose sc. |
exitus | |
| Anakinra high-dose: > 5 mg/kg/day iv.; Anakinra low-dose: 100-200 mg/day sc.; CLL: Chronic Lymphocytic Leukemia; CML: Chronic Myeloid Leukemia; HyperCVAD: Cyclophosphamide Vincristine sulphate Adriamycin Dexamethasone; DXM: Dexamethasone; FCR: Fludarabin Cyclophosphamide Rituximab; GVHD: Graft versus Host Disease; HSCT: Hematopoietic Stem Cell Transplantation; ICU: Intensive Care Unit; LHRH: Luteinizing Hormone Releasing Hormone; MP: Methylprednisolone | ||||||||
Table. Case reports of patients with malignancy and COVID-19 treated with anti-cytokine therapies in available literature (English).
It should be kept in mind that, anti-IL-6 therapy was effective only in severe and critically ill patients with COVID-19 in the studies mentioned. Tocilizumab was found to be associated with an increase in bacterial and fungal superinfections in COVID-19 patients in two different meta-analysis [73,74]. Therefore, anti-IL-6 therapies should be used with caution and patients should be followed in terms of secondary infections, considering the loss of acute-phase response after drug exposure.
Anti-IL-1 therapy
The rationale for anti-IL-1 treatment for COVID-19 can be summarized as the role of inflammasome and its products in the development of COVID-19 manifestations and cytokine storm which has been stated above. Anakinra is a recombinant human IL-1 receptor antagonist protein and approved by the European Medicine Agency for autoinflammatory conditions such as FMF, cryopyrin associated periodic syndromes, and AOSD [75]. It is used subcutaneously in standard doses, and the possibility of using high doses intravenously is one of its most important advantages. In addition to its subcutaneous use in standard doses (100-200 mg/kg), the possibility of using high doses (up to 5 mg/kg twice a day) intravenously is one of its most important advantages. In one of the first trials that evaluates the efficacy of anakinra in patients with mildmoderate COVID-19 pneumonia, the efficacy of low-dose subcutaneous administration could not be demonstrated [76]. However, in recent studies, encouraging data on the effectiveness and safety of anakinra both at standard and high doses is accumulating, when administered to severe and critical patients [77-81]. A meta-analysis of eight observational studies and one randomized controlled trial revealed that anakinra reduces the mortality risk in patients admitted to hospital with moderate to severe COVID-19 pneumonia, especially in the presence of hyperinflammation (CRP >100 mg/L) without increasing infection risk [82]. The safety and efficacy of anakinra were established in patients with secondary HLH due to rheumatological conditions, cancer and infection both in adults and children [15,83,84]. The short half-life (4-6 hours) of anakinra also has the advantage of rapid withdrawal in case of infections or other complications in critically ill patients [67].
Efficacy of another anti-IL-1 option, canakinumab, humanized anti–interleukin-1β antibody was evaluated in COVID-19, albeit less often. A meta-analysis of available data (four observational studies, two RCTs) regarding the use of canakinumab on mild to severe COVID-19 pneumonia revealed lower mortality rate and decreased CRP levels in patients treated with canakinumab.
As a result, anti-IL-1 therapies can be used up to high doses in patients with hyperinflammatory response associated with COVID-19 who has comorbidities and an increased risk of secondary infections, based on the current data.
Janus kinase inhibitors
JAK/STAT pathway provides signal transduction from cytokines, growth factors, and hormones, to the nuclei of cells. JAK members are activated by multiple interleukin receptors including IL-2, IL-4, IL-7, IL-9, IL-15, IL-21, and IFN-γ receptors [85]. Considering the role of these cytokines in severe COVID-19, interruption of the JAK /STAT pathway was thought to be beneficial [86]. Baricitinib exhibits anti-inflammatory effects by reversible JAK inhibition and is approved by EMA for the treatment of rheumatoid arthritis and atopic dermatitis [87]. One of the largest RCTs on the efficacy of baricitinib, The Adaptive COVID-19 Treatment Trial 2, enrolled 1033 patients and revealed that treatment with baricitinib was superior to placebo in reducing time to recovery and was associated with fewer serious adverse events (AEs), although 28-day mortality was similar between groups (5.1% with baricitinib and remdesivir vs. 7.8% with remdesivir alone). Another RCT which included 1525 patients (COV-BARRIER) found that baricitinib 4 mg/day up to 14 days reduces 28- day and 60-day all-cause mortality (8% vs. 13% and 10% vs. 15%, respectively). The frequency of serious AEs, secondary infections, and thromboembolic events were similar between groups in both studies. Increased rate of serious side effects on long-term treatment for rheumatoid arthritis such as increased rate of serious infections (including zoster zona) or venous thrombosis was not observed in COVID-19 studies [88,89], possibly due to short term treatment in COVID-19. A Phase I/II Clinical Trial to evaluate the efficacy of baricitinib in onco-hematological patients with COVID19 is still in progress [90]. However, particularly in immunosuppressed or cancer patients, the possibility of these AEs should be kept in mind during treatment with JAK inhibitors.
This paper has some limitations. Most of the studies about biological therapies are consisted of small retrospective observational studies and/or case reports due to exclusion of cancer patients from RCTs was the main limitation. Lack of comparative data with the biological treatments in patients with COVID-19 accompanying cancer was another limitation.
Conclusion
Patients with malignancy and/or receiving immunosuppressants are at high risk for complications, development of cytokine storm, and poor outcomes associated with COVID-19. Furthermore, recurrent/prolonged cytokine storm is an emerging potential life-threatening condition in patients with cancer or immunosuppressants beyond prolonged PCR positivity. Revealing the common pathways of inflammation for immune-mediated diseases, oncogenesis, and COVID- 19-associated cytokine storm is crucial for the development of targeted therapies in patients accompanying cancer. Tocilizumab may be a good option in the treatment of cytokine storm in patients with cancer due to the crucial role of IL-6 both in cancer development and COVID-19-associated cytokine storm. Further studies including new therapeutic strategies are needed to improve outcomes in these patients.
Funding
No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out work described in this article.
Conflicts of Interest
Authors declare no conflicts of interest.
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