Sunday, June 21, 2020

Ch 6. Candidate treatments - immunity to coronaviruses in context of COVID-19

What medications are candidates for COVID-19 treatment?
  1. Medicines the attack the virus, such as remdesivir.
  2. Medicines that boost an APPROPRIATE immune response.
  3. Medicines that calm down an INAPPROPRIATE immune response, and
  4. Medicines that can do both 1 and 3 such as hydroxychloroquine (HCQ).



COVID-19 virus, immune response and medication options


1. Medicines the attack the virus
REMDESIVIR

Why is Remdesivir a candidate to treat COVID-19?
This medicine has shown anti-virus activity. It binds and blocks an enzyme needed for the virus to make more copies of itself (Chapter 1). In experiments, animals treated with remdesivir had lower lung virus levels. They also had less lung damage than those who did not receive it.
Others like favipiravir are also being tried out.

2. Medicine that boost an APPROPRIATE immune response.
CONVALESCENT PLASMA

What is convalescent plasma?
When a person has recovered from COVID-19 infection, their blood has antivirus antibodies (Chapter 3). Plasma is part of blood that is rich in antibodies. Purifying plasma of such person provides COVID fighting antibodies.

How could convalescent plasma help?
Antibodies to the virus interfere with virus in several ways. Antibodies can bind to a virus particle. They can block a virus from entering new healthy cells. They can also activate immune cells to kill virus containing cells.

3. Medicines that calm down an INAPPROPRIATE immune response
MEDICINES TO TREAT CYTOKINE STORM (chapter 5)

How could medicines that calm down an INAPPROPRIATE immune response help?
A cytokine storm is an excessive immune response that can damage organs (Chapter 5). Medicines to calm an overactive immune system are helpful. Dexamethasone (a corticosteroid, also known as steroid) acts in this manner. Other medicines (tocilizumab, tofacitinib, ruxolitinib) act to block effects of specific cytokines involved in cytokine storm. Azithromycin a common antibiotic also has immune regulating properties.

4. Medicines that can do both 1 and 3 
HYDROXYCHLOROQUIN (HCQ).

Why is HCQ a candidate to treat COVID-19?
HCQ interferes with virus sticking to its receptor on cell (ACE2). It interferes with blending of virus with membranes of lung cells. These actions reduce entry of virus into cells. It can also block virus leaving the cell (Chapter 1). Finally, HCQ has effects on immune system, which may be beneficial in a cytokine storm (Chapter 5).

How does HCQ affect immune function?
Hydroxychloroquine (HCQ) can pass into our cells with ease. HCQ accumulates inside parts of the cell called lysosome. In immune cells, lysosome deals with processing and secretion of proteins. By increasing in the lysosome, HCQ interferes with its function in immune cell. HCQ can also block proteins recognizing "danger signals". This reduces the activation of early immune cells (Chapter 3). This is the reason patients with certain autoimmune diseases like SLE (lupus) take HCQ. It is the reason for treating joint inflammation in rheumatoid arthritis.

Why is HCQ used in prevention or treatment of malaria?
The same principle of lysosome interference works malaria parasite. In the lysosome of malaria parasite HCQ interferes with digestion of blood proteins. Thus, it is effective anti-malarial.

The medications listed above are all under trials to see which of these actually makes an impact on outcome of COVID-19 infection.


Reference
COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at https://www.covid19treatmentguidelines.nih.gov/. Accessed [6-21-2020].

Friday, June 19, 2020

Ch 5. A storm is coming - immunity to coronaviruses in context of COVID-19

What will this section talk about?
Cytokine storm, a hyper-immune reaction that can cause damage.

Readability grade 7
Reading time approximately 4:25 minutes

In the previous sections we have seen two possible outcomes. One, seen in majority of cases, is an appropriate immune response which eliminates the virus (Chapter 4). The other, if there is no or poor immune response to virus infection, virus overwhelms quickly causing death (Chapter 2). There is a third possible outcome which has gotten much attention and can also be problematic. This is an intense immune response to the virus called "cytokine storm", and damages organs. These outcomes are represented in figure below
Outcomes depending on immune response to virus infection

What other conditions can cytokine storm happen in?
The cytokine storm is an excessive and uncontrolled immune response. The abnormal immune response damages the health of the host and can lead to death. Besides COVID-19, it is also seen in other medical conditions. These other conditions can be other infections or non-infectious. Reports suggest that even some medications can be cause of cytokine storm. At the heart of the “cytokine storm”, are powerful chemicals called cytokines.

What do cytokines do?
The cells of immune system make cytokines for help with immune response. For example, an early immune cell will communicate with helper cell (Chapter 3) by cytokines. This signal may say to helper cell that infection is bacterial. The helper cells then, through different cytokines inform others (B-cells) to make antibodies. Thus, in the simplest of terms, cytokines are language, a communication between immune cells. Every unique immune cell type has its ability to signal and relaying it forward. A cytokine "storm" then is an excessive chaotic communication. This leads to hyper-activation and damage from this uncontrolled immune activity.

Are there different types of cytokines?
There are 5 major types of cytokines based on their function.
1. Some regulate early immune response, have anti-virus properties. (Interferons, discussed in Chapter 1)
2. Some promote inflammation. (Interleukins)
3. Some help direct movement of immune cells (Chemokines).
4. Some help different types of immune cells grow and survive (stimulating factors).
5. Some cause direct damage to diseased cells. A virus infected cell or cancer cells are examples. (tumor necrosis factor).

How does a cytokine storm start?
The start of a cytokine storm is local inflammation spilling over into the rest of the body. This happens by spreading of the immune cells and cytokines through blood. Many are familiar with the symptoms of local inflammation. For example, a local infection such an abscess or boil causes the affected part feels 1. Warm, there is 2. Redness, 3. Pain, 4. Swelling, and 5. Loss or reduced function. All 5 effects are results of immune system trying to remove the threat of local infection

How does a cytokine storm damage tissue?
In a rapid infection or an overstimulated immune system, the effects occur all over the body. Factors responsible for local symptoms spill over into other organs via blood. The lung and kidneys due to their high blood flows are at high risk from damage. Sepsis, a condition of excessive immune response to blood stream infection, is similar. In COVID-19, the lung gets affected three times. First, from infection of the virus in lung cells. Second, from immune response to kill the virus infected lung cells. Third, if cytokine storm occurs, immune damage to lung. This may be a basis for the severe and sudden cause of respiratory failure in COVID-19.

How common is a cytokine storm?
Cytokine storm is a less common outcome even in COVID-19 infection. Not every one will end up with a cytokine storm outcome. Evidence suggests genetic factors could increase or decrease the risk developing cytokine storm. These genetic differences are in genes responsible for “danger signal” detection (Chapter 1 and Chapter 3) , or cytokine production.

How can a cytokine storm be treated?
At present most treatment is symptom based. The goal of treatment for cytokine storm is to support vital organs like circulation (heart pump machine), respiratory (ventilators), kidneys (dialysis) etc until body recovers. Some medications like dexamethasone are corticosteroids (commonly known as steroids) and have shown benefit by calming down inflammation from over active immune system. Other medications to block cytokines are also available but their benefit is not clear.

Previous section: Ch 4. A favorable outcome - immunity to coronaviruses in context of COVID-19
Next Section: Ch 6. Candidate treatments for COVID-19 infection
List of all chapters 

Reference
Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. Into the eye of the cytokine storm. Microbiol. Mol. Biol. Rev.. 2012 Mar 1;76(1):16-32.

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