Cytokine Storm and COVID19
- fatema
- Jun 30, 2020
- 15 min read
What are cytokines?
Cytokines consists of a wide variety of small proteins that are synthesized and secreted by cells to generate signals and communicate with each other[1]. By producing cytokine signals our immune system regulates host responses to infection, trauma, or injury. That being said, cytokines are the modulators of immune response and inflammation.
Major types and functions of cytokines[1]
Interferons (IFNs, e.g., IFNγ)
-Critical regulator of innate and adaptive immunity
-Anti-viral activity
-Anti-proliferative effects
Interleukins (ILs, e.g., IL1, IL6, IL18)
-Promote leukocytes growth and differentiation
-Many of these cytokines are pro-inflammatory
Chemokines (4 types: CXC, CC, C, & CX3C, e.g., CXCR3, CXCL10, CCL2)
-Regulate immune cells migration via chemokine signals
- Many of them show pro-inflammatory effects
-Release of pro-inflammatory chemokines attracts immune cells to migrate to the infection site
Tumor necrosis factor (TNFs, e.g., TNFα)
-Proinflammatory
-Excessive production of TNF causes chronic inflammation & several autoimmune diseases
-Activates cytotoxic T cells
-Involved with systemic inflammation
-Plays central role in acute viral infection (causes rapid onset of disease), such as influenza, Ebola, dengue, and SARS-COV-2 infection as well
Colony-stimulating factors (CSFs, e.g., GM-CSF, M-CSF, G-CSF)
-Stimulate hematopoietic progenitor cells to grow and become specific immune cell types
Pro-inflammatory versus Anti-inflammatory cytokines
Pro-inflammatory cytokine makes disease worse, whereas anti-inflammatory cytokines promote healing via reducing inflammation. The severity of an inflammatory response depends on the balance between pro-inflammatory cytokines (such as TNFa, IL1B) and their inhibitors (or soluble receptors, such as TNFR1, TNFR2, IL-1RA) or anti-inflammatory cytokines (such as IL10), as it is critical to inhibit overactivation of immune system[1]. Disruption in any of the regulatory mechanisms that keeps the balance between pro- and anti-inflammatory cytokines may result in cytokine storm.
Cytokine storm
According to National Cancer Institute, cytokine storm is defined as “A severe immune reaction in which the body (overactive immune cells) releases too many cytokines into the blood too quickly”. Cytokine storm may result from a variety of infectious, non-infectious, and even autoimmune diseases.
Inflammation that results in cytokine storm starts locally at the infection site and then spreads throughout the body via systemic circulation. Upon infection, the acute inflammatory responses cause local rise in temperature, redness, swelling, and pain that facilitates host defense against pathogens. The repair process begins soon after the onset of inflammation, which most often completely repair and restore tissue/organ function. However, in case of severe and rapid inflammation or if the primary disease-causing agent triggers inflammation that damages tissues, the healing proceeds with progressive collagen deposition (fibrotic scar), leading to persistent organ dysfunction[1].
Cytokine storm may arise from a severe infection in urinary tract, central nervous systems, gastrointestinal tract, skin, joints, and other areas. However, severe lung injury is one of the best examples of cytokine storm, in which local inflammation spreads through the systemic circulation, resulting in sepsis and multi-organ failure. Lung injury induced by pathogens may progress into Acute Lung Injury (ALI) or its very severe form, Acute Respiratory Distress Syndrome (ARDS), as seen in patients with influenza, SARS-COV, and SARS-COV-2 infections as well[1]. The characteristic feature of ALI is acute mononuclear/neutrophilic response with subsequent chronic fibroproliferative effects, i.e., progressive deposition of collagen fiber in the alveolar space of lung[1]. Fibrin and subsequently excess collagen deposition compromises lung elasticity, and once this event takes place there is no return.
In patients with pulmonary or non-pulmonary septic shock shows time-dependent changes in blood cytokine profiles. TNFa, IL1B, as well as chemotactic cytokines, IL8 and MCP1 shows early onset after infection, within few minutes to hours which is followed by sustained production of IL6 (TNFa and IL1B may stimulate IL6 production)[1]. The systemic increase of IL10, an anti-inflammatory cytokine appears at late as the body tries to defense against systemic acute inflammatory response. This anti-inflammatory response is named ‘immunoparalysis’ since it suppresses the monocyte/neutrophil function in the systemic circulation. Constant immunosuppression is also a problem. It is believed that, survival of initial cytokine storm may die later if not successfully recovered from immunoparalysis[1].
Systemic hyper-inflammation has been observed in severe COVID19 patients with pneumonia or ARDS. When phagocytes and lymphocytes are overactive and attacks the body instead of just viruses, a phenomenon mimicking severe sepsis called Secondary Haemophagocytic lymphohistiocytosis (sHLH) or alternatively, macrophage activation syndrome (MAS) develops [34]. In MAS/sHLH syndrome, overactive immune cells (presumably macrophages and activated T cells[2]) releases too many cytokines in blood very rapidly, results in cytokine storm, tissue damage, and ultimately multi-organ failure. Highly increased ferritin and CRP (IL6 stimulates CRP expression) are observed in many COVID19 severe patients with pneonomia and is the key diagnostic features of MAS/sHLH, suggesting that a subgroup of COVID19 phnonomia patients develop MAS/sHLH[3].
Cytokines associated with COVID19 severity
Several studies found the exaggerated levels of wide variety of cytokines in the blood plasma from COVID19 severe patients[4]. This range from antiviral cytokines, IFNs to pro-inflammatory cytokines, TNFa, IL6, IL12 (p70), IL-13, and IL-15. Moreover, in patients with severe COVID19 pneumonia fifteen cytokines (IFNg, IFNa2, IL1RA, IL2, IL4, IL7, IL10, IL12, IL17, IP10, M-CSF, and G-CSF) were linearly correlated with lung injury and is thought to be potential biomarkers for disease outcomes[4]. Some of these cytokines, such as IL2, IL7, G-CSF, IP10, MCP1, and TNFa, MIP-1a (CCL3), overlapped with the cytokine profile found in Secondary Haemophagocytic lymphohistiocytosis (sHLH) syndrome[5]. Severe COVID19 pneumonia with ARDS and/or MAS showed highly elevated levels of TNFa, IL1B, IL6, and IFNg than the mild cases of COVID19[3].
SARS-COV-2: How it infects human and causes COVID19
SARS-COV-2 is a single-stranded RNA virus. Its physical appearance is spherical, with mushroom like spike (S) proteins protruding from their exterior, giving them the appearance of crown shaped, hence the name corona virus. The virus uses these spike or S proteins to gain entry into the cells by binding mainly ACE2 receptor on cell surfaces. Although, it shares genetic similarities with 2002-2003 SARS-COV virus (SARS-COV-1), the biophysical and structural analysis revealed that, the spike proteins on SARS-COV-2 binds ACE2 receptor at least ten times more tightly compared to the spikes on SARS-COV-1 virus[6]. Virtually all organs in our body can express ACE2 at mRNA levels, but the functional ACE2 proteins (or cell surface ACE2 receptors) are abundantly found in epithelial cells of lung alveoli, and enterocytes of small intestines[7]. ACE2 surface proteins were also present in endothelial cells of artery and vein, as well as smooth muscle cells in artery[7]. This explains why the lung and blood vessels are primary route of entry and pathogenesis by SARS-COV-2.
For all coronaviruses (such as SARS-COV-1, SARS-COV-2, MERS-COV, and less lethal HKU1, NL63, OC43, and 229E), the S protein is cleaved by host enzymes, called proteases before they gain entry into the cells, because this cleavage allows protein activation for membrane fusion through conformational changes that are irreversible[8]. That is, receptor-binding and proteolytic cleavage of S protein are coordinated response that ensures coronavirus entry into the host cells. Unexpectedly, the researchers discovered a polybasic furin cleavage site (PRRA sequence) at the S1/S2 boundary of S protein on SARS-COV-2, which is cleaved during viral entry. This makes SARS-COV-2 unique among all coronaviruses. This unique feature of SARS-COV-2 is presumed to be responsible for its high transmissibility or nature of pathogenicity[8].
Thirteen mutations on spike have been identified until the end of April, of those D614G (mutation of an aspartate (D) at position 614 found in Wuhan reference strain to a glycine (G)) mutation is of serious concern. It was the dominant form of virus in Europe and then spread globally[9]. It was predicted early in the pandemic that this mutation may strengthen SARS-COV-2’s infectivity, transmissibility, and disease severity.
It raises the possibility that if a person gets infected with one strain and made antibody against it, then these antibodies may not provide protection if he/she gets re-infection (if possible) with another strain. It is also a concern if developing a single vaccine can provide protection against multiple stain of SARS-COV-2 and to what extent. Fortunately, D614G mutation seems stable and it is now dominating globally.
Prophylaxis: Prepare your immune system to fight against SARS-COV-2
Vitamin C
Vitamin C is an anti-oxidant that neutralizes free radicals and prevent/reverse cellular damage. Its positive regulatory role on development and maturation of natural killer (NK) cells and T lymphocytes is demonstrated in several studies[10]. It also assists in reducing cytokine storm via inhibiting reactive oxygen species and remodulating cytokine network. Large doses of intravenous vitamin C infusion has shown to be beneficial for moderate to severe COVID19 patients in China[10].
Vitamin D
Basically, all cells in our body has vitamin D receptors. The role of vitamin D is not just limited to bone and mineral health regulation, but many……many more. Vitamin D is a crucial regulator of immune cell function. Separate clinical studies showed inverse correlations between vitamin D intake and/or 25OHD levels (active vitamin D in serum) and certain autoimmune diseases, such as type 1 diabetes, multiple sclerosis, Crohns disease, lupus, rheumatoid arthritis, Graves thyroiditis[11]. It is a potent modulator of T cell responses and boosts innate immunity by inducing the expression of cathelicidin gene, CAMP (Cathelicidin Antimicrobial Peptide)[12]. Cathelicidins are small peptides that destroy pathogens including viral particles. Vitamin D supplementations can reduce the risk of viral infection including COVID19 and associated disease severity[13, 14].
The reason we talk about vitamin D a lot because we only get a tiny amount (10%) of our required vitamin D from natural food sources. Most of it (90%) comes from direct sunlight, however it also depends on our skin color and time of exposure. The darker the skin color, the more time it takes to make vitamin D under sunlight. Many experts believe that, COVID19 associated high mortality rate among black and brown people is at least in a part via vitamin D deficiency.
Zinc
Decrease in blood zinc levels was observed in COVID19 patients. When SARS-VOC-2 enters into the cells, intracellular zinc blocks viral replication by inhibiting RNA-dependent RNA polymerase[15]. However, oral administration of zinc as a prophylaxis is probably not very beneficial, since without any external intervention (such as hydroxychloroquine which works as a zinc ionophore or zinc transporter through which zinc enters into the cells), it is hard to ensure substantial concentrations of zinc inside the cells for inhibiting viral replication[15].
Some others immune boosting vitamins and minerals are: Vitamin E, A, folate/folic acid, iron, and selenium.
Note: Vitamins and minerals are pretty much safe to take when the dose is within the suggested safest limit according to sex. However, if you have any underlying health conditions, for example, beta thalassemia which creates iron overload in your body then taking extra iron is not safe. And high dosage of zinc may cause dizziness. Therefore, it is always best to talk with your health advisor first.
Vaccine against SARS-COV-2
Three promising vaccine candidates have successfully passed phase 1 trial and is either in phase 2 trial or preparing for phase 3 study.
The two candidates that are in phase 2/3 study are: (i) Bacillus Calmette-Guerin (BCG) live-attenuated vaccine, and (ii) AZD1222 (University of Oxford).
The BCG vaccine is already been here for more than 80 years. It is routinely used in many countries as a part of childhood immunization program. This vaccine is documented to protect against disseminated TB and meningitis by helping the immune system to fight against these infections [35]. Research studies also shows its protective effects on respiratory infections and sepsis. BCG vaccine is now being studied in the randomized, controlled, phase 3 trial for SARS-COV-2 immunity.
AZ1222 (previously called ChAdOx1) vaccine is a replication-deficient chimpanzee adenoviral vector expressing SARS-COV-2 spike protein (full -length). In a phase 1 trial with mouse and pigs, a single dose of this vaccine induced both humoral (antigen -specific B cell mediated immunity) and cellular (T cell response) immunity. And a booster dose after 28 days significantly increased antibody responses and SARS-COV-2 antibody titers[16].
mRNA-1273 is another promising candidate by Kaiser Permanente Washington Health Research Institute which is in phase 2 trial for safety, reactogenicity, and immunogenicity. It is an mRNA vaccine encoding for a stable perfusion form of the spike protein on SARS-COV-2. The vaccine is inspired by a research finding that shows, the spike protein endures a massive structural rearrangement when binds and fuses with the cell membrane and the original spike stabilized in its perfusion structure could be potential target for vaccine-induced antibodies to inhibit infection[6].
The vaccine tracker can be found here.
Promising treatments
It has been predicted much earlier that the immunosuppressive drugs for hyperinflammation could be beneficial to treat severe COVID19 patients. However, severe COVID19 patients must be screened for increased levels of ferritin, decreased platelet levels, and a high erythrocyte sedimentation rate to assess if the immunosuppression can reduce mortality[5]. It is worth noting that, timing or disease stage is a critical factor for antiviral or immunosuppression or anti-cytokine therapy. For instance, antiviral drugs that interferes with the viral replication are mostly effective when they applied early phase of the disease. And we need to design studies based on therapeutic versus prophylactic effects of drugs.
Below are some of the drugs that have been studied in reducing COVID19 severity and mortality -
Dexamethasone
As of today, the most exciting drug reported to treat COVID19 patients is dexamethasone. In a well-defined, large-scale clinical trial (n=2104 randomly allocated for dexamethasone; n=4321 usual care) dexamethasone decreased deaths by one-third who were on invasive mechanical ventilation, by one-fifths in patients receiving some kind of oxygen other than mechanical ventilation, but no significant difference in mortality among patients not requiring respiratory support[17]. Dexamethasone is a corticosteroid. The mechanism of its efficacy in critically ill COVID19 patients is not yet revealed, however it can specifically inhibit TNFa synthesis[18].
Tocilizumab
Tocilizumab is a recombinant humanized monoclonal antibody. It is an immunosuppressive drug that is routinely used to treat rheumatoid arthritis. In 2017, FDA approved tocilizumab to treat cytokine release syndrome. Tocilizumab can specifically bind both membrane-bound and soluble IL6 receptor, thus inhibits IL6 ligation on target cells and consequently IL6 mediated signal transduction and disease progression[19]. It also showed promising results to reduce complications with severe COVID19 pneumonia. In this retrospective cohort study the researchers observed that, intravenous or subcutaneous administration of Tocilizumab reduced the risk of disease severity or deaths associated with COVID19 pneumonia[20]. Another study led by Xu et al[19] also found the benefits of tocilizumab administration on severe or critically ill COVID19 patients who needed oxygen. The lymphocytes count in peripheral blood and C-reactive protein returned to their normal level, the ground glass lung opacities completely absorbed, and all patients were discharged on average of ~15 days of tocilizumab administration. However, this study only comprised of 21 patients with a range of 25-88 year, and average age 56.8±16.5 year.
Anakinra
By blocking IL1, Anakinra is believed to suppress hyperinflammation and provide therapeutic effects in severely ill COVID19 patients with worsening respiratory function. A retrospective cohort analysis demonstrated its effectiveness on reducing the need for invasive mechanical ventilation and mortality in severely ill COVID19 patients[21].
Remdesivir
Remdesivir is an antiviral drug, originally developed to fight Ebola by Gilead Sciences. It inhibits viral replication by inhibiting RNA polymerase activity. In a phase 3 trial by Gilead sciences, remdesivir administration in severely ill COVID19 patients with reduced oxygen levels or pneumonia (did not require mechanical ventilation during study entry) were able to discharge more than half patients from hospital by day 14 of treatment [36]. However, the study also found that, the treatment with remdesivir was more effective when started within 10 days of symptoms outbreak than after 10 days of symptoms[36].
Statins
Statins are common cholesterol-lowering drugs for high risk cardiovascular patients. Coronaviruses induce inflammatory responses in host cells via Toll-like receptor (TLR)-MyD88-NF-kB pathway activation. Statins inhibit this pathway, and thus, inflammation. This makes it promising to suppress hyperinflammation in COVID19[22].
After initial entry via cell surface receptor ACE2, SARS-COV-2 downregulates ACE2 expression, results in angiotensin II accumulation and organ injury. Whereas statins are known to up-regulate ACE2 receptor through epigenetic modifications[23].
However, statins may show myotoxicity (toxic to muscle that causes muscle death) in certain health conditions or age group. Initiating statins may increase the risk of developing myopathies and acute kidney injury in COIVD19 patients[24].
Hydroxychloroquine
Hydroxychloroquine has also anti-viral and anti-inflammatory properties. It was believed that, when hydroxychloroquine gets into the cells it can elevate the endosomal pH of the cells and thereby, inhibiting virus entry via endosomal pathway. However, most research data or clinical studies shows it is not effective to reduce the mortality rate of hospitalized COVID19 patients. It seems that, the proposed belief does not work in human with COVID19. However, hydroxychloroquine may still play a role when administered with zinc.
Zinc inhibits SARS-COV-2 mRNA replication via inhibiting RNA-dependent RNA polymerase in the cell (host) cytoplasm, whereas hydroxychloroquine is a zinc ionophore, meaning that, it creates a channel in the cell membrane so that zinc can enter into the cells with sufficient concentrations to combat viral replication. That being said, hydroxychloroquine alone is probably not effective when you have zinc deficiency in your body. A retrospective study found that, instead of hydroxychloroquine and azithromycin alone, addition of zinc sulfate with hydroxychloroquine and azithromycin was significantly associated with the reduction in mortality among COVID19 patients who did not require ICU care, suggesting this therapeutic may inhibit disease progression[15].
Moreover, the administration of hydroxychloroquine with or without zinc was started late, in other words when the patients are already hospitalized with viral infection. If the purpose of a drug is to inhibit viral entry into the cells or replication, then the treatment should start possibly as early as the virus gains entry into the body and before they initiate replication and widespread infection. A large retrospective study with 3,119 COVID19 patients reported that, early diagnosis and treatment with hydroxychloroquine+Azithromycin significantly improved clinical outcomes and decreased the need for ICU transfer or death[25].
Azithromycin
Azithromycin is an antibiotic. An antibiotic cannot protect against viral infection but does protect against secondary bacterial infection. Although, two different in vitro studies evidenced that, azithromycin has anti-inflammatory and anti-viral effects towards single-stranded RNA viruses like zika, and rhinoviruses[26, 27]. Yet, in a retrospective study, azithromycin alone or together with hydroxychloroquine failed to show any significant effect on in-hospital COVID19 patient mortality[28].
Doxycycline (Tetracycline family)
Doxycycline is an antibiotic which is widely used in dermatology to treat acne. But it also shows anti-inflammatory response against IL6 which makes it promising in reducing COVID19 severity associated with cytokine storm[29]. In an in vitro study, doxycycline at both low (20-40mg/day) and high (100 or 200mg/day) doses showed inhibitory effects on metalloproteinases (enzymes that destruct tissue matrices) and anti-inflammatory effects on TNFa, IL6, and IL8[30]. In a porcine model, prophylactic use of chemically modified tetracycline prevented the development of sepsis-induced ARDS[31].
Moreover, tetracycline is a zinc chelator. It is assumed that, chelated zinc can easily pass through the cell membrane, thereby producing high intracellular concentration of zinc, tetracycline can inhibit SARS-COV-2 infection. A small study with 116 patients, Ivermectin-Doxycycline administration was more effective to gain symptomatic recovery and negative PCR test results compared to Hydroxychloroquine-Azithromycin in mild to moderate COVID19 patients[32]. In another study, Doxycycline-Hydroxychloroquine combination treatment reduced clinical severity and mortality among high-risks patients in care facilities (n=54), who received this combination therapy during the onset of their symptoms and either tested positive or presumed to have COVD19[33].
Note: Some of the study cited here are taken from pre-print and not peer-reviewed.
References
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