Tuesday, April 13, 2021

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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Sunday, April 4, 2021

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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Tuesday, March 16, 2021

Vaccines and clots: Is it a worry?

Recent headlines announced that European countries have halted use of the AstraZeneca Covid-19 vaccine because of fears that it causes clots. This was first done by Norway and Denmark, and more recently they were joined by Germany, France, Italy and Spain. The basis for this decision was the report of 37 clotting illnesses among some 17,000,000 people who had received the vaccine. The conditions reported were 15 people with clots in the legs (deep venous thrombosis, or DVT) and 22 with clots that had travelled to the lungs (pulmonary embolism, or PE).

Is this a rational decision? To help you think about it, you must realize there is a difference between correlation and causation. Let’s say you wash and polish your car and it rains, or a bird deposits its droppings on your windshield. Did the act of washing your car cause it to rain or motivate the bird to alter its flight path? Probably not. Or postulate that in years in which the American League team wins the World Series, the stock market goes up. Would you put all your savings in the market when the Red Sox win a World Series (if they ever do again)? I hope not.

Vaccines prevent or at least dramatically reduce the incidence of the infection against which they are targeted. They do not confer immortality or prevent unrelated illnesses (or make you taller, smarter or better looking).

How common are clotting diseases in general? Best estimates are that DVT and PE occur in about 1 person in a thousand per year. These conditions are very rare in children and get commoner as we age. This means that if you were to follow 17 million Europeans for a year, you would expect 17,000 cases of DVT and PE. Let’s be very cautious and estimate that of the vaccinated population, only an average of two weeks had passed since they were vaccinated. This would lead you to expect 654 cases to occur (17,000/26). I could argue that the numbers suggest that the vaccine protects against clotting rather than causing it. I will not, but I will argue that stopping vaccination based on a fear of clotting is irrational and dangerous.

Israel leads the world in vaccination, having administered 106 doses for every 100 people in the country. (They are using the 2-shot Pfizer vaccine.) They have also seen a halving of new cases in the past month. The larger European countries have been near the back of the pack in vaccine administration and are now seeing a spike in cases and imposing new lock downs. Which strategy would you prefer?

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Saturday, February 20, 2021

Tell me about these new vaccines

In February 2021, the only Covid-19 vaccines available in the United States are the very similar mRNA-based vaccines from Pfizer and Moderna, both of which were reported to be 94-95% effective at preventing symptomatic Covid-19 in study participants who got the vaccine. A “real world” test, following the results of vaccinated people in Israel, has reassured us that the trial results were valid. Among 600,000 people who got the Pfizer vaccine, there was a 94% drop in symptomatic cases, only 4 severe cases and no deaths.

The problems with these vaccines are that there is simply not an adequate supply to vaccinate everyone in the U.S. soon enough, and that the price, need for two shots and the logistics of storing and transporting the vaccines limit how widely they can be used. Given the interconnectedness of the modern world, mass vaccination of the entire planet will be needed before any of us are truly safe. Happily, many other vaccines are well along in development.

A vaccine from Johnson and Johnson is closest to getting emergency use authorization in the U.S. This vaccine uses an adenovirus, a generally harmless virus, modified to carry the gene for the Coronavirus “spike protein” into human cells, which then produce this protein, which induces our immune system to recognize and fight off Covid-19 if we are exposed to it. This vaccine has many desirable qualities: it only requires one shot and it can be stored for months at normal refrigerator temperatures, making it much easier to distribute and administer.

You may have seen headlines indicating that it was only 66% effective at preventing symptomatic Covid-19, well below the efficacy of the mRNA vaccines. To some degree this is not a fair “apples to apples” comparison. The J&J vaccine was tested later than the mRNA vaccines, and it was tested in South America, Mexico and South Africa as well as in the U.S., while the Moderna vaccine was only tested in the U.S. The J&J shot thus had to contend with the new strains of virus, and we now know that the mRNA vaccines are less effective against these new strains than the original Coronavirus. Importantly, the J&J vaccine was 85% effective at preventing severe Covid-19, and there were no deaths in the vaccinated group.

Another candidate on the near horizon is from U.S. biotech firm Novavax. This vaccine combines a protein mimicking the virus’ spike protein with a “adjuvant,” a non-specific immune system stimulator. Preliminary trial results have shown 95% efficacy against the original SARS-CoV-2 virus and 86% against the B.1.1.7 (British) and 60% against the B.1.351 (South African) variants. Trials have been done in Great Britain and South Africa, and the vaccine requires two shots, 3 weeks apart, and can be stored at normal refrigerator temperature.

The Russian “Sputnik V” is another two-shot adenovirus-based vaccine. While the Russians were criticized for rolling out the vaccine before testing was complete, the preliminary trials have shown a 92% efficacy at preventing symptomatic Covid-19. Efficacy was similar across all age groups, and there were no severe cases in people who received both shots.

The Oxford/Astra Zeneca vaccine uses a modified adenovirus with DNA coding for the spike protein to generate an immune response. It got a lot of bad press when preliminary results showed better protection in those who had mistakenly gotten a lower dose than planned for their first dose followed by the planned second dose. This did not make biologic sense and put the trial into question. The larger trial has now shown 76% efficacy after one dose and 82% after a second. There were no Covid-19 hospitalizations in the vaccinated group. The vaccine has been approved for use in the United Kingdom.

Which vaccine should you get? To answer that question requires you to grasp one crucial fact: there have been essentially NO DEATHS from Covid-19 in people who got any of the available or soon to be available vaccines. We are not going to “wipe out” Covid-19. There have been and will continue to be coronaviruses circulating among us. What we need to get life back to normal is to eliminate deaths and markedly reduce hospitalizations from the SARS-CoV-2 virus. If Covid-19 can become just another cold that we catch and get over, we can go back to eating out, attending concerts and hugging each other.

So: take which ever vaccine you are offered!

Wednesday, February 3, 2021

A "cure" for Covid-19?

When a new disease appears, doctors must try unproven remedies based on things that “might” work, based on test tube data or what seem like logical extrapolations from similar conditions. As time goes on, better data allows them to change their approach. In an ideal world, all therapeutic decisions are based on scientifically valid trials in which different therapies are compared in similar patients, the so-called “controlled clinical trial.”

When Covid-19 swept the world, there was no proven therapy, and patients were dying. A variety of remedies were tried and, in some cases, seemed to work. These results were posted on-line and rapidly adopted even when the evidence was sketchy. We now have good trials of many different agents, and I can summarize by saying that none of them are a magic bullet.

First out of the gate: hydroxychloroquine, an anti-malaria drug that is also used to treat lupus, and which appeared to have anti-viral effects in the test tube. KILL IT! Put a stake through its heart! There are now good trials that show that hydroxychloroquine has no benefit when used preventively in health care workers or spouses of Covid-positive patients or in moderately ill patients. A World Health Organization-sponsored trial in hospitalized patients found higher mortality in patients receiving the drug.

On the caveat emptor front, I saw a news item recently indicating that the state of Oklahoma is trying to get the wholesaler to take back 1.2 million hydroxychloroquine pills the governor insisted on buying, none of which were used. (This is the same governor who has refused calls for a mask mandate.)

Next up were antibodies, the chemicals our immune system makes to help fight off invading microorganisms. The whole basis of vaccines is to get the body to produce these antibodies before it is invaded by the virus, so that we can promptly mount a defense. It made sense to give transfusions of plasma from patients who had recovered from Covid-19 and who had high levels of antibodies to the virus to patients now sick, Like many things that “make sense,” giving convalescent plasma to hospitalized patients was of no benefit. A well-conducted trial in Argentina did find that this treatment given to older adults within 72 hours of their developing mild symptoms cut in half the number who went on to develop severe disease (16% vs 31%).

We have also seen trials of synthetic, laboratory-produced antibodies. Using these avoids the risk of infusing plasma from possibly unmatched donors and having a transfusion reaction. A “cocktail” of bamlanivimab plus etesevimab given to patients with mild to moderate disease showed a modest reduction in the amount of virus excreted and reduced the combination of ER visits plus hospitalizations from 5.8% to 1.5%. There were no deaths in either group. Another synthetic antibody, toclizumab, given to sicker patients who needed oxygen, showed no benefit and a trend toward worsening.

How about vitamins? These have the great virtue of safety. One trial of IV Vitamin C shortened hospital stays but had no benefit in reducing deaths or the need for ventilators. Vitamin D has had a lot of buzz, largely because of published data showing that patients deficient in Vitamin D were more likely to die. My take on this is that low Vitamin D levels are a marker of poorer overall health. There is no evidence that low Vitamin D patients are more likely to catch the coronavirus, but they are more likely to die, as are frail elders and those with other serious diseases. No trials have shown benefit from giving Vitamin D, but it clearly falls in the category of “it cannot hurt,” and I would support routinely giving it to patients. Note: one newly published study found that a single large oral dose had no benefit.

The one FDA-approved treatment for Covid-19 is remdesivir, an anti-viral drug. Patients receiving it showed fewer complications and less need for ICU care, but there is little mortality benefit.

For decades, doctors have used cortisone-like drugs as a “hail Mary” treatment for severely ill patients with a variety of conditions. These are potent anti-inflammatory agents, and the sickest Covid patients seem to have an over-reaction of the body’s inflammatory system, so again it “made sense.” The best evidence we have is that use of corticosteroids reduces mortality in very sick patients but increases mortality in less sick patients. The best guidance we have suggests that patients who require oxygen or ventilators to breath should receive these drugs while they should be avoided in the majority.

The latest on the scene, and a spin on the anti-inflammatory angle, is colchicine. This ancient drug has been used for centuries to treat gout and more recently to treat other inflammatory diseases such as pericarditis. A large well-controlled Canadian trial showed that giving oral colchicine to non-hospitalized patients with proven Covid-19 reduced the combined endpoint of hospitalization or death from 6% to 4.6%. The only adverse effect was increased diarrhea in the colchicine group, which is a known side-effect of the drug.

My main takeaway? Don’t count on cure. Prevention is much better. Get vaccinated as soon as you can – any vaccine is better than none – and continue to wear a mask and practice social distancing.

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Sunday, January 17, 2021

The virus mutates

The Boston Globe sent out a flash bulletin, clearly intended to worry its readers: “State health officials Sunday announced the first case of a more transmissible COVID-19 variant involving a Boston woman who developed symptoms after returning from the United Kingdom earlier this month. The woman, who is in her 20s, had traveled to the UK and became ill the day after she returned to Massachusetts, the department said.”

Be afraid. Be very afraid! Or not?

A key point to remember is that viruses mutate, particularly RNA viruses like the coronavirus and influenza virus. You are urged to get an annual flu vaccination not because your immunity has disappeared since last year’s shot but because the virus that circulates each winter is usually different than the one infecting people the prior year.

Mutations occur frequently; whether they become the prevailing strain depends on whether they give the mutated virus an advantage over the existing strains. Mutations that allow the virus to spread more easily, to reproduce faster or to be harder for the host immune response to destroy will have a selective advantage and soon become the dominant strain. Early in the pandemic, a mutation in the part of the viral RNA coding for the spike protein emerged and soon became the major strain. This was later found to be due to its higher transmissibility. The outbreak in Danish mink was due to a mutation that allowed the virus to better attach to receptors in the animal’s respiratory tract.

The most recent concern has been a new variant, called B.1.1.7, that appeared in the United Kingdom and which rapidly became common there. By the end of December, this strain had gone from undetected to causing 28% of all cases in the kingdom. Its “selective advantage” is clear: it spreads 56% more rapidly than the original strain. Similar but different mutations have been found in South Africa and Brazil, but as of this date seem confined to those countries.

The “UK strain,” however, has been detected in small numbers in at least 10 U.S. states as of Friday according to the CDC – and now 11 per the Globe report.

First the good news: this strain, while it spreads more rapidly, does not appear to cause more severe disease. Another piece of good news is that small studies done by Pfizer found that the neutralizing antibodies produced by their vaccine work on the B.1.1.7 variant virus.

The bad news is that because this variant spreads more easily, it is likely to become the dominant strain in the U.S. by March, and the increased transmissibility may lead to many more cases.

What does that mean for us? It adds urgency to the need to get as many people vaccinated as possible, and it means we cannot let down our guard. Basic hygiene measures: masks, social distancing, isolation and quarantine and hand washing must be maintained until a large majority have been vaccinated. So, don’t be afraid, but be sensible and cautious.

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Wednesday, December 30, 2020

Coffee with that?

Tired of reading about Covid-19? Me too. I will not blog about the novel Coronavirus until there is something new and important to say. (And, no, I do not think that a few serious but very rare allergic reactions fit that description. If they did, we would have to take penicillin and many other important drugs off the market.)

Coffee has a fascinating history. Legend has it that it was discovered by a goat herder in Ethiopia when he noticed that after his goats ate berries from a specific tree, they became so energetic they did not want to sleep at night. From Ethiopia, coffee spread throughout the Arabian peninsula, and coffee houses soon became a staple of social life in the Muslim world. (Based on our travels, this is still true.) European travelers to the Middle East brought back stories of this unusual black beverage, and by the early 17th century, coffee had made its way to Europe. Initially condemned by the clergy as Satanic, coffee got a new lease on life when Pope Clement VIII tasted it, liked it and gave it papal blessing.

While there are numerous chemicals in coffee that lead to differences in aroma, color and taste, the main active ingredient is caffeine. It is caffeine that makes us more energetic and alert (good) and can also make us jittery and unable to sleep (bad). The caffeine in your cup reaches peak levels in your blood some 30 to 60 minutes after you drink it and has a “half-life” of 3 to 5 hours, meaning that some its effect can persist for 10 hours or longer.

In the United States, some 85% of adults consume caffeine daily, most commonly from coffee, but also from tea, chocolate, energy drinks, colas or in tablet form. The estimated average daily consumption of caffeine is 135 mg/day, the amount in about 1.5 8 ounce cups of coffee.

What about health risks and benefits of coffee? The science is less than robust, because most studies are based on comparing differences between people based on their self-reporting of how much coffee they drink. We have, or at least should have, learned that such “observational studies” can suggest possible benefits and harms but cannot prove them. People who drink 2-3 cups of coffee a day may not be like people who do not touch coffee. They may smoke more (or less), exercise more (or less) or may be more (or less) obese. Hence, take everything I say below as hypothesis or conjecture, not Truth.

Caffeine clearly increases alertness, reduces fatigue and reduces reaction time. It improves vigilance in performing tasks that require a long time with minimal stimulation, such as flying aircraft, driving long distances or working on an assembly line. It contributes to pain relief when added to common pain killers such as aspirin or acetaminophen (Tylenol). Caffeine also delays falling asleep and reduces sleep quality. Particularly at higher doses, it can cause or increase anxiety. These effects vary widely between different individuals. I have friends who drink a strong cup of coffee routinely at bedtime and drop off “like a log.” When I eat dinner out (remember those days?), I will ask the server for a cup of decaf “and your phone number, so I know who to call when I am awake at 3 AM.”

What about coffee’s effects on overall health? While consuming pure caffeine chronically has been shown to modestly elevate blood pressure, coffee does not appear to do this. Unfiltered coffee contains a compound that lowers the “good” cholesterol, HDL. This is not true for instant or filtered coffee, so if you are concerned about your lipids, avoid French press or Turkish coffee. There is no evidence that consuming as much as six cups of coffee daily increase the risk of heart attack or stroke.

There have been isolated reports of severe cardiovascular reactions, including sudden death, in people who took very large quantities of “energy drinks,” particularly when taken for weight loss or prior to gym work-outs.

The effects of coffee on cancer are, if anything, beneficial. Many cancers are less frequent in coffee drinkers, including liver, prostate, endometrial, skin and breast. A study published in November of 2020 found a lower risk of progression of metastatic colon cancer in coffee drinkers. Coffee drinkers also have fewer gallstones and kidney stones. Caffeinated (but not decaf) coffee appears to be protective against the development of Parkinson’s disease.

There is controversy about coffee consumption in pregnancy. A study published in the British Medical Journal claimed that maternal caffeine consumption was associated with increased risk of miscarriage and low birth weight. Both the British and American obstetric societies reviewed the study and disagreed with its recommendation that pregnant women avoid caffeine. The best advice seems to be to limit intake to the equivalent of 2 cups of coffee a day.

Several studies have found an association of drinking 2-5 cups of coffee daily with reduced mortality, and none have shown an increase.

A gentle reminder to older readers: caffeine is a diuretic - it will make you go more.

Bottom line: enjoy your morning Cup of Joe, guilt-free, but don’t overdo it.

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