Showing posts with label Cytokine storm. Show all posts
Showing posts with label Cytokine storm. Show all posts

Thursday, 19 March 2020

The CDC Suggests People with Severe Autism are at Elevated Risk from Covid-19 – Time to ACE it?

Elvin Jail in Iran, a hotbed for Covid-19 transmission. Iran has released 70,000 prisoners on furlough, including some foreign political prisoners

I was a little surprised to hear that people with neurodevelopmental disabilities are on the US Center for Disease Control (CDC) list of those at risk from the current Corona virus (Covid-19).  I can see no biological reason for this, but I can see the elevated risks for anyone living in an institution rather than at home, rather like cruise ships and prisons not being safe places to be living right now.

I did check that the CDC have such a list and indeed they do:

Appendix A: Underlying medical conditions that may increase the risk of serious COVID-19 for individuals of any age.

• Blood disorders (e.g., sickle cell disease or on blood thinners)
• Chronic kidney disease as defined by your doctor. Patient has been told to avoid or reduce the dose of medications because kidney disease, or is under treatment for kidney disease, including receiving dialysis
• Chronic liver disease as defined by your doctor. (e.g., cirrhosis, chronic hepatitis) Patient has been told to avoid or reduce the dose of medications because liver disease or is under treatment for liver disease.
• Compromised immune system (immunosuppression) (e.g., seeing a doctor for cancer and treatment such as chemotherapy or radiation, received an organ or bone marrow transplant, taking high doses of corticosteroids or other immunosuppressant medications, HIV or AIDS)
• Current or recent pregnancy in the last two weeks
• Endocrine disorders (e.g., diabetes mellitus)
• Metabolic disorders (such as inherited metabolic disorders and mitochondrial disorders)
• Heart disease (such as congenital heart disease, congestive heart failure and coronary artery disease)
• Lung disease including asthma or chronic obstructive pulmonary disease (chronic bronchitis or emphysema) or other chronic conditions associated with impaired lung function or that require home oxygen
• Neurological and neurologic and neurodevelopment conditions [including disorders of the brain, spinal cord, peripheral nerve, and muscle such as cerebral palsy, epilepsy (seizure disorders), stroke, intellectual disability, moderate to severe developmental delay, muscular dystrophy, or spinal cord injury].

Treating Covid-19

There are well established strategies in place to treat flu pandemics, but Corona virus is different, although there are similarities.

There is already a great deal of research published, thanks to very fast working Chinese researchers.

In simple terms there are two strategies:-
1.     Inhibit the spread of the virus
2.     Halt the cytokine storm that triggers pneumonia and respiratory failure, should the disease progresses that far

If you fail in these two steps you are left with the same situation as occurred in the Spanish flu epidemic, where you treating what has become a bacterial infection in your lungs and hoping for the best. Nowadays we have antibiotics and a small number of ventilators.

Fortunately, initial studies have already been completed and show positive results in both (1) and (2) above.

Some of the drugs used to inhibit the spread of the virus are cheap generics, while one is a Japanese drug originally developed to treat the flu.

The last time the world was worried about a pandemic people stocked up with an antiviral drug called Tamiflu.  Tamiflu does not work for Coronavirus.

What does work are some old drugs originally used to treat malaria that include:-

1.     Hydroxychloroquine (HCQ), sold under the brand name Plaquenil
2.     Chloroquine, a 70 year-old drug sold under names including Resochin

In France Sanofi is offering to donate millions of doses of Plaquenil to the Government and in the US Bayer has offered to donate Resochin. 

It appears that Plaquenil works better and has less side effects.

In Japan they have a drug developed to treat flu called Favipiravir (also known as Avigan).  In trials it has the same effect as the old malaria drugs, it shortens the duration of the disease by about half and so reduces severity.

In all cases the drugs that target the replication of the virus need to be taken early on in the disease progression, to give any benefit.  This makes perfect sense.

What kills people in Covid-19 is the same thing as in the Spanish flu of 1918, it is a cytokine storm when the body’s immune system over-reacts and attacks your lungs.
If the disease progresses to this point you have to look at therapies to treat cytokine storms associated with severe influenza.

Here we have at least two interesting approaches:

1.     IL-6R antibodies (Roche’s Actemra)   
2.     S1P1 receptor agonist like Fingolimod (Gilenya)

Actemra is already in trials to treat Covid-19, but is injected.

Gilenya is an immunomodulating drug, mostly used for treating multiple sclerosis, taken by mouth.

One feature of Covid-19 is hypokalemia.  When sick these people excrete potassium in urine and become hypokalemic, they may need 3,000mg a day of potassium supplement.  As they get better, they stop losing potassium. This all relates to the angiotensin system, disturbed by the virus.

If you take bumetanide you excrete potassium, so if you get Covid-19 you would be wise to stop bumetanide, but keep taking potassium supplements. 

ACE2 Coronavirus and Italians

The reseach has already identified how the Covid-19 virus spreads in humans.  It uses Angiotensin converting enzyme 2 (ACE2) and ACE2 receptors.

To inhibit the spread of the virus you want less ACE2.

In normal times ACE2 is a very good thing to have and it is a marker for a healthy person. In some people they have variations of the gene that produces ACE2 or its receptor.  This variation is seen in Italians and also in sportsmen - not a good time to be an Italian sportsman.

Certain drugs increase ACE2 and certain drugs you might expect to lower ACE2 appear not to.

You might think Grandma’s ACE inhibitor, she takes to lower blood pressure would inhibit ACE2, but ACE inhibitors inhibit ACE1.  It appears they increase ACE2 receptor expression and ACE2 itself.

There are two issues, the number of receptors and the amount of the enzyme, both are relevant.

Chinese research on real patients found that those taking ACE inhibitors and ARBs had elevated levels of ACE2.

Ibuprofen has been reported to increase ACE2.  In children treated in France, there condition became much worse after treatment with Ibuprofen.

Glitazone drugs, that can help treat a cytokine storm, unfortunately seem to increase ACE2.  These drugs are used to treat type 2 diabetes.

ACE inhibitors and ARBs are also useful un treating a cytokine storm, but raise ACE2 and so must be avoided.

Practical Strategies

I should start by pointing out that researchers at Imperial College in London, who have analysed the data from a town in Northern Italy where 100% of the residents were tested for Covid-19, suggest that only one in eight people with the virus actually show symptoms.

German researchers think that over the next two years 60-70% of their population will catch the virus.

It is only the at-risk groups where mortality is going to be widespread.

I started writing this post when I heard some of Donald Trump’s “experts” standing beside him talking about the virus. I was not very impressed.  Then I read a newspaper interview with an “expert” in England saying how they would treat a new patient with Covid-19.  He would use Tamiflu and later antibiotics.

Where we live, they have very few ventilators and so it really makes sense to change the course of the disease so that you will never need one.

The generic drugs to stop the virus replicating are cheap, while the modern immunomodulatory drugs to halt the cytokine storm are extremely expensive.

My choice is Hydroxychloroquine (Plaquenil).  In France the published adult dose used is 600mg for 10 days. UPDATE I would also add Azithromycin, based on the chart at the end of this post.  In a small French trial the combination is remarkable, after 5 days the virus has gone in 100% of patients. This a cheap macrolide antibiotic, with long known immunomodulatory effects. 

If you look at the half-life of this drug, it is extremely long, over one month.  If I was treating myself for Covid-19 I would start with a higher dose and then taper it.  You need the greatest effect at the start, not the end of the therapy.

I do not actually believe that a healthy boy with autism, living at home, is at elevated risk of Covid-19, but if I am wrong, I will be giving Hydroxychloroquine (Plaquenil) immediately, should Covid-19 be confirmed.

These drugs have side effects and you would not want to use them when it is just a cold or flu.

Since Ibuprofen is reported to increase ACE2, I certainly will not be using it.

Paracetamol/acetaminophen has the big problem of depleting the body’s key antioxidant GSH.

GSH itself has a benefit on inhibiting virus replication.

Since I already give a large daily dose of NAC (N-acetylcysteine) to boost GSH levels, I would use paracetamol to treat a very high temperature in Covid-19.

I think Monty’s grandparents are the ones that might need the anti-cytokine storm therapy.

People with autism often have potent immune systems.  In the Spanish flu, it was young adults with good immune health that died.  They died because they generated potent cytokine storms in their lungs, which express ACE2 receptors and then they developed bacterial pneumonia. In medical jargon they developed acute respiratory distress syndrome (ARDS) and sepsis, causing death. 

In the first stage of Covid-19 a potent immune system should be an advantage, if it identifies the virus.  In the final stage of the disease, which most people avoid, an overactive immune system might not be a good thing.

I think that Hydroxychloroquine (Plaquenil) is a good insurance policy.

If I was a US Presidential candidate, or any other rich elderly person, I would put my order in for Actemra, just in case I needed it.

Actemra (Tocilizumab) is an expensive drug to treat arthritis in adults and children.  It is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Interleukin 6 (IL-6) is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many disease.  IL-6 is a key player in the cytokine storm in Covid-19.  It is taken by I/V infusion.

An advantage of the S1P1 agonists is that they are taken as tablets.

The following paper is very good and has links to the latest research papers from China, which are also very relevant:-

The most distinctive comorbidities of 32 non-survivors from a group of 52 intensive care unit patients with novel coronavirus disease 2019 (COVID-19) in the study by Xiaobo Yang and colleagues  were cerebrovascular diseases (22%) and diabetes (22%). Another study  included 1099 patients with confirmed COVID-19, of whom 173 had severe disease with comorbidities of hypertension (23·7%), diabetes mellitus (16·2%), coronary heart diseases (5·8%), and cerebrovascular disease (2·3%). In a third study, of 140 patients who were admitted to hospital with COVID-19, 30% had hypertension and 12% had diabetes. Notably, the most frequent comorbidities reported in these three studies of patients with COVID-19 are often treated with angiotensin-converting enzyme (ACE) inhibitors; however, treatment was not assessed in either study.
Human pathogenic coronaviruses (severe acute respiratory syndrome coronavirus [SARS-CoV] and SARS-CoV-2) bind to their target cells through angiotensin-converting enzyme 2 (ACE2), which is expressed by epithelial cells of the lung, intestine, kidney, and blood vessels.

The expression of ACE2 is substantially increased in patients with type 1 or type 2 diabetes, who are treated with ACE inhibitors and angiotensin II type-I receptor blockers (ARBs).

 Hypertension is also treated with ACE inhibitors and ARBs, which results in an upregulation of ACE2.

ACE2 can also be increased by thiazolidinediones and ibuprofen. These data suggest that ACE2 expression is increased in diabetes and treatment with ACE inhibitors and ARBs increases ACE2 expression. Consequently, the increased expression of ACE2 would facilitate infection with COVID-19. We therefore hypothesise that diabetes and hypertension treatment with ACE2-stimulating drugs increases the risk of developing severe and fatal COVID-19. 

Severe influenza remains unusual in its virulence for humans. Complications or ultimately death arising from these infections are often associated with hyperinduction of proinflammatory cytokine production, which is also known as ‘cytokine storm'. For this disease, it has been proposed that immunomodulatory therapy may improve the outcome, with or without the combination of antiviral agents. Here, we review the current literature on how various effectors of the immune system initiate the cytokine storm and exacerbate pathological damage in hosts. We also review some of the current immunomodulatory strategies for the treatment of cytokine storms in severe influenza, including corticosteroids, peroxisome proliferator-activated receptor agonists, sphingosine-1-phosphate receptor 1 agonists, cyclooxygenase-2 inhibitors, antioxidants, anti-tumour-necrosis factor therapy, intravenous immunoglobulin therapy, statins, arbidol, herbs, and other potential therapeutic strategies.

Cytokine storm in the lung following severe influenza infection. (1) Viruses infect lung epithelial cells and alveolar macrophages to produce progeny viruses and release cytokines/chemokines (mainly contains interferons). (2) Cytokine/chemokine-activated macrophages and virally infected dendritic cells lead to a more extensive immune response and the initiation of cytokine storm. (3) Released chemokines attract more inflammatory cells to migrate from blood vessels into the site of inflammation, and these cells release additional chemokines/cytokines to amplify cytokine storm.

Summary of immunomodulatory therapy or strategies against severe influenza

Therapeutic agents or strategies
Alleviated the 2009 pandemic H1N1 influenza-infected patients with pneumonia.30 Ineffective as monotherapy in H5N1 influenza-infected mice.29 Increased long-term mortality in influenza-infected patients with pneumonia.27
PPARs agonists
Ciglitazone and troglitazone decreased the mortality of influenza-infected mice.34 Bezafibrate partially protected patients with influenza-associated encephalopathy.33 Gemfibrozil also decreased the production of IL-1, IL-6, and IFN-γ, but has no effects on the mortality of H5N1-infected mice when administered 48-h post-infection.31,32
S1P1 receptor 1 agonists
Reduced mortality of 2009 pandemic H1N1 influenza-infected mice over 80%, compared with 50% protection of oseltamivir.36
COX inhibitors
Ineffective as monotherapy in H5N1 influenza-infected mice, while effective when in combination with neuraminidase inhibitors.32
N-acetylcysteine and glycyrrhizin inhibited H5N1 replication and pro-inflammatory gene expression in vitro39,40 but ineffective as monotherapy in vivo.45
Anti-TNF therapy
Effective in reducing the cytokine production and inflammatory cell infiltrates in influenza-infected murine lung but ineffective in improving survival of infected mice.47,48
IVIG therapy
Reduced 26% to 50% mortality of 2009 pandemic H1N1 and 1918 Spanish H1N1 influenza-infected patients.50,52
Combined with caffeine or antivirals, alleviated lung injury and inhibited viral replication in H1N1, H3N2, and H5N1 influenza-infected mice.54 Ineffective in protecting 2009 pandemic H1N1-infected patients.55
CCR inhibitor
Increased survival of influenza-infected mice by 75%.58
AMPK activators
Increased survival for influenza-infected mice by 40%, while a combination with pioglitazone improved survival by 60%.59
Imparted a survival signal to the T cell via upregulating anti-apoptosis gene expression and eliminated weight loss in influenza-infected mice.60
Participated in a negative feedback loop in the JAK and epidermal growth factor receptor pathway to protect against severe cytokine storm during severe influenza.61
Decreased mortality, pro-inflammation, and inflammatory cell counts of influenza-infected mice.62
Reduced the mortality, lung lesion formation, and inflammation of severe influenza-infected mice.64
Favorable in laboratorial data but limited clinical data for severe influenza.65,66,67,68,69,70,71

Polytherapy - Hydroxychloroquine plus Azithromycin (a macrolide, from the table above)

Click on figure below to enlarge it

Saturday, 25 May 2013

A Cytokine Storm? Mr Spock

I have recently started learning the workings of the human immune system, while 12 year old Ted (“normal” except for a Star Wars obsession) has been discovering Star Trek.  Last weekend we went to the cinema with Adrian “Mole” to see the latest release.  Mr Spock made one interesting observation, regarding what can happen when the interests of the many outweigh the interests of the few; this will be the tittle of a forthcoming post about the fate of Dr Wakefield and his vaccine theory.


Cytokines really do exist, even though they sound like something from science fiction.  They are signalling molecules associated with inflammation.  Several inflammatory cytokines are induced by oxidative stress.  The fact that cytokines themselves trigger the release of other cytokines and also lead to increased oxidant stress, makes them important in chronic inflammation.  In extreme cases, there is a downward spiral of inflammation making it worse and worse.  The Spanish Flue in 1918 and SARS in 2003 are given as examples of such deadly cytokine storms.

The Research

There is a vast amount of research about the role of cytokines in autism and some very good work has been done by Paul Ashwood.  Finally, I have found an Englishman, even though he has gone to live in California, publishing some really high quality and useful research.  It turns out he is a colleague of Dr Wakefield.  Much of Paul Ashwood’s research is not available for free.  This one is:-  The role of immune dysfunction in the pathophysiology of autism

This paper is very readable and shows how a dysfunction of the immune system is without doubt a major part of the autism story. In typical post-Wakefield fashion, nobody wants to stick their necks out and draw usable, if only hypothetical, conclusions; it is easier to just suggest further research.

All the research shows high levels of cytokines in autistic subjects in the brain, spinal fluid, blood and in the gut.  Recent research also shows high levels of cytokines in the siblings of autistic people:- Plasma cytokine profiling insibling pairs discordant for autism spectrum disorder

The researchers comment:-

Thus, the lack of significant differences between sibling pairs discordant for ASD found in our study is in line with the results of previous studies. It is possible that a common immunogenetic background shared by siblings might eventually lead to different clinical outcomes when an environmental stress (for example, prenatal exposure to environmental toxins, viral and bacterial infections, parental microchimerism, etc.) occurs during development.

This last finding was deftly understood by 12 year old Ted, who commented, “Well Dad, you nearly had two autistic children”

Well isn’t he a chip off the old block.

Peter Interpretation

So combining this knowledge with my other readings, drew me to the logical conclusion that the inherited immune dysfunction, combined with the oxidative shock, so well described by Chauhan et al,(in the 400 page book) most likely resulted in a cytokine storm that damaged the brain, and autism resulted.  Due to the feedback loop of the cytokines, the neuroinflammation continues for life.

This then led me to research cytokine storms, to see how the cycle could be stopped and some kind of homeostasis reinstated.  I did not expect to find an answer, but I did.   

First we have to introduce new terms, TNF and TNFR.

Tumor necrosis factors (or the TNF family) refer to a group of cytokines whose family can cause cell death or apoptosis.  19 members of the TNF family have so far been identified; the one that caught my eye was OX40L, a cytokine that co-stimulates T cell proliferation and cytokine production.

A tumor necrosis factor receptor (TNFR), or death receptor, is a cytokine receptor that binds TNFs.  The matching TNFR for the TNF OX40L is called OX40 (also known as CD134).
OX40 binds to receptors on T-cells, preventing them from dying and subsequently increasing cytokine production. OX40 has a critical role in the maintenance of an immune response beyond the first few days and onwards to a memory response due to its ability to enhance survival. OX40 also plays a crucial role in both Th1 and Th2 mediated reactions in vivo. T helper cells (type 1 and 2) are white blood cells that play a major role in the immune system
OX40 has been implicated in cytokine storms.

Cause of the Cytokine Storm

When the immune system is fighting pathogens, cytokines signal immune cells such as T-cells and macrophages to travel to the site of infection. In addition, cytokines activate those cells, stimulating them to produce more cytokines.  Normally, this feedback loop is kept in check by the body. However, in some instances, the reaction becomes uncontrolled, and too many immune cells are activated in a single place. The precise reason for this is not entirely understood but may be caused by an exaggerated response when the immune system encounters a new and highly pathogenic invader. Cytokine storms have potential to do significant damage to body tissues and organs.

TNF inhibitors and Cytokine Storms

The cytokine storm is kept going by the TNF cytokines.  So if these cytokines could be inhibited the storm might abate. An existing medication developed for arthritis called a TNF-alpha blocker was proposed as a possible drug. Corticosteroids and NSAIDS (Non-steroidal anti-inflammatory drugs) have been found ineffective.

In 2003 researchers at Imperial College demonstrated the possibility of preventing a cytokine storm by inhibiting or disabling T-cell response. A few days after T cells are activated, they produce OX40, a "survival signal" that keeps activated T-cells working at the site of inflammation during infection with influenza or other pathogens. OX40 binds to receptors on T-cells, preventing them from dying and subsequently increasing cytokine production. A combined protein, OX40- immunoglobulin (OX40-Ig), a human-made fusion protein, prevents OX40 from reaching the T-cell receptors, thus reducing the T-cell response. Experiments in mice have demonstrated that OX40-Ig can reduce the symptoms associated with an immune overreaction while allowing the immune system to fight off the virus successfully. By blocking the OX40 receptor on T-cells, researchers were able to prevent the development of the most serious flu symptoms in these experimental mice.  Sadly, it appears this discovery has been abandoned by the small company that tried to develop it.

And now for the shock …

In 2009 researchers in China found that a statin induced down-regulation of OX40 and OX40L in a concentration-dependent manner.

"These findings improve our understanding of the anti-inflammatory and immunomodulatory properties of simvastatin"

Antioxidants have been successfully trialled in cases of Acute Respiratory Distress Syndrome (ARDS), which is another example of cytokine storm.  Organ damage was reduced and there was an improved survival rate.


It would seem that the combination of antioxidant and statin is about as good a combination as is currently possible, to dampen down the remaining effects of a cytokine storm, which is the extreme case of neuroinflammation.

By skill, or luck, this combination is exactly what I am trialling with Monty.