COVID-19: animal origin or lab leak? Which is true? Does it matter?

There is one thing we all agree on: COVID-19 originated in Wuhan, a major industrial city in China, and spread from there around the world. What is still being hotly debated is whether the virus causing COVID-19 crossed over to humans from bats, probably via an intermediate host such as the pangolin, or whether it originated in a Chinese virology lab and accidentally escaped.

What do we know with reasonable certainty?

1. Previous coronaviruses, including those responsible for SARS and MERS, followed the animal-to-human route.

2. The Wuhan Institute of Virology has done extensive research on bat viruses, including coronaviruses and could have created this variant.

3. The World Health Organization (WHO) expert panel that concluded that the animal-to-human model was most likely did not have full access to all the data they requested.

So: lab leak or animal to human transmission? On-going studies of the virus’ genome may push the evidence one way or the other but will almost certainly not be 100% conclusive.

I contend that while it will give China a huge black eye if the lab-leak hypothesis seems most likely, because they have stone walled the investigation, in the end it really does not matter all that much. How can I say that when the media are so obsessed with the issue?

A. In either scenario, most experts agree that the safety protocols at the Wuhan Institute of Virology were not adequate, and this may be true at other labs around the world that study dangerous infectious agents. Going forward, an independent body should be empowered to inspect all labs in all countries that are studying infectious agents. Do you want a biohazard lab in your city that does not meet the highest safety standards?

B. Even if this particular virus did escape from a lab, we know there are literally thousands of nasty viruses in animal hosts around the world that have the potential to cause the next pandemic at any moment.

The lessons we should take from the COVID-19 pandemic are that we must prepare NOW for the next one, whatever its origin. The WHO must be empowered to go to all countries without limits or preconditions like those imposed by China.

The U.S. must take immediate steps to insulate public health from politics. There is no “Democratic” or “Republican” science, only valid science or bad science. Just as the Chair of the Federal Reserve has the independence to take the long view of the economy, the heads of the NIH and FDA must be able to offer advice based on science rather than political pressure.

Since it is not a question of if we will have another pandemic but when, we should start now to prepare by stockpiling necessary supplies and building up a more robust and nationally coordinated public health system. Whether it comes from a bat or a lab, it is out there and we must be ready.

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Why medications cost so much

This post was prompted by a short news item noting that even many patients with “good” commercial health insurance saw their out-of-pocket costs for medication rise 15% last year.

As readers of Prescription for Bankruptcy know, the U.S. is a dramatic outlier when it comes to the cost of pharmaceutical products. A RAND study published online January 28 showed that in 2018, prices for drugs in the U.S. were 256% higher than the average in 32 OECD comparison countries – 2 ½ times as expensive! This was driven by the cost of brand-name drugs, as our generic prices were slightly lower.

Why are drug prices in this country so high? The major reason is that the pharmaceutical manufacturers can get away with it. Medicare is prohibited by law to negotiate prices and the “middlemen,” the prescription benefit managers, keep most of any price reductions they get.

Brand name manufacturers have developed many strategies to maintain their monopolies, often skirting the law to prevent generic competition. They may make minor tweaks to a product to get an extension of their monopoly or may simply pay generic manufacturers to not make their products.

Big pharma, which usually cites the high cost of R&D to justify their profits, spend more on marketing than on R&D, usually by a wide margin. They bribe doctors to prescribe their products – not overtly, of course, but by sending in attractive young “detail reps” bringing lunch and samples. There is solid data showing this is money well-spent, because even though most doctors may feel they are not influenced by this type of marketing, studies have repeatedly shown they are. Considerable sums are also spent on direct-to-consumer ads to drum up demand for new expensive products.

Do high prices matter? Yes, as they not only hurt middle income earners badly in the pocket, they also lead to patients simply stopping their medications. Several recent studies have shown high rates of people skipping or stopping important medications and suffering serious health consequences as a result.

What can be done? Major change must begin at a national level. The most obvious step is to allow Medicare to negotiate for lower drug prices. Both the VA system and the Department of Defense do this, so there is clearly no philosophical objection. Since the older we get, the more prescriptions we tend to use, this step would make a huge difference in national health spending.

We can piggyback on the effective drug price strategies our peer countries all use by setting a ceiling on allowable drug prices based on the average price in Western European countries and Canada.

In the meantime, and my cynical side says that the deep pockets of the pharmaceutical industry are likely to thwart or delay any major changes, here are some ideas you can use now.

Always ask your doctor if the medication you are taking is available generically, or if a very similar drug is. For new ultra-expensive biologic drugs, ask about “biosimilars,” very close matches that work as well. If you are using tablets rather than capsules, it is often much less expensive to get a larger strength tablet and cut it. SHOP: the difference in price between different pharmacies can be dramatic.

Finally, if you or a family member are taking many drugs, ask your primary doctor to review them and see which you may be able to stop. This can be good for your health as well as your pocketbook.

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OK, what's the skinny on masks?

The CDC recently announced that fully vaccinated people could do away with masks indoors and out (with limited exceptions). If the change in advice has left you uneasy and confused, you are not alone. Many infectious disease and public health experts experienced a bit of vertigo after hearing this news. I would like to make things as simple as possible for you.

A few facts (and while everyone is entitled to his/her own opinion, they are not entitled to their own facts):

1. Vaccinations are extremely effective at preventing serious illness and death and very effective at preventing even mild illness and transmission of Covid-19 to others.

2. Masks, while not nearly as effective, cut down viral transmission.

3. Transmission is much more likely indoors than outdoors.

4. People with immune deficiency, from disease or immune-suppressing drugs, may not respond as well to vaccination.

So, what should you do? The easy ones first:

1. Masks are still required for all people on planes, buses, trains, and other forms of public transportation traveling into, within, or out of the United States and in airports and stations.

2. Masks are still recommended (and may be required) for anyone visiting a healthcare setting, correctional facility or homeless shelter.

3. You can safely forget the mask for all outdoor activities (unless you are packed like sardines with strangers).

4. Omit the mask indoors when everyone is fully vaccinated and/or from the same household or when you are unlikely to be close to others for an extended time.

More problematic is what to do when you are indoors in close quarters, such as having a haircut or manicure or sitting very close to strangers, as in a packed theatre. You are probably safe, but if you feel more comfortable and/or want to help protect others who may not be vaccinated, go ahead and wear your mask – there is certainly no harm in doing this.

If you have a disease likely to leave you with a weakened immune system such as cancer, or if you are taking immunosuppressive drugs, you should ask your doctor to have your antibody levels checked. There have been many reported cases of fully immunized people in these categories who have no detectable response to vaccination. (Note that many DO get protection, and there is no harm in getting vaccinated, but the response is not as predictable.)

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What's new in Alzheimer's disease?

Dementia is a huge and growing problem. An estimated 50 million people around the world suffer dementia, with Alzheimer’s disease the most common cause. It is estimated that some six million Americans are living with Alzheimer’s disease. The impact on the person with dementia is exceeded by the impact on their family, as the enormous care-giving needs are rarely covered by health insurance.

While there are genetic factors (particularly the APOE4 allele) that increase one’s risk of developing AD, and a rare familial form that occurs in younger people, the major risk factor is age. While rare in young adults, dementia occurs in some 10% of adults over 80. Thus, as we live longer, the incidence of AD will inevitably rise. The diagnosis of AD remains clinical. While all primary care clinicians should be able to detect dementia, a specialist should be consulted at least once to confirm the diagnosis and try to distinguish AD from other less common causes of dementia.

In 2021, the laboratory plays little role in routine care. After a new diagnosis of dementia, both serum vitamin B12 levels and a test of thyroid function such as TSH should be done. While uncommon, both B12 deficiency and an underactive thyroid can cause dementia and are easily treated. Some form of brain imaging should also be done to look for uncommon but surgically treatable conditions.

There is a growing interest in new diagnostic tools including advanced brain imaging techniques such as PET scans and measuring specific proteins in the spinal fluid, but Medicare does not pay for these expensive tests and their use is generally confined to clinical trials. On the horizon are blood tests that may confirm a diagnosis of AD.

To date, treatment of AD has largely been limited to a class of drugs called cholinesterase inhibitors that improve transmission of nerve impulses. The first, donepezil (Aricept), was approved by the FDA in 1996 and was soon followed by rivastigmine and galantamine. A different type of medication, memantine, targets glutamate, another “neurotransmitter.” None of these drugs cure AD but they do slightly improve symptoms and will often allow the sufferer to be able to avoid the need for nursing home care for several months longer.

Despite immense amounts of research, no new drugs for AD have been approved since 2003. Many promising candidates showed no benefit or even worsening. Recently there has been an explosion of research on a new class of drugs called monoclonal antibodies that target the pathologic markers of AD in the brain: proteins called tau and amyloid-beta.

This post was prompted by a full page ad in the Wall Street Journal from the Alzheimer’s Association calling on the FDA to approve one of these new agents, aducanumab, based on a trial reporting a 22% reduction in decline compared to placebo. I also found a more recent trial of another monoclonal antibody, donanemab, that also reported positive results.

Delving into these trials showed several factors that gave me pause. The first was the very small group that were entered into the trials after screening. The donanemab study began with 1955 people 60 to 85 with mild dementia, but entry required specific findings on PET imaging and in the end, only 272 were entered into the trial. The generalizability of the study was thus clearly limited when thinking of the broad group of people suffering dementia. Secondly, while there was a “statistically significant” difference in a score evaluating AD severity, the absolute difference was only 3.2 points on a score that ranged from 0 to 144. Hardly a “miracle.”

The data on aducanumab similarly showed an absolute difference of 0.39 on a different scoring system that ranged from 0 to 18, and this was in one of two studies, the other showing no benefit. Almost 1% of the patients receiving aducanumab had major side effects.

This class of drugs clearly warrant further study, but delaying their approval for general use seems prudent. While they have been shown to be of some modest benefit in a carefully selected subset of patients, FDA approval would almost certainly lead to an explosion of use in patients who were not studied in the trials and who might as likely be harmed as helped.

In the interim, some lifestyle changes have been shown beneficial and are both safe and free: regular aerobic exercise (walking), diet rich in leafy greens and flavanols (berries, nuts), staying socially active and trying to learn new things.

We should also be pressuring the federal government to do more to assist caregivers and improve payment for such things as adult day care and home health aides.

I am optimistic that within a few years, we will have both better and less invasive ways to diagnose Alzheimer’s disease and better treatments.

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"Long Covid:" does it exist? What is it?

Hopefully most of you realize that Covid-19 is not “just like the flu.” The death rate is much higher and there are many more complications involving other organ systems, including blood clots. As we (hopefully) dig our way out of the pandemic thanks to vaccinations and see fewer desperately ill patients on ventilators and many fewer deaths, another issue has been getting attention. Many people who have recovered from the worst of the illness, and many who had only mild symptoms or none are complaining of on-going problems.

The medical profession does not yet understand the cause of these symptoms, and there is vigorous debate over whether the complaints are psychosomatic or physical. The NIH plans to fund research into Covid “long-haulers,” but that research is unlikely to answer our questions in the near future.

The issue is two-fold: persisting symptoms in those who were seriously ill and new symptoms in those (often younger people) who had no or only mild symptoms when infected.

It is not surprising that the sickest Covid-19 patients, those hospitalized, remained sub-par for many weeks or months. An Italian study looked at 143 patients 60 days after onset of illness and 36 days after hospital discharge and found that only 12% felt back to normal. Half still complained of fatigue and shortness of breath and a quarter had joint and/or chest pain. A Swedish study found that among patients needing ICU care, over half still had abnormal lung function four months after discharge. A French study contacted 478 patients who had been admitted to a university hospital for Covid, also four months after discharge, and found that half had at least one complaint not present pre-Covid. Those who complained of shortness of breath were offered a chest CT scan and 61% of these showed persisting abnormalities.

We can hope that time will resolve or at least lessen these persisting symptoms.

More difficult to understand are the new complaints in patients who were not seriously ill.

A Swedish group looked at 323 health care workers who had serum evidence of Covid but had not reported symptoms. Compared to their co-workers with no evidence of prior infection, 5 times as many (15% vs 3%) had at least one moderate or severe complaint 8 months or more after their exposure. In Mexico, researchers looked at 115 patients with mild symptoms and a positive PCR who recovered at home with no treatment; 30 days after the positive test, some 60% had persisting fatigue and shortness of breath. In California, of 1400 patients with a positive PCR and minimal symptoms, 27% studied 60 days later reported symptoms. The symptoms in all of these groups included chest pain, cough, shortness of breath, joint pain and impaired thinking (“brain fog).

While skeptics might say these were all due to anxiety, there is evidence of very “real” and very severe illness coming after infection with the coronavirus. In Singapore, where the virus spread rapidly among “guest workers” from other Asian countries, there was mass testing. Researchers there reported a series of strokes in young (mean age 41) men who had positive Covid antibody testing but had never experienced obvious illness. A larger study in the U.S. used electronic medical records to compare patients diagnosed with Covid-19 with a matched group who had been diagnosed with flu or other respiratory illnesses at six months after diagnosis. The Covid patients had 2.5 times as many brain hemorrhages, ischemic strokes and new diagnoses of dementia. They also found higher numbers with insomnia, anxiety, psychosis and substance use disorders.

What is “long Covid?” The only honest answer is that at this point we really do not know. One theory is viral persistence. Another is auto-immunity. Favoring the former are reports that many patients with persistent symptoms report marked improvement after vaccination. Favoring the latter is that women are disproportionately affected, and we know that women have more auto-immune disorders than do men. And yes, some of the symptoms may be psychosomatic. Having a scary illness would tend to make one focus on bodily symptoms.

What can we do?

If you are a physician, I would ask you to maintain some humility and remain open-minded about an illness still under study. Do not dismiss the complaints as being due to anxiety.

If you have persisting symptoms and have not been vaccinated, I would encourage you to get the vaccine, as patients with mild or no symptoms are at risk of reinfection and many of your fellow sufferers have improved after vaccination.

If you have never had Covid, take this as one more reason to get a vaccine as soon as you can.

All of us: stay tuned!

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J &J Vaccine "paused." Should you worry?

The news media and our email in-boxes this morning were filled with the news that the CDC had recommended a pause in use of the Janssen/Johnson & Johnson Covid-19 vaccine pending investigation of six reported cases of an unusual illness that occurred following its use. Of the 6.8 million doses given in the U.S. to date, 6 women aged 18 to 48 had developed severe clotting disorders along with low platelets. [Platelets are the body’s first line of defense against bleeding, and you expect low platelet counts to be accompanied by bleeding, not clotting.]

This mirrors the concerns raised earlier in Europe about a similar illness that followed use of the AstraZeneca vaccine, leading many European countries to stop using it or to restrict its use to older people, since there, also, the rare illness was reported in younger people only. In Great Britain, which has given more than 20 million doses of the AZ vaccine, there have been 79 cases of blood clots associated with low platelets. In two papers published in the New England Journal of Medicine, 13 of 16 patients described were women, and their ages ranged from 22 to 54, with most being in their 30’s.

The common thread seems to be that both the AZ and J&J vaccines share similar technology, using harmless adenoviruses to get Covid spike protein code into human cells to produce antibodies. This is different than the mRNA technique used by the Pfizer and Moderna vaccines, which to date have not been linked to this rare disease.

Is there any similar disease unrelated to vaccines? There are two. A condition called TTP (thrombotic thrombocytopenic purpura) occurs at a rate of about 3 people per million per year, is commoner in women and has an average age of onset of 41. While this disease has clotting, the clots occur in very tiny vessels, unlike the vaccine-associated illness. Much more similar is HIT (heparin-induced thrombocytopenia). This disease, caused by an immune reaction to the blood-thinner heparin, occurs in some 2% of patients receiving heparin and is commoner in women, but tends to occur in older individuals, being very rare in people under 40. This does cause the type of clotting now being reported. Our best guess at this point is that the vaccine-associated illness is caused by an immune reaction like HIT, albeit to what is still unknown.

What are the important things you should know?

1. This is a rare side-effect if it is indeed a side effect, occurring in 1 to 4 people per million.
2. There is no reason to believe that it would happen with the Pfizer or Moderna vaccines.
3. It has so far only been reported in younger vaccine recipients, predominantly women.

What should you do?

1. If you have a chance to get the Pfizer or Moderna vaccine, get it!
2. If you are over 65 and have the choice of the J&J or AZ vaccine or no vaccine, I would personally take the vaccine.
3. If you have recently had the J&J or AZ vaccine, relax. You are VERY unlikely to have this illness happen to you.

Remember that all medications have side effects. It is your doctor’s job, working with you, to decide if the benefits exceed the risks of any medication you may take.

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You can teach an old dog new tricks!

Colchicine is one of the longest-used remedies in the modern medical armamentarium. It was mentioned in the Ebers Papyrus, dating from Egypt in 1500 BC, and its use to treat gout was described by the ancient Greeks. It is derived from the autumn crocus, scientifically named Colchicum autumnale. The active ingredient was isolated in the early 1800’s and it has been widely used to treat gout ever since.

When I was a pup, the dictum was to treat an acute gout attack by taking one colchicine tablet every hour until either the gout was resolved or the diarrhea was so bad that the patient did not care about the gout. In the intervening years we have learned a much more civilized approach. Lower doses work just as well and have much less GI side effects.

Readers of Prescription for Bankruptcy know that colchicine is also a sordid example of pharmaceutical company greed, with this ancient remedy manipulated into becoming a high cost branded product.

My focus here, however, is to note that this “one trick pony,” which 50 years ago was considered as useful only to treat gout has become a hot new product, with a rapidly expanding portfolio of uses.

Amazingly for a product of this lineage, the exact mechanism of action of colchicine is still being studied, but it clearly has strong anti-inflammatory properties, and works to reduce the effects of the body’s white blood cells. It is this anti-inflammatory property that is being exploited to treat a broad and growing range of diseases. The first new use was to treat a rare disease, Familial Mediterranean Fever, a disease whose victims suffer repeated attacks of fever, joint and abdominal pain, and many of whom go on to develop chronic kidney failure. Two trials published in 1974 showed that colchicine could dramatically reduce the frequency of acute attacks, and it was later shown that it largely prevented the kidney disease.

A variety of rare skin diseases characterized by local inflammation also respond to colchicine. More recently, colchicine has shown the ability to reduce recurrences of pericarditis, a non-fatal but very painful inflammation of the sac surrounding the heart.

As most of you know, the leading cause of death in the U.S. and most western countries is coronary disease. While we tend to simplistically think of heart attacks as caused by build up of cholesterol deposits in the coronary arteries, inflammation has long been felt to play a part. It is thus not surprising that several trials have looked at the effect of colchicine on heart attack. Two large trials, one in patients who had recently suffered an acute heart attack and one in patients with stable coronary disease found that daily low-dose colchicine reduced the risk of heart attacks, stroke, coronary surgery and cardiovascular death. Before we anoint colchicine the Fountain of Youth, it must be noted that overall death rates were not reduced, and may have even been a bit higher, in the colchicine group than in those taking placebos.

Finally, it would be remiss in 2021 not to note the potential role of colchicine in the fight against Covid-19. You may be aware that cortisone-type drugs, which have an anti-inflammatory effect, have been proven to improve outcomes in very sick Covid-19 patients, so a trial of colchicine was obvious. A small trial done in Brazil at the beginning of the year gave colchicine or placebo for 10 days to 72 patients hospitalized with Covid-19. Those given colchicine had shorter time in the hospital and less need for oxygen. While the small size of the trial prevented conclusions about the effect on survival, the only two deaths were in the placebo group.

A much larger trial was conducted by a group from Montreal. They studied 4159 patients not sick enough initially to be hospitalized. Half were given 0.5 mg of colchicine 3 times daily for three days and then once daily for another 27 days. Since this was a less sick group, the absolute numbers were not high in either group, but the patients given colchicine had reduced rates of needing to end up in the hospital, require a ventilator or die.

Just because a drug has been around for a long time, it can still be very useful, and there are always new things to learn about it.

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