Covid-19, Immunology

Targeting the cytokine storm: An Immunologic perspective to address the role of Hydroxychloroquine in COVID-19 treatment

Student contributors: Megha Dutta, Shatarupa Biswas , Sayandip Jana

When we hear the word “trending” it reminds us of some form of new entertainment, fashion, incidence, or habit. But in the current scenario, the prevailing trend is to divert all aspects of our life towards the only seemingly persistent difficulty of our life and that is the pandemic of COVID-19 caused by the novel coronavirus, officially known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease has been jeopardizing human civilization since December 2019 to date.

The immune system in COVID-19 patients

In all afflicted parts of the world, the apparent mild cases of COVID-19 rapidly transmute into severe cases with pulmonary involvements. Patients infected with COVID-19 are reported to have elevated amounts of proinflammatory cytokines in serum (e.g., IL1B, IFNγ, IP10, IL-1Ra, IL-2Ra, IL-6, IL-10, IL-18, HGF, MCP-3, MIG, M-CSF, G-CSF, MIG-1a and MCP1), that probably leads to activated T-helper-1 (TH1) cell responses. As a result of this cytokine profile similar to SARS and MERS-CoV, critically ill patients with COVID-19 suffer from pulmonary inflammation and substantial lung damage. Interstitial mononuclear inflammatory infiltrates in the lungs, dominated by lymphocytes together with increased concentration of IL-1Ra, IL-2Ra, MCP-3, and IL-6 in serum are also reported to be associated with the COVID-19 disease severity and prognosis. Over-activation of T cells accounts for the severe immune injury characteristic of the disease. Moreover, patients requiring respiratory support are observed to have increased concentrations of GCSF, IP10, MCP1, MIP1A, and TNFα than less severe patients, suggesting that the disease severity could be associated with a cytokine storm.

What is a cytokine storm?

The cytokines are a group of low molecular weight secreted proteins/glycoproteins that mediate the complex cellular interactions involving cells of immune, inflammatory, and hematopoietic systems. A cytokine storm is an overproduction of immune cells and their activating compounds cytokines—namely, GCSF, IFNϒ-induced protein 10, MCP1, MIP1α, and TNFα, which is often associated with an outpouring of activated immune cells into the lungs. The subsequent lung inflammation and fluid accumulation can progress to respiratory distress and can be worsened by ancillary bacterial pneumonia. Also, the surge in immune molecules can contribute to fatal multi-organ failure. As a result, the mortality rate is increased.

Treatment – Is there any?

Despite an untiring attempt of the scientists and clinicians, till now this situation no proper treatment measures are available to confront this state of “public health emergency”. Several antiviral drugs like remdesivir, favipiravir, ivermectin, and antiparasitic drug like the chloroquine (CQ) and its derivative hydroxychloroquine(HCQ) with/without Azithromycin have been tested. Among them, CQ and HCQ in combination with azithromycin have shown some promising effects.

Mode of action of CQ and HCQ

Chloroquine is well-known for its use in the treatment of malaria and amoebiasis. Hydroxychloroquine (HCQ) sulfate, a derivative of CQ with an additional hydroxyl group, was demonstrated to have less toxicity than the parent compound. HCQ is still widely used for the management of autoimmune diseases like systemic lupus erythematosus and rheumatoid arthritis. Being a weak base and immune system modulator, CQ, and HCQ are potential candidates of therapeutic activity against COVID19with following mode of actions:

  • CQ increases endosomal pH and interferes with the glycosylation of the cellular receptor of SARS-CoV. CQ also inhibits the enzyme quinone reductase that is involved in sialic acid biosynthesis. These attributes confer this drug with a wide-spectrum antiviral activity.
  • CQ alters the pH of lysosome and inhibits cathepsin that results in the formation of autophagosome where SARS-CoV 2 spike protein is cleaved off.
  • CQ inhibits MAP-kinase and alters virion assembly, budding, and interfering with proteolytic action of the M protein(membrane protein).
  • CQ can also bind the angiotensin-converting enzyme 2(ACE2) receptor glycosylation thus prevents SARS-CoV-2 attachment to the target cell.

Proposed Immunological Aspects of HCQ treatment of COVID-19:

There is an uncontrolled cytokine release as COVID-19 symptoms transform into acute respiratory distress syndrome (ARDS). HCQ inhibits the cytokine storm of proinflammatory factors by suppressing T cell activation. Moreover, since acidification is essential for maturation and function of the endosome, and hence membrane fusion, it is assumed that HCQ therapy might suppress endosome maturation at intermediate stages of endocytosis, failing further transport of virions to the eventual releasing site. Therefore, chemoprophylaxis with CQ or HCQ can prevent COVID-19 associated pneumonia and thus block the transmission of disease by decreasing the number of the asymptomatic carrier by inhibiting viral transmission.

Cautions and contraindication with CQand HCQ:

  • Use of both the drugs need some precaution to be undertaken that include frequent monitoring of hematological parameter(RBC, WBC, platelet count), serum electrolyte, blood glucose, hepatic as well as renal function.
  • Before starting the therapy with this drug routine electrocardiography is required.
  • All doctors must know contraindication before they prescribed these drugs like hypersensitivity, epilepsy, retinopathy, Glucose-6-phosphate dehydrogenase (G6PD) deficiency, recent myocardial infarction.
  • HCQ is less toxic than CQ, but prolonged usage or overdose can cause poisoning.

Conclusions:

Evidence of effectivity of CQ and HCQ in COVID-19 treatment is limited based on in vitro experiments and only two small human trials. A recent report also claims no effect of HCQ in reducing the risk of mechanical ventilation in patients with COVID-19, although they could not infer about asymptomatic and mildly symptomatic patients. Although according to the theoretical concept of immunology, HCQ is a promising drug to delimit the disease spread from both asymptomatic and symptomatic patients; more experimental evidence in a larger cohort of the patient population is needed to confirm the effectivity of the drug for COVID-19 treatment in practicality.

 

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