Cytokine Storm and Failed Resolution in COVID-19: Taking a Cue from Multiple Sclerosis

Abstract

Introduction:

Excessive inflammatory responses and failed resolution are major common causes of tissue injury and organ dysfunction in a variety of diseases, including multiple sclerosis (MS), diabetes, and most recently, COVID-19, despite the distinct pathoetiology of the diseases. The promotion of the natural process of inflammatory resolution has been long recognized to improve functional recovery and disease outcomes effectively. To mitigate the excessive inflammation in MS, scientific investigations identified a group of derivatives of omega fatty acids, known as specialized pro-resolving lipid mediators (SPM) that have been significantly effective in treating preclinical disease models of MS.

Methods:

This chapter is based on our observations from MS. It is being increasingly deliberated that the ongoing COVID-19 infection induces severe cytokine storm that ultimately triggers rampant inflammation. The impact of infection and associated mortality is much higher in patients with co-morbid diseases. Also, reports suggest a better outcome in diabetic patients with reasonable glycemic control, which certainly hints towards a hidden role of anti-hyperglycemic drugs such as metformin in alleviating disease pathology through its anti-inflammatory feature. Notably, SPM and metformin share common therapeutic features in exerting a broad-spectrum anti-inflammatory activity in human patients with a superior safety profile.

Results:

When there is an immediate need to encounter the fast-rampant infection of COVID-19 and control the viral-infection associated morbid inflammatory cytokine storm causing severe organ damage, SPM and metformin should be seriously considered as a potential adjunctive treatment.

Conclusion:

Given the fact that current treatment for COVID-19 is only supportive, global research is aimed at developing safe and effective therapeutic options that can result in a better clinical course in patients with comorbid conditions. Accordingly, taking a cue from our experiences in controlling robust inflammatory response in MS and diabetes by simultaneously inhibiting inflammatory process and stimulating its resolution, combinatorial therapy of metformin and SPM in COVID-19 holds significant promise in treating this global health crisis.

13.1. Introduction

Inflammation is considered as a physiologically protective in-built immune response to external and internal insults such as injury (burn, trauma, and wound), infection by pathogenic attack (bacteria, fungi, and viruses), and surgical procedure (Kumar et al. 2014). It is a desirable self-limited defense mechanism used by the body to retaliate against any damage due to harmful stimuli, eliminating the threat to the normal functioning of the body. The immunologic players involved in the activation and sustenance of physiologic inflammatory response include classical lipid-derived pro-inflammatory mediators known as eicosanoids, cytokines, chemokines, and immune cells (Duffy et al. 2014; Nathan 2002). Under normal conditions, inflammation is actively resolved in a timely manner by a highly coordinated process of resolution, mediated by an endogenously synthesized family of omega fatty acid-derived specialized pro-resolving lipid mediators (SPM), including resolvins, lipoxins, maresins, and protectins (Serhan 2004; Serhan et al. 2004; Serhan and Chiang 2004). Interestingly, this transition is governed by switch-over within the resolution window, by shifting synthesis of pro-inflammatory lipid mediators to resolution mediators, which shows how onset signals termination (Levy et al. 2001) (Fig. 13.1). During the process of inflammation and its resolution, there occur a plethora of changes affecting the cellular permeability and immune cell trafficking (Nathan 2002). SPM promote inflammation resolution by acting through specific G-protein coupled receptors (GPCR), which subsequently results in the regulation of pro-inflammatory cytokine and chemokine production, macrophage-based phagocytosis of dead cells and pathogens, leukocyte trafficking, and recruitment of polymorphonuclear neutrophils (PMN) and monocytes (Serhan 2014). Resolution is a restorative process meant to clear the inflammatory exudate and repair the damage caused by inflammation and hence re-establish the normal cellular homeostasis essential for maintaining a healthy state (Serhan 2014; Serhan and Savill 2005). However, its failure leads to uncontrolled and unresolved inflammation, causing disturbance in the homeostatic status that gives rise to a pathological state of chronic inflammation (Nathan and Ding 2010). This makes the timely resolution of inflammation critical in health and disease.

Fig. 13.1.

Inflammation-driven resolution showing how onset signals end

While inflammation is governed by the classical pro-inflammatory mediators such as chemokines, cytokines, and omega-6 derived eicosanoids in the initial phase, the transition from the synthesis of pro-inflammation to pro-resolution mediators, mediated by class switching of lipid mediators marks the resolution phase

Dysregulated immune response and failed resolution pose the biggest challenge in treating inflammatory conditions. Multiple reports have shown altered levels of resolution mediators in various disease models owing to the defects in their biosynthesis or their receptors through which they act, causing catastrophic inflammation as the trigger for several inflammatory diseases (Dalli 2017; Serhan 2017; Zahoor and Giri 2020). Consequently, SPM have shown beneficial effects in preclinical models of several human diseases, including multiple sclerosis (MS), neuromyelitis optica, Alzheimer’s disease, diabetes, asthma, stroke, sepsis, obesity, rheumatoid arthritis, atherosclerosis, and cancer (Nathan and Ding 2010; Abdolmaleki et al. 2020; Kooij et al. 2019a; Poisson et al. 2015; Shang et al. 2019; Wang et al. 2015, 2019) (Fig. 13.2). Ongoing research is primarily focused on promoting inflammation resolution by using these intrinsic resolution mediators as prospective therapeutic candidates for treating multiple inflammatory and infectious conditions (Dalli 2017; Serhan 2017; Zahoor and Giri 2020; Kooij et al. 2019a; Poisson et al. 2015; Russell and Schwarze 2014). There are also some ongoing clinical trials exploring the impact of SPM on the inflammation parameters and resolution in human inflammatory conditions such as acute tissue inflammation and MS (ClinicalTrials.gov 2018; ClinicalTrials.gov 2020a). Based on our work on inflammation resolution in MS, we put forth our perspective in treating COVID-19-induced robust inflammation. Further discussion is based on unresolved inflammation common to MS and COVID-19.

Fig. 13.2.

Resolution and SPM in the backdrop of inflammation

Defective resolution and altered levels of resolution mediators (SPM) due to dysfunction in their biosynthetic pathway or receptors are involved in the pathogenesis of several inflammatory diseases

13.2. Metformin and SPM Therapy in COVID-19: A Perspective from MS

Multiple sclerosis (MS) is the leading non-traumatic neuroinflammatory disease that occurs due to hyperimmune response against components of nervous system, mediated primarily by autoreactive T cells (Reich et al. 2018). There is mounting evidence to suggest the role of environmental (non-infectious or infectious) and genetic factors in altering disease risk, with exact trigger behind disease development still unknown, which complicates its accurate diagnosis, prognosis, and management. Owing to the immune-mediated nature of this chronic debilitating disease, the ongoing research is aimed at mitigating the inflammation by promoting endogenous mechanisms of resolution. As a result, there have been few metabolomics studies showing an imbalance in the levels of immunoresolvent mediators (SPM) and their precursor omega polyunsaturated fatty acids (PUFA) in patient-derived samples (Kooij et al. 2019a; Poisson et al. 2015; Aupperle et al. 2008; Bjornevik et al. 2017; Bjornevik et al. 2019; Kooij et al. 2019b; Pruss et al. 2013). The altered resolution mediators include, resolvin D (RvD1, 3, 5), lipoxin A4 (LXA4), lipoxin B4 (LXB4), aspirin-triggered 15-epi-lipoxin A4 (ATLXA4), neuroprotectin D1 (NPD1), and protectin DX (PDX). Interestingly, the current MS studies are based on resolving inflammation using SPM treatment on preclinical cellular and animal models of the disease (Zahoor and Giri 2020). Based on few studies of SPM treatment in experimental autoimmune encephalomyelitis (EAE) model of MS, the possible mechanism of amelioration in disease progression and improved pathology involves protective actions of resolution mediators on various aspects of immune response that result in modification of cellular response to promote resolution phase of inflammation (Kooij et al. 2019a; Poisson et al. 2015; Kooij et al. 2019b) (Fig. 13.3). The key resolution mechanisms involve the polarization of T cells and macrophages towards anti-inflammatory phenotype, reduction in the overall synthesis of pro-inflammatory mediators, attenuation of monocyte activation and transendothelial migration, and inhibition of inflammation-induced blood brain barrier (BBB) dysfunction. Like MS, the ongoing global pandemic of coronavirus disease 2019 (COVID-19) also has excessive inflammation as a key element in its pathophysiology. The findings from MS research suggest potential role of inflammation resolution in combating this recent uncontrolled inflammatory condition.

Fig. 13.3.

Several mechanisms mediate the protective effects of SPM treatment on cellular and animal models of MS, resulting in overall amelioration of disease pathology

SPMs, in relation to MS, have been found to inhibit auto-reactive T cells, pro-inflammatory cytokine production, monocyte activation, inflammation-induced blood brain barrier (BBB) dysfunction, and transendothelial migration of monocytes. They also induce T regulatory cells and promote polarization of macrophages and microglia towards anti-inflammatory M2 phenotype, resulting in overall inhibition of inflammation

COVID-19 is caused by infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with its first outbreak reported in December 2019 in Wuhan, China (Lai et al. 2020). It has already led to over 100,000 deaths across the United States. The number of infected cases and mortality are still rising throughout the world due to its high transmission rate and lack of effective treatment. Currently, our knowledge of this novel infectious disease is minimal. However, a prominent hyperinflammatory response induced by the viral infection has been observed in patients of all age groups and strongly associated with disease severity and death. It has been found that the infection primarily starts from the respiratory system and causes pneumonia and acute hypoxia due to massive pulmonary hyperinflammation that often induces life-threatening chemokine/cytokine response, often termed as the ‘cytokine storm’ syndrome (Mehta et al. 2020). While some patients have mild symptoms and recover on minimal medical intervention, many others show rapid deterioration and develop complications like cardiac inflammation, lung failure, blood clots, kidney failure, sepsis, brain inflammation, and even death (Chen et al. 2020a; Chen et al. 2020b; Huang et al. 2020). It has been observed that people of any age having uncontrolled comorbid conditions are at the highest risk for COVID-19 due to their impact on disease outcome and prognosis. These underlying conditions mainly include hypertension, cardiovascular disease, diabetes, chronic respiratory disease, cancer, renal disease, and obesity (Cai et al. 2020; Guan et al. 2020; Centers for Disease Control and Prevention 2020; Wu et al. 2020; Yang et al. 2020a; Zhang et al. 2020). Also, age has a substantial impact on the disease course, clinical characteristics, comorbidities, outcomes, and prognosis due to the effect of ageing on the functional status of biological system that apparently results in immunological and physiological changes (Miller and Linge 2017; Du et al. 2020; Liu et al. 2020; Zhou et al. 2020). There are reports that have found worse outcomes and higher mortality associated with COVID-19 in aged patients (Wu et al. 2020; Yang et al. 2020a; Du et al. 2020; Liu et al. 2020; Zhou et al. 2020). These findings make it very important to identify risk groups and take into account age factor while evaluating and treating such patients.

The robust hyperimmune response observed in infected patients leads to the activation of inflammasomes, which induce eicosanoid storm due to elevated levels of pro-inflammatory mediators and hypercytokinemia that fuel multiple organ damage and acute respiratory distress syndrome (ARDS) in critically ill patients (Fung et al. 2020; Yuki et al. 2020). Serum profiling of patients has revealed that the inflammatory rampage is characterized by disproportional activation of tumor necrosis factor-alpha (TNF-α), interleukins 1, 2, 6, 7, 8 (IL-1, IL-2, IL-6, IL-7, IL-8), and monocyte chemoattractant protein 1 (MCP-1) (Mehta et al. 2020; Huang et al. 2020; Coperchini et al. 2020; Ye et al. 2020). Studies from China have identified biomarkers of fatality and progression in patient-derived samples that included elevated levels of ferritin, IL-6, IL-10, TNF-α, and several other inflammatory markers which certainly point towards the virus-induced hyperinflammatory response; however, plasma levels of IFN-γ–induced protein 10 (IP-10) and MCP-3 were highly associated with severity and disease progression (Ruan et al. 2020; Yang et al. 2020b). There are also reports of immune dysregulation in COVID-19 that primarily affects T lymphocytes by causing a significant reduction in counts of CD4+ and CD8+ T cells and decrease in IFN-γ production by CD4+ T cells, particularly in severe cases requiring intensive care unit (ICU) than moderate cases (Chen et al. 2020a; Diao et al. 2020). Further, there is a case report of overactivation of T cells that resulted in an increase of Th17 cells and high cytotoxicity of CD8 T cells, which in part accounted for severe immune injury observed in the infected patient (Xu et al. 2020). This highly derailed immunological profile of patients suggests compromised resolution pathways in infected individuals, which results in loss of ability to restore cellular homeostasis.

To date, the overall treatment of COVID-19 is supportive, as there are no approved effective vaccines or antiviral medications against this highly contagious virus with current research efforts aimed at finding the one. This necessitates the need for multi-center research collaborations to find a rapid and effective treatment for the disease that could lower the magnitude of inflammatory response and cytokine storm in the initial stage to combat the fatality of the disease. At present, there are precisely no treatment options with absolute safety profile; however, some of the treatment strategies which are being investigated come from the theoretical knowledge of past experiences on viral infections such as, severe acute respiratory syndrome (SARS) and middle east respiratory syndrome (MERS), and other inflammatory conditions. Commonly used treatment options include antiviral therapy, immunomodulators, antithrombotic therapy, and cytokine antagonists (COVID-19 Treatment Guidelines Panel 2019). The National Institutes of Health (NIH) has maintained an exclusive website on COVID-19 treatment guidelines based on the outcome from ongoing studies, to provide the most updated and refined recommendations on different treatment modalities (COVID-19 Treatment Guidelines Panel 2019). A very recent report has evaluated the clinical efficacy of antiviral drug remdesivir in a double-blind, randomized, placebo-controlled trial in 1063 coronavirus infected patients with lower respiratory tract involvement (Beigel et al. 2020). Their preliminary findings showed that intravenous remdesivir was efficient in improving the outcome in patients with severe disease by shortening the recovery time compared to placebo. At the same time, the mortality rate was still higher, which accentuates the use of combinatorial therapy to augment the efficacy of known antivirals. Based on the evidence to control cytokine storm in rheumatoid arthritis by using IL-6 antagonists, tocilizumab, a monoclonal antibody has been shown to be effective in treating severely ill patients with higher serum levels of IL-6 (Biggioggero et al. 2019; Tanaka et al. 2016). On that basis, a randomized controlled trial has been started to test the safety and efficacy of tocilizumab on Chinese COVID-19 patients with pneumonia and raised IL-6 (Chinese Clinical Trial Registry 2020). However, there is still lack of concrete evidence on the use of IL-6 inhibitors (sarilumab, siltuximab, tocilizumab) (COVID-19 Treatment Guidelines Panel 2019). The much-hyped hydroxychloroquine is another drug that has been tried in few cases but lacks scientific acceptance due to poor quality of data, which has forced clinical trials in the United States and other parts of the world to test its safety and efficacy in combination with azithromycin (ClinicalTrials.gov 2020b). Altogether, there is insufficient evidence in support of any treatment; however, management strategies being used are decided on the basis of the severity of patients. The need of the hour is to identify the strategy aimed at controlling the disproportionally activated inflammatory responses in COVID-19 infection using protective therapies with proven effectiveness and safety profile to address the immediate need to fight off the virus-induced pathology.

The endogenous resolution pathways have been recognized in the cessation of infectious pathologies like influenza due to the regulation of antiviral B lymphocytic activity of resolution mediators (Morita et al. 2013; Ramon et al. 2014; Tam et al. 2013). There is prior evidence to support the role of SPMs or their precursors to confer protection against influenza by promoting adaptive immune response that has led to the recognition of their potential as vaccine adjuvants, especially for 17-hydroxydocosahexaenoic acid (17-HDHA) (Morita et al. 2013; Ramon et al. 2014). This indirectly provides compelling evidence of exploiting SPM or their precursors as potential therapeutic interventions for suppressing immune response and hypercytokinemia to achieve a better clinical outcome in infectious diseases like COVID-19. Also, there is evidence of protectin D1 to significantly attenuate replication of the influenza virus and reduce its severity in a mice model, even when regular antiviral drugs do not come to the rescue (Morita et al. 2013), implicating the therapeutic potential of SPM in lethal COVID-19 infection. There is a previous report that has studied the effect of exercise on pro-inflammatory and pro-resolving lipid mediators, and they have suggested against the use of non-steroidal anti-inflammatory drugs (NSAID) such as ibuprofen due to its ability to block exercise-induced prostaglandin increase and more specifically it resulted in a decrease in the levels of resolution mediators after recovery from exercise (Markworth et al. 2013). This could severely affect the outcome in COVID-19 individuals, which supports the use of resolution mediators as promising therapeutic options for promoting the resolution of inflammation. SPM therapy has an added advantage over conventional anti-inflammatory agents, which completely block the inflammation in its initial phase rather than downregulating by promoting its resolution and are associated with adverse effects. Based on the past evidence of inflammation resolution with SPM treatment in preclinical disease models, reports are strongly suggesting using SPM or their precursors in treating COVID-19 infection in conjunction with other supportive therapies (Panigrahy et al. 2020; Regidor 2020).

Moreover, human coronavirus enters into cells by binding to angiotensin-converting enzyme 2 (ACE2), which is a receptor expressed on cellular epithelia of lungs, kidneys, and blood vessels (Wan et al. 2020). Some studies have reported the upregulation of ACE in hypertensive and diabetic patients, and that treatment with ACE inhibitors and angiotensin II type I receptor blockers (ARB or angiotensin II inhibitors) further stimulates its expression (Li et al. 2017). Also, there is evidence of its increased expression by thiazolidinediones and ibuprofen. These findings suggest the possibility of higher infectivity of COVID-19 in patients with underlying conditions of diabetes and hypertension because the higher expression of ACE2 fairly eases entry of the virus into the system, and that somehow explains higher complications and fatality in such cases (Fang et al. 2020). With higher infectivity, there is a comparatively massive inflammatory response that induces marked increase in blood sugar level leading to diabetic ketoacidosis, which confers poor outcomes in such cases. A recent study found that COVID-19 patients with pre-existing type 2 diabetes are at increased risk of a poor outcome, especially those with poorly controlled blood glucose (Zhu et al. 2020). Moreover, the fast deterioration in these patients was associated with higher serum levels of neutrophil counts and inflammatory markers, including IL-6, C-reactive protein (CRP), and lactic acid dehydrogenase (LDH). Metformin has been recently found to inhibit IL-6 signaling and reduce CRP and LDH in patients (Kahn et al. 2010; Karam and Radwan 2019; Mishra and Dingli 2019), vouching for its use as a potential therapy to improve the outcome of COVID-19 infection through an anti-inflammatory mechanism.

Metformin is currently the single most prescribed, oral anti-diabetic drug in the US and worldwide, with long history of being safely used in humans (~ 60 years) and about 100 million patients taking it every day (Holman 2007). Apart from the glucose-lowering property, it has several pleiotropic therapeutic effects, including anti-inflammatory and antioxidant properties, and the ability to improve endothelial function (Karam and Radwan 2019; Forouzandeh et al. 2014; Hattori et al. 2015). Our previous work on EAE model of MS treated with metformin provides direct evidence in support of the therapeutic role of metformin in attenuating inflammation by down-regulating pro-inflammatory cytokine production, promoting expression of anti-inflammatory cytokine IL-10, and overall inhibition of T cell-mediated immune response in EAE (Nath et al. 2009). Similarly, we have reported its beneficial effects in reducing cancer growth and promoting better survival in ovarian cancer, which further emphasizes its therapeutic potential, making it a budding treatment option for several inflammatory conditions (Al-Wahab et al. 2015; Kumar et al. 2013; Tebbe et al. 2014). Its role has also been implicated in mitigating mortality associated with diabetes in patients with chronic obstructive pulmonary disease (COPD) (Zhu et al. 2019; Ho et al. 2019). Metformin drives its anti-inflammatory effects by targeting macrophages via regulating monocyte-macrophage differentiation and macrophage polarization involving stimulation of adenosine monophosphate activated protein kinase (AMPK) activation and signal transducer and activator of transcription 3 (STAT3) inhibition (Hattori et al. 2015; Vasamsetti et al. 2015). Keeping in view high virulence, infectivity, pathogenicity, and fatality of COVID-19, it is highly recommended to identify and control the disproportionally activated lethal inflammatory responses using therapies with proven effectiveness and safety profile to address the immediate need to reduce the rising global mortality. The cumulative outcome from above-discussed findings suggests that both SPM and metformin are relatively safe for human use and have a significant role in regulating inflammation. Metformin is already an approved drug by US Food and Drug Administration (FDA), which will save both time and money related to the drug development, and will be easy to move into clinical trials for targeting COVID-19. Based on the current data and considering the urgency in finding rapid and effective drug combinations with a good safety profile, a combination of metformin and SPM seems to be an effective approach to encounter the COVID-19 infection as both have a different mode of action. Metformin treatment will abrogate inflammation and oxidative stress, and SPM will resolve inflammation by inducing efferocytosis and possibly reduce virus replication (Fig. 13.4).

Fig. 13.4.

Metformin and SPM as adjunctive therapy for COVID-19

A novel combinatorial therapeutic approach using metformin and SPM as potential intervention in COVID-19, which would possibly abrogate robust inflammatory response by simultaneously inhibiting it and promoting its resolution

13.3. Conclusions

Inflammation resolution has become the core of recent therapeutic approaches for targeting inflammation as underlying cause of several inflammatory conditions, such as autoimmune, metabolic, neurodegenerative, respiratory, and cardiovascular diseases. In recent years, the logistics of diabetes treatment has evolved beyond merely glycemic control to a stage that anti-inflammation became essential in improving the dire macrovascular and microvascular complications. As a proven first-line drug for blood glucose control in type 2 diabetes, metformin has been increasingly recognized to have pleiotropic therapeutic properties, including anti-inflammation and improve vascular endothelial functions. On that basis, our work on MS involving simultaneous inhibition of inflammation and promoting its resolution in cellular and animal models emphasizes the utility of metformin and resolution mediators (SPM) in treating hyperinflammatory conditions. Both SPM and metformin have a fairly good safety profile for human use. Considering overwhelming inflammatory response in form of ‘cytokine storm’ in COVID-19, there is an urgent need to combat that process and its associated damage, which leads to multiple organ failure and even death. Altogether, taking perspective from MS and diabetes, there is a possible role of metformin and SPM as a novel combinatorial therapy that should be tested on COVID-19 patients under present crisis situation.

Abbreviations

17-HDHA

17-hydroxydocosahexaenoic acid

ACE2

angiotensin-converting enzyme 2

AMPK

adenosine monophosphate activated protein kinase

ARB

angiotensin II type I receptor blockers

ARDS

acute respiratory distress syndrome

ATLXA4

aspirin-triggered 15-epi-lipoxin A4

BBB

blood brain barrier

COPD

chronic obstructive pulmonary disease

COVID-19

coronavirus disease 2019

CRP

C-reactive protein

EAE

experimental autoimmune encephalomyelitis

FDA

Food and Drug Administration

GPCR

G-protein coupled receptors

ICU

intensive care unit

IFN-γ

interferon-gamma

IL

interleukin

IP-10

IFN-γ–induced protein 10

LDH

lactic acid dehydrogenase

LXA4

lipoxin A4

LXB4

lipoxin B4

MCP-1

monocyte chemoattractant protein 1

MERS

middle east respiratory syndrome

MS

multiple sclerosis

NIH

National Institutes of Health

NPD

neuroprotectin D1

NSAID

non-steroidal anti-inflammatory drugs

PDX

protectin DX

PMN

polymorphonuclear neutrophils

PUFA

polyunsaturated fatty acids

RvD

resolvin D

SARS

severe acute respiratory syndrome

SARS-Co-V-2

severe acute respiratory syndrome coronavirus 2

SPM

specialized pro-resolving lipid mediators

STAT3

signal transducer and activator of transcription 3

TNF-α

tumor necrosis factor-alpha