The most commonly used drugs for immunomodulatory therapy are corticosteroids, which in COVID-19 patients can suppress the host immune system and delay viral clearance. Through the findings of two recent patient studies, it is now believed that corticosteroid usage is beneficial in severe cases of COVID-19 (particularly in patients with ARDS), not in patients with mild cases of COVID-19. Therefore, corticosteroids are only recommended for patients in critical conditions. 

The decision must still be made carefully even in critical cases of COVID-19 due to their potential negative side effects. There is no available data illustrating the success of corticosteroids in SARS-CoV or MERS. 

Corticosteroids and COVID-19

Chloroquine, and hydroxychloroquine, have become recent treatments for COVID-19, and as of June 2020, chloroquine appears to be effective in the limitation of SARS-CoV-2 reproduction in vitro. A study from February 2020 showed good efficacy from chloroquine phosphate in over 100 Chinese patients. French doctors also identified relatively good efficacy in 20 COVID-19 patients who received hydroxychloroquine.  

The major treatments studied so far include: chloroquine phosphate, hydroxychloroquine sulfate, and carrimycin (all varying in dosage and delivery system). However, more data (particularly safety data) from high-quality clinical trials is still needed. 

Chloroquine and COVID-19

Immunomodulatory agents which directly targets cytokines involved in COVID-19 also have the potential to lower hyperinflammation in severe cases, which is important when elevated levels of IL6 in the blood has proved to be a predictor for fatal outcomes in COVID-19 patients. Tocilizumab, an antibody which blocks IL6 has been recommended for patients with severe or critical illness, extensive lesions in bilateral lungs, and confirmed elevated levels of IL6. A study on 20 patients with severe COVID-19 illustrated reduction in fever and lung lesion opacity and recovery of percentage of peripheral blood lymphocytes after treatment with tocilizumab. 

Tocilizumab and COVID-19

Proposed Doses for COVID-19 Immunomodulatory Therapy 

New treatment strategies in addition to antiviral therapy has potential to significantly improve clinical outcome. One of those new potential treatments is immunomodulatory therapy. Immunomodulatory agents for the reduction of cytokine storms combined with antiviral agents could aid in the treatment process. 

- Corticosteroids
- Chloroquine
- Tocilizumab
- Proposed Doses for COVID-19 Immunomodulatory Therapy 

Hamilton College

COVID-19 cytokine storms refer to the overproduction of pro-inflammatory stimuli (antigens, superantigens, adjuvants, allergens, pro-inflammatory cytokines) and/or the inadequate regulation of inflammation following severe/critical SARS-CoV-2 infection. Current evidence suggests that this chemical overproduction can have dangerous repercussions, with ties to more severe clinical outcomes. 

- Cytokine storms increase the risk of vascular hyper-permeability, acute respiratory distress syndrome (ARDS), multi-organ failure, and consequently, patient mortality 
- Cytokine storm syndromes are disorders that represent various inflammatory etiologies
- Immunomodulatory therapy for the reduction of cytokine storms could aid in the treatment process


 Cytokine Storms in COVID-19 

Zhao, M. (2020). Cytokine storm and immunomodulatory therapy in COVID-19: role of chloroquine and anti-IL-6 monoclonal antibodies. International journal of antimicrobial agents. doi: 10.1016/j.ijantimicag.2020.105982 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161506/

Cytokine Storm and Immunomodulatory therapy in COVID-19: Role of Chloroquine and Anti-IL-6 Monoclonal Antibodies

The inflammatory mediators associated with the cytokine storm in COVID-19 leads the increased permeability of the lungs.  This allows for SARS-CoV-2 and the inflammatory mediators to enter the bloodstream and migrate from the lungs to the intestine.  SARS-CoV-2 can decrease ACE2 expression and alter the gut microbiota which can alter normal immune responses.  Additionally, the inflammatory mediators can weaken the integrity of the gut, allowing for microbes and their metabolites to leak out.  This can cause microbial dysbriosis which may contribute to why diarrhea is a common symptom of COVID-19.  

Gut-Lung Axis of COVID-19

Cytokines are inflammatory proteins that play a crucial role in an inflammatory response. But a response that is too strong is characterised as a "cytokine storm", which can also be harmful for the patient. It was previously thought that a cytokine storm was responsible for a severe immune response to COVID-19, but researchers compared several cytokine levels of patients with COVID-19 to patients with other diseases and found no increase in cytokine concentration. This indicates to the fact that severe COVID-19 immune responses are not liked to a cytokine storm. 
The cytokines that were tested were TNF-alpha, IL-6 and IL-8. It was found that the concentration of these cytokines in COVID-19 patients was significantly less elevated.

COVID-19 Cytokine Storm may not exist

The increased production of cytokines is a result of many mechnisms, for example:

- CD14+CD16+ monocytes are triggered by activated pathogenic T helper cells to release IL-6 (a major component of the development of the cytokine storm)
- An increase in a subpopulation of CD14+IL-1β+ monocytes may increase IL-1β levels
- Th17 cells that produce IL-17 go on to recruit more monocytes/macrophages and neutrophils, which then triggers other cytokine cascades 
- Monocytes/macrophages may produce additional inflammatory cytokines
- Eosinophils can may release a large amount of cytokines, including IL-6 

Potential Mechanisms of SARS-CoV-2-induced Cytokine Storm 

Obesity and the COVID-19 cytokine storm reinforce one another in a bidirectional relationship. In one direction, obesity is a risk factor for cytokine storm onset: obese patients carry elevated baseline levels of pro-inflammatory cytokines, increasing their risk of hypercytokinemia after SARS-CoV-2 infection. In the other direction, an active cytokine storm is a risk factor for greater morbidity and mortality in obese patients, because inflamed adipose tissue and pro-inflammatory adipokines amplify the immune over-response and impair pulmonary function.

Cytokine Storm and Obesity Relationship in COVID-19

- The target location of COVID-19 is the lung 
- The etiology attribute is "damp and toxin plague"
- The QPD concoction has 16 herbs that are lung-specific, making it a great treatment for respiratory illnesses like COVID-19. Studies have shown that it has the ability to reduce the cytokine storm triggered by SARS-CoV-2 infection.
- The aim of TCM is the holistic balance of Ying and Yang in the body., which strengthenes the body to fight infection 

Strategies of Traditional Chinese Medicine

Cytokine storms in COVID-19 can lead to severe downstream inflammatory complications and hyperinflammatory syndromes. These conditions include acute respiratory distress syndrome (ARDS), multi-organ failure, vascular hyperpermeability, cytokine release syndrome, secondary haemophagocytic lymphohistiocytosis (sHLH), and multisystem inflammatory syndrome in children (MIS-C).

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