Table 2.
Various immunomodulatory strategies targeting cytokine storm in COVID-19 patients.
| Strategies or agents | Studies and indications | Safety/drug to drug interactions* | References |
|---|---|---|---|
| Cyclooxygenase (COX) inhibitors | The use of COX inhibitors in COVID-19 has not been evaluated. It should be used on a case-by-case basis. | Should not be used in patients with previous history of stroke, or prior heart bypass surgery (coronary artery bypass graft, or CABG). Cox-2 inhibitors (Celecoxib) have less gastrointestinal side effects than non-steroidal anti-inflammatory drugs (NSAIDS). Similar cardiovascular event risk profiles of Cox-2 and non-selective NSAIDS (ibrufen, diclofenac and naproxen). Cox inhibitors increases risk of cardio-thrombotic events, congestive heart failure. | (83) |
| Corticosteroids | The use of high-dose corticosteroids is not recommended in cases of COVID-19. | Mild to intermediate dose may be considered to reduce inflammation in initial treatment of cytokine storm and in specific cases of COVID-19-induced pneumonia. | (83) |
| Anti-tumor necrosis factor (TNFa) therapy | Anti-TNFa is widely used for several autoimmune diseases. Its use in COVID-19 should be explored. | May be protective against SARS-CoV-2 pneumonia. | (84) |
| Intravenous immunoglobulin (IVIg) therapy | Due to its lack of side effects, IVIg may be beneficial in COVID-19 patients especially in settings of cytokine storm or hyperinflammatory state and septic shock. | Could be explored as an alternative to corticosteroids. Low dose IVIg may require complement activation; whereas, high doses of IVIg may act directly on immune cells (85). | (86) |
| Angiotensin-converting-enzyme inhibitors (ACEIs) or angiotensin-II-receptor-antagonists (ARBs) | The use of ACEI/ARB is associated with lower mortality in COVID-19 in-patients. | ARBs preferable in preventing kidney failure in patients with established (diabetic) nephropathy (87). ACEIs advantageous in prevention of new onset albuminuria ACEIs have relatively higher mortality benefit than ARBs in the setting of prior MI, coronary artery disease or heart failure. ACEIs (as a monotherapy or with a diuretic) have greater benefit in recurrent stroke prevention. ARBs can be considered in patients who do not tolerate ACEIs owing to cough and angioedema. | (88) |
| Peroxisome proliferator-activated receptor (PPAR) agonists | PPAR agonists increase the production of anti-inflammatory cytokines and thus, may be beneficial in COVID-19 patients. PPAR-γ agonists are often used in treatment of type 2 diabetes. | PPAR-γ agonist thiazolidinediones (TZDs), like pioglitazone and rosiglitazone, have anti-inflammatory properties with potential for corrective effects on severe viral pneumonia. Nutritional ligands of PPAR-γ, such as lemongrass, pomegranate, and curcuma may be used in conjunction with PPAR pharmacological agents (89). | (90) |
| 5′ adenosine monophosphate-activated protein kinase (AMPK) activators | AMPK activators such as metformin have direct anti-inflammatory effects. Could have benefit in reducing cytokine storm in COVID-19 infected patients. | AMPK activators has shown to increase survival rates in influenza infected animal models. Combination with pioglitazone could have added survival benefits (91). | (92) |
| Macrolide | The antiviral effects of macrolide may benefit COVID-19 patients. | Macrolide may reduce inflammation in infected patients. | (93) |
| Arbidol | Arbidol is an antiviral that has been shown to prevent COVID-19 infection. | Studies on animal model of influenza has shown benefits in reducing mortality, inflammation and lung lesion formation (94). Arbidol could be explored in targeting cytokine storm. | (95) |
| OX40 (CD134) | There are several limitations in the therapeutic use of OX40. | OX40–immunoglobulin fusion protein treatment has previously demonstrated clinical benefit in influenza animal models by eliminating weight loss and cachexia without preventing virus clearance (96). | (97) |
| Antioxidants | Antioxidants, such as vitamin C, have anti-inflammatory effects when administered intravenously. | Could be used in combination with other anti-inflammatory agents to target cytokine storm. | (98) |
| Suppressor of cytokine signaling (SOCS) | SOCS is involved in regulating antiviral immunity. | Could be protective against severe cytokine storm during severe COVID-19 infection. | (99) |
| Extracorporeal therapy | Extracorporeal therapy is a proposed mechanism to remove cytokines in septic patients | Extracorporeal cytokine removal may have protective effects on vascular integrity and could reverse cytokine storm (100). | (101) |
| Pyrrolidinedithiocarbamate (PDTC) ammonium | Inhibits IκB phosphorylation and thus blocks NF-κB translocation to the nucleus and reduces the expression of downstream cytokines. | PDTC ammonium may have a role in limiting cytokine storm by inhibiting reactive oxygen species (ROS) production (102). | (103) |
| Diacerein | An inhibitor of IL-1B—an acute response cytokine which appears in hypercytokinemia. | Diacerein attenuates inflammation in severe sepsis, and hence improves survival (104). Could be beneficial in reducing sepsis induced insulin resistance as an alternative to insulin therapy in severe sepsis cases where intensive insulin therapy is associated with adverse outcomes. Diacerein could be beneficial in managing diabetes patients infected with SARS-CoV-2. | (105) |
| Tranilast | An anti-allergic drug which inhibits NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) which plays an important role in the pathogenesis of COVID-19. | Tranilast has been shown to attenuate ischemia reperfusion injury by inhibiting inflammatory cytokine production and PPAR expression (106). | (107) |
| Statin | In-silico evidence on efficacy of statins as SARS-CoV-2 Mpro inhibitors | As drugs of choice—Rosuvastatin (with preference for starting a low dose and titrating up) and Fluvastatin should be administered. | (16, 108) |
| Chloroquine/Hydroxychloroquine | Strong anti-inflammatory activity may be of use in targeting cytokine storm. | Not recommended currently by Food and Drug Administration (FDA) and Europeans Medicine Agency (EMA) outside of the hospital setting or a clinical trial due to risk of heart rhythm problems and fatal conditions including congestive heart failure. | (109) |
*
With standard therapy used for SARS-CoV-2 infection: antiviral drugs (remdesivir), antiretroviral drugs (lopinavir/ritonavir), macrolides (mainly azithromycin), anti-malaria (chloroquine and hydroxychloroquine) and anti-rheumatoid (tocilizumab).