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   Table of Contents      
Year : 2021  |  Volume : 11  |  Issue : 4  |  Page : 255-261

Managing the Cytokine Storm in COVID-19: Can Melatonin Play a Part?

1 Department of Periodontology, JSS Dental College and Hospital, Mysore, Karnataka, India
2 Public Health Dentistry, JSS Dental College and Hospital, Mysore, Karnataka, India
3 Department of Pharmaceutics, JSS College of Pharmacy, Mysore, Karnataka, India
4 Department of Oral Pathology, School of Dental Sciences, Krishna Institute of Medical Science, Karad, Maharashtra, India
5 Department of Periodontology, Maratha Mandal Institute of Dental Sciences, Belgaum, Karnataka, India
6 Department of Periodontology, Government Dental College and Hospital, Bangalore, Karnataka, India

Date of Submission08-Jul-2021
Date of Decision14-Jul-2021
Date of Acceptance26-Jul-2021
Date of Web Publication26-Oct-2021

Correspondence Address:
Aruna Ganganna
Department of Periodontology, JSS Dental College, Mysuru 570015
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijnpnd.ijnpnd_53_21

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Some drugs with immunomodulatory and anti-inflammatory activity are identified as adjunctive therapy in the coronavirus disease 2019 (COVID-19) infections and researchers believe that such pathophysiologic pathway treatment approach is rational and important for future development of new therapeutic agents in managing this pandemic. This review will discuss various cytokines which go berserk and cause serious life-threatening complications in COVID-19 infections. Additionally, different therapeutic modalities in managing “cytokine storm,” with a special note on melatonin is discussed. The foundation laid by scientists on this wonder molecule may pave the path toward development of drug with satisfactory results either used alone or as an adjunct to other drugs. However, calming the angered cytokine profile seems pivotal during management of the devastating storm.

Keywords: Cytokine storm, cytokines, melatonin

How to cite this article:
Ganganna A, Chandrashekar BR, Venkatesh MP, Belgaumi U, Shivnaikar S, Bhandari P. Managing the Cytokine Storm in COVID-19: Can Melatonin Play a Part?. Int J Nutr Pharmacol Neurol Dis 2021;11:255-61

How to cite this URL:
Ganganna A, Chandrashekar BR, Venkatesh MP, Belgaumi U, Shivnaikar S, Bhandari P. Managing the Cytokine Storm in COVID-19: Can Melatonin Play a Part?. Int J Nutr Pharmacol Neurol Dis [serial online] 2021 [cited 2023 Feb 1];11:255-61. Available from:

   Introduction Top

In the human body, diverse pathogens such as virus, bacteria, fungi, and protozoa are repelled before they trigger any inflammatory response. This protective mechanism is reported from the lowest protozoans to humans wherein, organisms possess means of distinguishing self-components from non-self-components. When this mechanism goes berserk, the immune system displays self-sabotaging characters shifting the equilibrium from health to disease. This not only impacts the individual but also presents extreme challenges to health workers in providing effective treatment. Hence, the name “double-edged sword” as referred by researchers to this complex immune mechanism seems appropriate.

In this regard, mentioning the havoc created by the dreaded virus coronavirus disease 2019 (COVID-19) which swept millions across the globe in its wake, sets as a classic example of immune dysfunction. This virus with the help of four structural glycoproteins, including spike (S), membrane (M), envelope (E), and nucleocapsid (N), establishes itself in the host cell. More specifically, the S protein is responsible for viral binding followed by cellular penetration, whereas the M, N, and E proteins favors viral assembly and release.[1] Angiotensin-converting enzyme 2 (ACE2) receptors, expressed both in lung and extra-pulmonary tissues, have strong affinity for the S protein of the virus. The binding of the S protein with ACE2 receptor results in internalization of protein–receptor complex. Like key turning in a latch, the virus enters and hijacks the cell machinery to make copies of itself to establish itself in the human body. However, the role of ACE2 receptor protein expression on the cell surface is still open to debate and several authors have argued that the correlation of ACE2 cell-surface protein and COVID-19 pathology may not be possible at all times and the disparity may be related to selective, transient expression of ACE2 in many organs.[2],[3],[4]

   Understanding Renin-Angiotensin-Aldosterone System Top

Being a well-orchestrated hormonal system, renin–angiotensin–aldosterone system regulates fluid and electrolyte balance, blood pressure, and vascular resistance. Derangement in any of these mechanisms is sensed by juxtaglomerular cells in the kidneys to secrete renin, a hormone which circulates in the blood to reach the hepatocytes. Liver produces angiotensinogen which is a renin substrate and is cleaved at the N-terminus to form angiotensin I. Angiotensin I is further modified to angiotensin II (ANG II) with the help of ACE within the pulmonary and renal cells. ANG II acts as an endocrine, autocrine/paracrine, and intracrine hormone to cause vasoconstriction, sodium retention ultimately restoring the blood pressure and volume.

ANG II, apart from re-establishing the fluid dynamics, also increases inflammation and the death of cells in the alveoli which are critical for bringing oxygen into the body. Therefore, ACE2 converts ANG II to other molecules that counteract the effects of ANG II and acts as signal-braking mechanism to stop extraneous inflammatory signals.

   The Tale of cytokines and Cytokine Storm in COVID-19 Infections Top

Though the direct effect of the invading pathogen takes the spotlight, collateral damage by hyperactive immune responses to the pathogen and the release of inflammatory mediators such as interferons (IFNs), interleukins (ILs), tumor-necrosis factor-alpha (TNF-α), and chemokines cannot be underrated.[5] Cytokines, being small short-lived proteins, are at the crossroads of bridging the communication between the innate and adaptive immune responses. They act as beacon while body wards-off infectious agent in well-orchestrated mechanisms. Once secreted, they bind to specific receptors on the cell surface of the target cell triggering a signaling cascade. The signal ultimately reaches the nucleus resulting in gene transcription, protein expression, and a complex cascade which determines the resultant effect as proinflammatory, anti-inflammatory, or deadly.[6]

During 1918 to 1919, an exaggerated immune response was suspected to contribute to the lethality of influenza pandemic and it was recognized that the immune response to the pathogen, but not the pathogen itself contributed to multiorgan dysfunction.[7] Similarly, COVID-19 infection has presented with classical features of pneumonitis along with other features most often occurring outside the lungs such as fever, adenopathy, hepatosplenomegaly, cytopenia, liver function derangement, and activation of intravascular coagulation which is a result of marked hypercytokinemia.[8]

   Deciphering the Cytokine Storm Top

The term cytokine storm was first coined by Ferrara et al. in graft versus host disease; a condition where excessive and self-perpetuating cytokine release is highlighted. Subsequent discussions appeared in 2002 and 2003 in reference to pancreatitis.[9],[10]

Hypercytokinemia is caused by multiple inflammatory processes, characterized by continuous fever, multiorgan failure, hyperferritinemia, and potentially, death.[11] Various etiologies such as iatrogenic, inflammatory, and infectious factors initiating this syndrome are recognized. It is also known to share similarities with other hyperinflammatory disorders, such as secondary hemophagocytic lymphohistiocytosis, macrophage activation syndrome, macrophage activation-like syndrome of sepsis, and cytokine-release syndrome. These disorders share overlapping clinical manifestations and a common pathway of macrophage activation and a self-perpetuating cycle of cytokine production.[12]

While the researchers unveiled the course of COVID-19 infection, the proposition of hypercytokinemia as a pathologic event is met with skepticism. Critics of COVID-19 stated that excess cytokine release was necessary for viral clearance and observed that median IL-6 levels were low in COVID-19 infections compared to other inflammatory conditions such as acute respiratory distress syndrome and bacterial sepsis.[13] In contrast, many studies using prognostic models such as the International Severe Acute Respiratory and Emerging Infections Consortium Coronavirus Clinical Characterization Consortium model stated that elevated IL-6 and C-reactive protein (CRP) levels are best laboratory predictor of respiratory failure and death.[14],[15]

   Well-studied Cytokines in COVID-19 Top

IL-6: A chemokine which is secreted by T-cells and macrophages stimulates immune response. Among patients with COVID-19, overproduction of IL-6 is known to activate coagulation pathways resulting in disruption of procoagulant–anticoagulant homeostasis and induction of disseminated intravascular coagulation.[16] Reports have described hyperactivation of the humoral immune pathway and elevated IL-6 as a critical mediator for respiratory failure, shock, and multiorgan dysfunction in critically ill patients with COVID-19.[17]

D-dimer: Being a product of cross-linked fibrin, D-dimer is considered a sensitive biomarker of venous thromboembolism. Several studies have shown that COVID-19 predisposes patients to thrombosis in blood vessels. Hence, people with COVID-19 are at risk for deep vein thrombosis and possible pulmonary embolism.[18],[19] Increased D-dimer levels may be due to inflammatory responses to viral infections, and/or dysfunction of endothelial cells. Additionally, hypoxia increases both viscosity and the transcription factor-dependent signaling pathway raising patients’ risk of coagulation disorders.[20]

TNF-α: A detailed autopsy result from COVID-19 deaths has demonstrated bilateral diffuse alveolar damage and small fibrous thrombi in pulmonary arterioles. Among the COVID-19 subjects, researchers have highlighted that TNF-α alters the sodium-chloride transport leading to disturbed airway. It also disintegrates the endothelial and epithelial cytoskeleton, hence, a key mediator of pulmonary edema.[21]

Migration inhibitory factor (MIF): Macrophage MIF produced by immune cells upon inflammatory and stress stimulation is involved in defense cell activation, cell growth, apoptosis, tumor angiogenesis, and carbohydrate metabolism.[22] Studies have shown that raised MIF levels increased the duration of patient’s intensive care unit stay up to eight folds.[23]

IL-10: It is known as human cytokine synthesis inhibitory factor and is an anti-inflammatory cytokine. There exists an ambiguity among researchers that early induction of IL-10 might represent a negative feedback mechanism that counterchecks the inflammation caused by proinflammatory mediators. However, as production of IL-10 increases, it might function as proinflammatory agent and contribute aggressively to the tempest.[24],[25]

Numerous other studies have described abnormal levels of IL-2, IL-4, IL-7, IL-12, IL-13, IL-17, macrophage-colony stimulating factor (M-CSF), IFN-γ, hepatocyte growth factor, and other noncytokine markers such as CRP, lactate dehydrogenase, ferritin, and procalcitonin. However, the available data have opened avenues in understanding the pathophysiology of the infection thereby exploring different treatment modalities in effectively managing the disease. Additionally, identifying patients with immune misfiring and selecting an appropriate immunomodulatory therapy will require additional clinical trials.

   Strategies to Manage Storm Top

Nonsteroidal anti-inflammatory drugs (NSAIDs): Paracetamol may be preferred over NSAIDs in COVID-19 management, as there are concerns that NSAIDs upregulate ACE2 levels in the lung, worsening the disease outcome.[26]

The ACE inhibitors or angiotensin receptor blockers: Considering the role of ACE2 receptor in COVID-19 pathogenesis, use of ACE inhibitors or angiotensin receptor blockers gained momentum till researchers hypothesized that patients with cardiac diseases, hypertension, or diabetes are at higher risk for severe COVID-19 infection, as these drugs upregulate ACE-2 receptor expression and their use may aggravate the situation.

Chloroquine and hydrochloroquine: Through the alkalization of endosomes, these drugs prevent endosome–lysosome membrane fusion that leads to membrane viral receptor recycling, viral uncoating, and viral genome release into the cytosol.

   Cell-based Therapies Top

  • It is hypothesized that mesenchymal stem cells (MSCs) could reduce the acute lung injury and inhibit the cell-mediated inflammatory response induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Furthermore, because they lack the ACE2 receptor that SARS-CoV-2 uses for viral entry into cells, MSCs are resistant to infection.[27] MSCs work by three different mechanisms: “Homing” − their ability to migrate toward the lesion site by chemotactic mechanisms, multilineage differentiation capacity, and secretion of bioactive factors, modulating both local and systemic physiological processes. Immunomodulation potential of MSCs resulted in reduced levels of proinflammatory cytokines and elevated levels of IL-10 and vascular endothelial growth factor in patients’ serum. They controlled inflammation and protected the lung endothelial barrier with increased dendritic cells migration to the injured tissue. Additional to MSCs, soluble proteins, free nuclei acids, lipids, and extra cellular vesicles which are released as secretomes into the extracellular matrix are also being included in the management of COVID-19 infections. Their use as conditioned media has shown to have promising regenerative potential.[28]
  • Adoptive natural killer (NK) and chimeric antigen receptor engineered cells are another group of cells for managing patients with COVID-19 and are thought as “living drugs.” The NK cells are cytotoxic lymphocytic cells and play a crucial role in bridging innate and adaptive immune system activity along with inducing viral clearance.[29]
  • Interferons: Both IFN-α and IFN-β have been used in the management of COVID-19 infections, as they induce hundreds of antiviral effectors to achieve a cell-intrinsic state of viral resistance.[29]
  • Monoclonal antibodies: Recombinant human monoclonal antibodies (casirivimab and imdevimab) bind to nonoverlapping epitopes of the spike protein receptor binding domain (RBD) of COVID-19 virus and the combination of these two antibodies blocks the binding of the RBD to the host cell.[30]
  • Convalescent plasma (CP): Obtained by apheresis in survivors of COVID-19 infection in the interest of obtaining antibodies against the virus is considered as an emergency intervention. In addition to neutralizing antibodies, proteins such as anti-inflammatory cytokines, clotting factors, natural antibodies, defensins, pentraxins, and other undefined proteins merit attention of CP.[31]

Vaccine: From the first clinical trial data published in June 2020 using recombinant adenovirus type-5 vectored S to-date, there are over 200 COVID-19 vaccine candidates which are being pursued globally. Using a variety of generic platforms, such as inactivated virus, purified recombinant viral proteins with or without adjuvant, replicating and nonreplicating viral vectored antigens, antigen-encoding DNA or mRNA, the availability of vaccine for all seems promising. However, the lack of clarity in safety and immunogenicity is the prime concern. Some of the hurdles include difficulty in validating, obtaining long-term immunity and inability to calm the cytokine storm. Additionally, the massive financial resources poured into vaccine development also cannot be underrated.[32]

Antibiotics: Despite the paucity of evidence for antibiotic coverage among COVID-19 infected individuals, about 72% reported usage of antibiotics. Confirmed bacterial and fungal respiratory co-infection or a hospital acquired infection mandates an empirical antibiotic regimen. Wide range of drugs such as cephalosporins, quinolones, carbapenems, tigecycline, and linezolid has been used to have more favorable outcomes. However, there have been concerns of sudden cardiac arrest secondary to QT prolongation that is associated with treatment for atypical organisms with the use of macrolides, tetracyclines, and quinolones.[33] Additionally, decision driven by detecting procalcitonin level seems appropriate to differentiate between bacterial and viral infections. Procalcitonin being a hormone of calcitonin is undetectable in healthy states, but it is upregulated by cytokines released in response to bacterial infections. Conversely, procalcitonin production is blocked by IFN-γ, a cytokine released in response to viral infections.[34]

Antivirals: Remdesivir, monophasic nucleotide analog prodrug, metabolizes to an active C-adenosine nucleoside triphosphate analog. It inhibits the viral RNA-dependent, RNA polymerase, thereby interrupting viral replication.[35] Eight clinical trials have reported both beneficial and neutral effects in attaining the clinical end points and a few addressing the adverse events in the form of acute kidney dysfunctions leading to trial closure.[36] However, considering the risk benefit, remdesivir is approved by the Food and Drug Administration in hospitalized adult and pediatric patients.[37]

   Anticytokines Top

  • Tocilizumab: Jointly developed by Osaka University and Chugai, tocilizumab is a humanized monoclonal antibody against the IL-6 receptor. Since experimental models have shown that IL-6 can either suppress or facilitate viral replication, the optimal timing for anti-IL-6 administration is very crucial. Early administration of anti-IL-6 may adversely affect viral clearance and if too lately administrated, the drugs may not be effective.
  • TNF-α inhibitors: Researchers argue that TNF inhibitors neutralize SARS-CoV-2 infection in animal models and rapidly decrease IL-6 and IL-1 concentrations.[38]
  • IL-1Ra: Anakinra, a recombinant IL-1Ra, is known to have a short half-life; no clinical data is available but clinical trials are registered to test its efficacy in COVID-19 infections. Similarly, canakinumab, a monoclonal antibody targeting IL-1β, is also under investigation.[38]

   Adjuvant Therapy Top

To maximize the effectiveness of primary therapy, researchers have discussed lateral therapeutic options and focused on development of potential adjuvants for clinical management of COVID-19. These are summarized in [Table 1].[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49]
Table 1 Lateral therapeutic options and development of potential adjuvants for clinical management of coronavirus disease 2019

Click here to view

   Melatonin Top

When time was not a luxury in the pandemic, researchers proposed many safe molecules which were used to slow or completely eliminate the COVID-19 virus. Melatonin, the chemical of darkness, is one such endogenous substance which is released from the pineal gland, and possesses significant antimicrobial activity. Its role as anti-inflammatory, antiapoptotic, immunomodulatory, and antioxidant molecules has been well studied; however, its antiviral activity has been put to test in the recent times.

During the cytokine storm, adjunctive use of melatonin in reducing the levels of circulating cytokines seems logical. Though limited number of studies are registered to test its use in COVID-19 infection, enormous data substantiating its effect in sepsis, diabetes, and other conditions with high cytokine levels cannot be underrated wherein, the clinical features parallel those of COVID-19.[50]

In any viral infection, excessive oxidative stress and escalated unfolded and misfolded proteins induce autophagy. Melatonin is known to reduce oxidative stress and modulates autophagy pathway. Additionally, melatonin unlocks autophagy blockage, allowing autophagosomes to bind to lysosomes, completing the process of autophagy and decreasing viral replication capacity.[51]

Mediators of inflammation such as prostanoids, leukotrienes, cyclooxygenase, and inducible nitric oxide synthase are known to be suppressed by melatonin.[52] Melatonin being a potent immune regulator controls the innate immune response and promotes the adaptive immune response which can significantly alleviate inflammatory response.

The free radical quenching property of melatonin against the hydroxyl radical, glutathione, and peroxyl radical has been extensively explored. Along with lowering the number of free radicals, melatonin can also interact with nonradical oxidants such as hydrogen peroxide, singlet oxygen, and peroxynitrite. Melatonin is known to bind to copper, iron, and zinc reducing their cytoplasmic pool and availability of these metal ions leads to microbial cell.[53]

Considering the high pharmacologic safety profile, use of melatonin in treatment of infectious diseases, such as COVID-19 seems promising. With the suggestion of researchers, prophylactic use or in combination with drugs such as remidisvir, hydroxychloroquine, lopinavir, and melatonin use can be proposed. Melatonin can be administered at a total dose of 120 to 1000 µg/kg/subject weight and 100 or 400 mg per day as an adjunct.[54]

   Conclusion Top

As quoted by Hippocrates “Natural forces within us are the true healers of disease” and melatonin being an endogenous chemical with a plethora of functions caught the attention of researchers. Repurposing melatonin to avail the benefit of its pharmacologic actions, coupled with its high safety profile to treat COVID-19 if found effective, would be a welcome addition drug to the existing drug cabinet. In the absence of approved antivirals for the treatment of COVID-19, the cornerstone of management has been supportive care, with adjunctive treatments playing a major role but, little evidence exists on the prescribing patterns for these drugs in routine clinical practice.

There is an urgent need to collect data related to the melatonin use as an adjunct or as a prophylactic drug in patients with COVID-19. Analysis of such information will enable us to test the hypothesis that melatonin alleviates abrupt cytokine release and also critically evaluate other beneficial effects.

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Conflicts of interest

There are no conflicts of interest.

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  [Full text]  
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