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Showing posts with label Covid-19. Show all posts
Showing posts with label Covid-19. Show all posts

Thursday, 16 April 2020

Life with Autism under Lockdown






I thought there should be at least one post about how life has changed during Covid-19.  Where we live, Monty’s life goes on pretty much as before, now we are back to home schooling - but that is nothing new for us.

School starts at 9am, there are 3 or 4 classes a day online from school and then activities and exercises till 3.30pm. 

We have PE, art and music like at school.  Piano practice continues most days.

Monty’s latest addition to his routine is reading 30 pages a day of a novel in the evening.  Now that he has started, he insists on doing it every day.  Having finished the (boring) books from school, he is going to start reading his brother’s collection of Biggles novels. They are about a fictional fighter pilot, the series starts in 1916 and continues for 50 years (the author got old, but Biggles did not).  We are going to set the scene with one of the old epic films about fighter aces from 1914-18.

The parks are closed and we have a curfew starting at 5pm weekdays and now across the entire weekend.  If you live in a small apartment, as many people do in the areas with the most strict lockdowns, life clearly will be difficult for people who do not understand why their movements have suddenly been restricted.

In many countries parents have asked for special treatment for those with autism, so that they can go outside more often. This has just been implemented where we live.

Parents are now going outside to walk their child with autism during the curfew and then neighbours are calling the police to report them.  In some countries you can get a special paper confirming your right as a disabled person to be taken outside, when everyone else has to stay at home.

In our case, Monty accepts that schools, parks, restaurant and cafes are all closed, but he expects that come September life will return to normal and his brother will go back to University.  Monty is lucky to live in a house with a garden, so he has plenty of space and lots of things to do.

Life with autism under control is not so demanding, even under lockdown.

When Monty was eight years old, we had nine months of autism out of control, which then results in a self-imposed lockdown.  That period ended just before Monty started his Polypill therapy in 2012.

I would not want to be in lockdown with an adult-sized person with untreated severe autism.


The Big Issue

Recently I was asked for some advice by Monty’s assistant; her friend works publishing a magazine homeless/disadvantaged people sell on the street.  One of their best “sellers” is a young man with mild autism.  He actually lives with his parents – he is not homeless.  He is struggling under the lockdown, because the magazine is not being published; he still turns up at the office to collect his copies to sell, even though there are none.

The young man became very anxious and so his parents gave him something to calm his nerves (which turned out to be Valium).

I was told that he had been given some pills, but in spite of these pills he got worse and started being aggressive, which is totally out of character.  This was all (falsely) attributed to the Corona virus changes to life.

As usual you do have to double check the facts.  Where we live a man with “mild autism” does not mean a person with Asperger’s, it means a person with Autistic Disorder (i.e. severe autism), but not such a bad case, so the young man can walk to work by himself and has some speech. 

I was asked what pills the parents could ask for, to calm him down. I explained that for anxiety people with autism often get prescribed benzodiazepines, but for aggression and self-injury they might get antipsychotics.  Neither are a good choice in most cases.

“And … there should not be any side effects.
The pills he currently takes are just something very mild”

So, what pills had he been given? It was a local brand name I did not know, so I looked it up and it was Valium/Diazepam, the benzodiazepine.

Adult with autism going crazy after Valium? that sounds familiar.

You don’t want Valium, you want 2mg of Bumetanide.

People who show a negative reaction to benzodiazepine drugs, usually prescribed to calm you down, are very likely to be bumetanide responders.

Benzodiazepine drugs increase the effect of the neurotransmitter GABA. In most people GABA is inhibitory, so increasing its effect will calm you down and ultimately sedate you.

In people with GABA working in reverse, it acts as excitatory.  This will reduce cognitive function and affect mood and behavior.  If you “turn up the volume” of GABA by taking a Benzodiazepine drug like Valium, you will make such people go crazy, with aggression and self-injury.

Hopefully the parents of the young man will get my message and stop giving Valium.  It would be nice to think they will also start to give Bumetanide, but that is their choice and I assume they most likely will not.  A diuretic for autism? How crazy is that.



How crazy is an anti-malarial for Covid-19?

How are the French doing with an antimalarial and an antibiotic for Covid-19, that I referred to in an earlier post? Say farewell to Covid-19 in just five days, it appeared.







By now the French have treated thousands of people with their new off-label therapy.  Also being developed in Marseille is Bumetanide as an off-label autism therapy by Neurochlore.  It looks like free thinking is flourishing on the Cote d'Azur.   

The data below is from the Marseille University Hospital Institute for Infectious Diseases (IHU Méditerranée Infection) and the wider hospital group in Marseille called APHM, which means Assistance Publique-Hôpitaux de Marseille.

The public hospitals in Marseille have treated 4,337 Covid-19 patients and 78 died (1.8%).

Within that group 2,671 were treated at the specialist IHU hospital with the antimalarial hydroxychloroquine (and some with azithromycin in addition) and of those that received at least 3 days of treatment 11 died (0.4%).

I think we can infer that 1,666 patients did not have hydroxychloroquine and 67 died (4%).

So if taken sick with Covid-19 in Marseille, tell the ambulance:

         "IHU Méditerranée Infection et vite !!"

If needed you can add:

        "Appuyez sur le champignon!"





As I suggested in my post on Covid-19, hydroxychloroquine looks a very good bet.  The supposedly fact-based media (CNN, BBC etc) continues to say there is no hard evidence to support the use of hydroxychloroquine.  How much evidence do you need?

To measure the success of hydroxychloroquine, you just count the bodies.

If this is such a struggle, what hope is there to ever prove a drug can work for such an ill-defined condition as autism?

Until you have been vaccinated against Covid-19, it appears that what you need is hydroxychloroquine + azithromycin and some potassium, to treat the hypokalemia caused by Covid-19. Ideally you would also have a home test for Covid-19, which are getting much cheaper, so you do not take the drugs unnecessarily.

Fortunately where we live hospitals are routinely giving hydroxychloroquine + azithromycin, but ideally you would start the antiviral therapy before getting ill enough to go to hospital.

Tom Hank’s wife was complaining recently in the media about the side effects (nausea, vertigo etc) of the chloroquine she was given in hospital in Australia for Covid-19.  I think that is a little ungrateful. Untreated Covid-19 can have a pretty terminal side effect.






Thursday, 26 March 2020

Covid-19 – Friends, Survival of the Fittest, Focus on Reality and Forget about PC



Replacing the EU Flag with the Chinese Flag in Italy

In times of crisis people often find out who their friends really are.  In Northern Italy teams of doctors and equipment arrived from China, Russia and Cuba.  The citizens of a town in Italy have taken down the blue EU flag and replaced it with a red Chinese one.

Some Americans on social media think it is a "photoshop job".  Where we live Chinese doctors have also arrived, along with donated ventilators and other equipment.  The Chinese flag is fluttering on many video/digital billboards.

We should note that Italy sent aid to China, when Covid-19 first appeared. 
  
In most countries treatment guidelines have been published to determine how to treat patients and how to ration the limited available medical resources.  There is nothing new in rationing medical resources, it happens every day.

In terms of therapy, the note linked to below (in English), is very good.  It includes both chloroquine and hydroxychloroquine, mentioned in my initial post.  Note the dosage is tapered, as I suggested in my post.  In the case of hydroxychloroquine, you only need 12 tablets; so a standard pack can treat 5 adults.  Time for emergency production to start? Or we have to wait for the Chinese to do that for us?




Note that these drugs may have side effects, in particular QT prolongation of your heart beat.  This is a possible side effect of many drugs,  You would not want to combine multiple drugs that prolong QT. The QT interval is measured by ECG.






I am pretty sure I took chloroquine many years ago when travelling in a malaria infected area and never had an ECG.  It is clearly a case of balancing risks.  



Back to triage 

In the Napoleonic wars the French came up with the word triage and by the time of the World War One they had fine-tuned it. Those collecting the injured had to categorize patients into one of three groups:-

·         Those who are likely to live, regardless of what care they receive
·         Those who are unlikely to live, regardless of what care they receive
·         Those for whom immediate care might make a positive difference in outcome

In the current Covid-19 outbreak patients are first split into two groups: -

·        At-risk group, based on age and existing medical conditions 
·        Not in an at-risk group, based on age and existing medical conditions

Severity of the Disease

·        Mild to moderate, the case for most people (no pneumonia or oxygen required)
·        Severe, breathing difficulties requiring oxygen
·        Critical, ARDS (Acute Respiratory Distress Syndrome), Sepsis, Multi organ failure.  The people with critical severity require mechanical ventilation and intensive care

Frailty assessment

The clinical frailty scale (CFS) is used to give a rating from 1 (very fit) to 9 (terminally ill).  Each patient is given a CFS score when it is necessary to ration care.

People with a disability obviously do not want to get a black mark in the frailty assessment.

When overwhelmed with sick people, those working in hospital are not going to be able to devote time to people who are disruptive (aggression, self-injury etc) or those who need a family member at their bedside.

Another issue is where to put disabled people after treatment, so they do not block hospital beds needed for others.  In Italy hotels have been taken over to house people who are still infectious, but not seriously ill.

People who have intellectual disability (ID/MR) are not so easy to house, as this recent article highlights.

Developmentally Disabled New Yorkers Stuck in Hospital After COVID-19 Recovery
According to AABR ( Association for Advancement of Blind and Retarded), a non-profit with a New York State contract to house roughly 200 adults with developmental disabilities, their staff does not have enough necessary masks and gowns to safely retrieve 12 autistic and developmentally disabled residents who are ready for discharge after being treated for coronavirus.

Nine of those patients tested positive and six more hospitalized are awaiting test results. The 12 patients no longer require hospitalization, but are still considered contagious.  

“We have twelve individuals who have been hospitalized who are ready for discharge and isolation at home, but we don’t have a safe plan to bring them home,” said Libby Traynor, executive director of AABR, which used to be known as the Association for Advancement of Blind and Retarded, an 80-year-old organization that runs 22 group homes in the five boroughs.  Residents in six of those group homes have tested positive for COVID-19. 

Because of their intellectual disabilities, many of the AABR clients are unable to speak, let alone comprehend and follow safe social distancing and isolation rules, and the virus appears to be spreading rapidly within their facilities.

"It’s a pretty big ask to ask folks to take care of individuals, and they don’t have the protective equipment that they need,” Traynor said.


Survival of the Fittest

People affected by disabling conditions are worried that they might suffer from the rationing of hospital resources.  In times of crisis political correctness goes out of the window and it is back to survival of the fittest.  Younger healthier people get priority because they have more potential future years ahead of them and they recover faster and make space for the next patient.
  
Complaining that it is not fair is not going to help you.  Assigning ventilators by lottery, as some suggested, is just deluded. Fortunately, rationing life-saving treatment is nothing new and systems are in place to maximize the public good.



He, too, asked the Department of Health and Human Services to take action to stop rationing.
The letter, dated March 18, asked the department to "quickly issue a notice to physicians and hospitals specifying the applicability of non-discrimination requirements" of federal disability civil rights law.
Romano says he got a response from Roger Severino, who heads the HHS Office for Civil Rights and that he's now been talking to officials there about taking action.
"We're working very, very closely and very hard to make sure that we get some form of guidance out to the medical community as soon as possible," Romano says.
It's still unclear. If the federal government will respond. And if so: How forcefully.

If you are at high risk, self-isolate.  It is up to you if you want to self-treat, but it is wise to know what you are doing.



An Arizona man has died and his wife is in critical condition after they ingested chloroquine phosphate - an aquarium cleaning product similar to drugs that have been named by US President Donald Trump as a potential treatment for coronavirus infection.
The couple, in their 60s, experienced immediate distress after swallowing the drug, an additive used at aquariums to clean fish tanks, according to Banner Health Hospital in Phoenix.
Chloroquine phosphate shares the same active ingredient as malaria drugs that Trump has touted as possibly effective against Covid-19, the potentially life-threatening disease caused by the coronavirus.

According to the CDC’s at-risk list, people with Classic/ Kanner’s/ Severe autism are at elevated risk from Covid-19.  I have my doubts that young people in this group are at any elevated risk, if they are in good general heath.  Admitting a child with this level of autism to hospital for several days, alone, might cause problems (for the child and the hospital).


Missed Chemotherapy

Many medical procedures have been cancelled.

People are complaining that the delay disembarking from their cruise ship is affecting their chemotherapy. 

They might want to skip the article below from an oncologist.




In the above article the oncologist is brutally frank about the benefit of chemotherapy in most cases.

In effect, she is saying not to worry if you have to stop your chemotherapy.  The positive results in trials do not reflect the real world, where people have comorbidities etc. She says that “Patients are often astonished to hear that common therapies offer less than 5% benefit. The more lines of chemotherapy, the less the chance of success. Hand in hand with benefit goes harm.”

You do wonder why the bar is set so low for not very effective cancer therapy and yet so high for autism therapy. One pill is supposed to works for hundreds of different autism variants. All avenues are pursued to treat a person with cancer, but no avenues are pursued for someone with autism and intellectual disability. 

The same is actually true with dementia drugs, which are pretty much a placebo for the family members, rather than an effective therapy.


Conclusion

The currently recommended Chinese solution is mass testing to identify all those carrying the virus, most of whom have minor symptoms or no symptoms and then isolate them, so they cannot infect their family members and others.

My solution would be mass treatment of healthy people (no people with abnormal ECGs) with prophylactic doses of Chloroquine, to stop the virus spreading.  The drug is very cheap and it is much easier to make more of this drug than millions of ventilators. Once you take the drug the effect will last for weeks (the half-life is one month), so you could treat whole cities, one by one.  Many old people with arthritis take chloroquine or hydroxychloroquine every day, so I think the QT risk can be managed. 

Chinese doctors found that treating health workers with prophylactic doses of Chloroquine gave them protection from catching the virus from their patients.  15% of those with confirmed Covid-19 in Spain are health workers, so a little advice from China might be in order.   A trial in the UK is planned.

Chloroquine Prevention of Coronavirus Disease (COVID-19) in the Healthcare Setting (COPCOV)

Once hospitals get over-loaded, as they now are in Italy and parts of Spain, there are inevitably people who do not get fully treated.

If you are in the CDC’s at-risk group, it would seem smart to start treatment at home, when the symptoms start, and hopefully avoid the need for triage and “frailty” assessment a few days later.

Anti-viral therapy is most effective when taken early on and in later stages, not surprisingly, has little benefit.

Fish tank cleaner will kill you rather than the virus, but the pharmaceuticals proposed in the medical guidance note from Belgium are saving lives.







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
Summary
Corticosteroids
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
Antioxidants
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
ACEIs or ARBs
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
OX40
Imparted a survival signal to the T cell via upregulating anti-apoptosis gene expression and eliminated weight loss in influenza-infected mice.60
SOCSs
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
Macrolide
Decreased mortality, pro-inflammation, and inflammatory cell counts of influenza-infected mice.62
Arbidol
Reduced the mortality, lung lesion formation, and inflammation of severe influenza-infected mice.64
Herbs
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