There’s just a small bit about COVID in this installment, and because it’s not very cheerful news, I’ll put it in at the beginning of the piece and attempt to work up to more uplifting items so as to finish off with a few positive bits.

What it comes down to is that Paxlovid doesn’t appear to be efficacious in the treatment of long COVID. This unfortunate conclusion is based on a 15 week study in 155 subjects. A 15-day course of Paxlovid was not more effective than placebo in reducing fatigue, brain fog, shortness of breath, body aches, or gastrointestinal or cardiovascular symptoms.

The study was funded by Pfizer and conducted at Stanford University in collaboration with Kaiser Permanente and Pfizer. Stanford Medicine Professor Dr Upinder Singh noted that investigators were not able to detect any measurable difference in the six composite COVID symptoms, nor yet any benefit from Paxlovid treatment in any of the individual symptoms. The study did confirm that Paxlovid is safe when used for 15 days, which is much longer than the treatment course for an acute COVID infection. The standard dose for an acute COVID infection is three Paxlovid pills twice daily (in the morning and at bedtime) for five days for a full course that adds up to 30 pills.

The trial participants on average had been experiencing the long COVID symptoms for more than sixteen months before enrolling in the trial. Dr. Singh said she believes that further study of the treatment for long COVID still has merit, perhaps in longer courses than 15 days or in patients who haven’t been sick for as long.

In Pfizer’s original clinical trial Paxlovid was shown to reduce hospitalizations and death from COVID by around 90% for unvaccinated people at risk for serious disease. But in a subsequent trial, Pfizer was not able to show benefit for persons considered at standard risk, including both vaccinated and unvaccinated patients.

My personal comment on this particular news item is that it confirms my overall take on Paxlovid: yes, it’s the best option currently available for treating COVID. Paxlovid definitely helps prevent the worst outcomes from COVID infections, but its overall effectiveness is limited. However, the failure of Paxlovid in long COVID may have more to do with the shifting nature of the coronavirus infection than with the effectiveness of the drug. I’m not aware of any current efforts to find or develop a different drug for the management of the coronavirus, and as the threat of COVID diminishes, the impetus for drug discovery specifically related to COVID also diminishes. Of course, drug development is always going to continue, and it’s possible – and even likely – that a new drug, or several new drugs, will be found to be effective in treating new cases of COVID.

…but at the last minute a bit of positive news about long COVID

This just turned up in an article in the New England Journal of Medicine (N Engl J Med. 2024 Jul 17. doi: 10.1056/NEJMe2407575). It reported the findings of a study that evaluated the medical records of nearly 450,000 persons who had COVID between March 1, 2020 and January 31, 2022, as well as about 4.7 million people who were not infected during that time. The main take-away from that study was that the rate of long COVID among the vaccinated contingent was 3.5%, while that rate among the unvaccinated was 7.8%, more than twice as high.

The researchers also found small differences in the emergence of long COVID that varied with the coronavirus strain that was prevalent at the time, for example, when the dominant strain changed from Delta to Omicron. From mid-June to mid-December 2021, when Delta was the dominant strain, the long COVID rate in the unvaccinated decreased slightly from the 10.5% rate that had held during the previous period to 9.5%. Then, when Omicron became the prevalent strain, the long COVID rate decreased further, to the 7.8% rate that characterized the long COVID rate in the unvaccinated over the whole study period.

The study was based on the medical records of millions of individuals in the files of the Department of Veterans Affairs. That population is significantly less diverse than the US population as a whole. About three quarters of the subjects were white, 91% were male, and the average age was 64. This is, of course, significantly different from the US population as a whole, and can certainly have some effect on the findings.

But, on balance, the finding in that study group that vaccination cut the rate of long COVID in half, from 7.8% to 3.5%, is clearly positive.

Millions of people now taking statins may not need them

This optimistic statement is based on PREVENT, which is a new method of predicting the risk of atherosclerotic cardiovascular disease adopted by the American Heart Association in 2023. The PREVENT calculations take into account variables which were not considered under the previous risk estimates. These new factors include kidney and metabolic function, and are based on more recent data and a more representative sample of people, and also incorporate physiologic factors relevant to people who may take statins. Also, it no longer includes race. Taken together, experts believe that these changes make the tool more accurate than the previous PCE estimates.

“PCE” does not refer to a particular cardiovascular risk calculator. The initials stand for “patient care encounter.” Here’s what the NIH says about PCE:

“The PCE helps guide physician-patient discussions and decisions about ways to offset these risks. Using nine factors – including age, gender, race, cholesterol, blood pressure, smoking history, and diabetes – it generates one of four risk scores: low, borderline, intermediate, or high. If a patient has borderline or intermediate risks for developing heart disease, they may benefit from additional screenings. Patients with higher risks are often prescribed statins, a cholesterol-lowering treatment.

Yet, as useful as the PCE has been, it has limitations, some researchers say. Now, they are studying how to improve future models to allow for more personalized risk assessments.”

The PREVENT criteria are clearly more accurate and precise. PCEs were derived based on a sample of 30,000 persons, some from older birth cohorts that have not lived in contemporary conditions (different exposures to food, smoking, etc). PREVENT was developed in a larger and much more contemporary sample of around 3.2 million adults, and validated in another 3.3 million different US adults.

Using race as a factor in predicting the risk of developing heart disease is based on the statistical evidence that in the US, African-Americans have a significantly higher rate of cardiovascular issues including heart attacks and strokes. Only a part of this increased risk is based on physiologic factors; the elevated rate of heart-related issues is based more on life-style than genetics.

A possible exception to that general statement is that African-Americans probably have somewhat different genetic roots than the general African population. The majority of enslaved persons brought to the Americas were captured by coastal-dwelling Africans and then sold into slavery to European traders. They largely came from the interior regions of Africa, where salt was exceedingly scarce, and the introduction of salt into their diets had disproportionately adverse effects in terms of elevating cardiovascular risk. It is theorized that their descendants are still more sensitive to dietary salt than the general population, and that this factor accounts for some of the increased risk of cardiovascular disease in the African-American population.

In any case, the deletion of race as a factor in assessing cardiovascular risk in PREVENT has a sound physiologic basis and is not merely rooted in political correctness.

To investigate how PREVENT works, the scientists took data from the National Health and Nutrition Examination Survey (NHANES) from January 2017–March 2020. This nationally representative data included information from 3,785 adults ages 40–75.

After crunching the numbers, significant differences emerged between the PCE and PREVENT estimates. First, looking at the entire group of subjects, PCE estimated an 8% risk of developing atherosclerotic cardiovascular disease over 10 years. Using PREVENT, this figure dropped to 4%.

These changes were most pronounced in African-Americans and adults aged 70–75. For African-Americans, the overall risk in the entire cohort dropped from 10.9% to 5.1%. In subjects aged 70–75, it changed from 22.8%–10.2%.

They also found that if PREVENT were to be employed nationwide, the number of people meeting the criteria for statins would decline from 45.4 million to 28.3 million. That’s the decrease in the number of people who would meet the PREVENT criteria for statins – not the decrease in the number of people now actually taking statins if the PREVENT criteria were applied.

Based on the PREVENT criteria, the authors of the study concluded that about 17 million adults who would be recommended to take statins based on the previous criteria would no longer be recommended to take statins. That conclusion applies only to statin recommendations and not to current statin use.

In terms of current statin use, widespread adoption of the PREVENT criteria would reduce the number of adults in the US now taking statins by about four million.

However, they also found that 15.8 million people who are currently not taking statins might in fact benefit from the medications. Statins, as you know, have the effect of reducing the deposition of arterial plaque by reducing concentration of the low-density lipoprotein molecules that transport cholesterol in the bloodstream.

Discontinuing statins could be a boon to individuals who experience muscle aches and pains as a side effect, and especially to that very small minority of statin users who are affected by rhabdomyolysis, which can cause extreme muscle pain, liver damage, kidney failure and death. However, the risk of very serious side effects is extremely low. Only a few cases of rhabdomyolysis occur per million people taking statins. Rhabdomyolysis can occur when patients take statins in combination with certain drugs, such as cyclosporine or gemfibrozil, or if they take a high dose of statins.

Occasionally, statin use might cause an increase in the level of certain inflammation-signaling enzymes in the liver. If the increase is only mild, patients can continue to take the drug. Rarely, if the increase is severe, patients may need to try a different statin.

All in all, the PREVENT criteria could be a significant benefit to the many persons now on statins who could, without increasing their cardiovascular risk, discontinue statins. And widespread adoption of those criteria could also benefit the many individuals now not stating statins by adding statins to their regimen and thereby reducing their cardiovascular risk.

Might Tattoos Increase the Risk of Some Cancers?

Many healthcare professionals have questioned whether tattoos are safe. After all, the process involves penetrating the skin and inserting a foreign substance. These days, we assume that tattoos “artists” are fairly careful about sanitizing their instruments, but pathogens lurk everywhere, looking for a chance to invade our bodies.

Might tattooing be related to cancer? The International Agency for Research on Cancer has classified some chemicals found in tattoo ink as carcinogenic or potentially carcinogenic, though mostly only when ingested, inhaled, or applied on top of the skin. Studies have also shown that pigment from tattoos ends up being filtered by and stored in the lymph nodes, where some lymphoma cases begin.

A recent study conducted in Sweden found that having a tattoo was associated with 21% higher odds of a lymphoma diagnosis. The finding was based on research published in May in the journal eClinicalMedicine.

Lymphoma was highest in people who had gotten a tattoo less than two years before their diagnosis. That risk gradually decreased, but then approximately 11 years after the tattooing and initial diagnosis, it rose again. There was no association between the size of the tattooed area and the incidence of lymphoma.

Lymphoma is a rare disease; thus, the increase in risk relates to a very low baseline. Lymphoma affects the part of the body that helps the immune system fight off infections. There are two types: non-Hodgkin’s lymphoma, which accounts for about 4% of cancer diagnoses in the U.S., and Hodgkin’s lymphoma, which is even more uncommon.

Some environmental factors do indeed raise the chances of cancer. In the case of lymphoma, a weakened immune system and exposure to chemicals such as benzene and some herbicides are known risk factors. The links between cancer and smoking or nuclear radiation exposure are dramatic and undeniable. But that clear connection has not been established for tattoos, according to hematologists and oncologists not connected with the study. In fact, two previous studies that investigated whether there’s a link between tattoos and lymphoma didn’t find one. Also, they observed that the finding that there was a heightened risk of lymphoma within two years of getting a tattoo and then again after 11 years, but no heightened risk in the in-between years, doesn’t make much sense.

Catherine Diefenbach, MD, a hematologist–oncologist at NYU Langone in New York, also questioned the study. She said, “the other thing that doesn’t make sense is if this is a toxin that gets put into the body through ink, there isn’t an association between the size of the tattoo and cancer risk. The study does raise questions, but the majority of patients with tattoos don’t develop lymphoma.”

Doc Gumshoe acknowledges that he is not favorably disposed to tattoos. I was hoping, to be frank, that this study would definitively put the kibosh on tattoos. Clearly, it has not done so. I suspect that the authors of the study were similarly not favorably disposed to tattoos, and were similarly hoping that their findings would have the effect of persuading the multitudes to shun tattoos. Again, clearly it will have no such effect.

A simple and low-cost test could improve flu diagnosis

Before COVID came along, influenza was the most common infectious disease in the US, other than the much less consequential common cold. According to the Centers for Disease Control, during the 2022-2023 season 31 million persons in the US were sick with the flu, resulting in 14 million visits to a health care provider for flu, 360,000 hospitalizations for flu, and 21,000 flu deaths.

In this context, it’s surprising that less than one percent of people who contract the flu get tested for that illness. This is in part because most tests require trained personnel and expensive equipment. The good news is that researchers have developed a low-cost paper strip test that could allow more physicians to identify the specific type of flu and prescribe the right treatment for their patients.

The test uses CRISPR to distinguish between the two main types of seasonal flu, influenza A and B, as well as seasonal flu subtypes H1N1 and H3N2. It can also identify strains that resist antiviral treatment, and with further work, could potentially detect swine and avian flu strains, including H5N1, which is currently infecting cattle and spreading to other species, including humans. It was developed by a team from the Broad Institute of MIT and Harvard and Princeton University, and supported by the CDC.

CRISPR is short for Clustered Regularly Interspaced Short Palindromic Repeats. It is a much-used abbreviation for a form of genome editing, which refers to a group of technologies that give scientists the ability to change an organism’s DNA. These technologies allow genetic material to be added, removed, or altered at particular locations in the genome. The CRISPR-Cas9 system has generated a lot of excitement in the scientific community because it is faster, cheaper, more accurate, and more efficient than other genome editing methods.

The test is based on a technology called SHINE, which uses CRISPR enzymes to identify specific sequences of viral RNA in samples. SHINE was initially employed to test for SARS-CoV-2, and later to distinguish between the Delta and Omicron variants. Then, in 2022, the originators of the SHINE assay began adapting it to detect other viruses they knew were always circulating – specifically, the influenza viruses. They wanted to create tests that could be used in the field or in clinics rather than hospitals or diagnostic labs with expensive equipment.

The senior authors of the study expressed the hope that these tests would be as simple as rapid antigen tests and would still have the specificity and performance of a nucleic acid test that would normally be done in a laboratory setting. Using a paper strip readout instead of expensive fluorescence machinery is a big advancement, not only in terms of clinical care of individual patients, but also for epidemiological surveillance purposes where the goal is to be aware of the prevalence of the infection in the general population.

Typical diagnostic approaches such as polymerase chain reaction (PCR) require lengthy processing times, trained personnel, specialized equipment, and freezers to store reagents at -80°C, whereas SHINE can be conducted at room temperature in about 90 minutes. Currently, the assay only requires an inexpensive heat block to warm the reaction, and the researchers are working to streamline the process with the goal of returning results in 15 minutes.

The researchers also adapted SHINE to distinguish between different flu strains. In the future, they say the assay could be adapted to detect two different viruses with similar symptoms, such as influenza and SARS-CoV-2.

Being able to distinguish between the strains or subtypes of influenza that are infecting a patient has repercussions both for treating the individual patient, and for determining public health interventions. The tests could help clinicians decide which antiviral to use. For example, Oseltamivir is a widely-used antiviral, but it is only effective against some specific flu strains. Thus, a rapid test that could single out specific flu strains would be highly valuable.

The study was published online in The Journal of Molecular Diagnostics on June 18, 2024. (DOI: 10.1016/j.jmoldx.2024.04.004).

Dengue virus is spreading northwards, and climate change will make it worse

That’s definitely not good news, but what I can say to temper it somewhat is that even as it invades the parts of the planet that most Gumshoe Citizens inhabit, it will not be an epidemic in the same category as the coronavirus pandemic or flu.

Globally, dengue is a major threat. As many as 3.6 billion people, or 40% of the world’s population, reside in dengue-endemic areas. An estimated 400 million people are infected with the dengue virus and about 100 million become ill with dengue. The annual global death toll attributed to the dengue virus is about 21,000.

In the US, the picture is very different. Most dengue cases reported in the 49 continental US states occur in travelers infected elsewhere. However, these travelers can bring home the disease and infect others. This can happen occasionally in the continental US. As of mid-June this year, around 2,500 cases of the dengue virus have been reported in the US.

The virus is transmitted to us humans when we’re bitten by the nasty Aedes aegypti mosquito, which has never been fully eradicated from the United States. Across the Americas, mosquitoes are infecting people with dengue at historic levels and US travelers are bringing the potentially life-threatening virus home with them. The alarming rise in infections has spurred American health officials to warn about the risk.

In South America cases of this tropical disease are currently decreasing during cooler winter months. But summer and hurricane season in the Northern Hemisphere increase the threat of infection in Central America, Mexico and the Caribbean.

While risk of local transmission in the US remains low, officials are concerned about the extent to which the dengue virus will take up residency in the US in the years ahead. Climate change is creating scorching droughts followed by intense rainfall ‒ which could sustain dengue’s transmission vector, the pesky  Aedes aegypti, which loves to feast on people’s blood. Dense urban areas offer opportunities for it to spread, posing a risk for sustained local dengue transmission in this country.

The number of people in the US and its territories sickened by dengue in just the first half of 2024 has surpassed any year in the last decade. The cases are occurring via travel, with people bitten by Aedes aegypti in foreign countries, as well as in Puerto Rico, where local transmission led officials to declare a public health emergency in March.

In late June, the CDC issued a health advisory warning about increased risk of dengue in the U.S. Recent extreme weather events, such as Hurricane Beryl, pose additional risks with just tiny amounts of standing water making suitable bases for mosquitoes to breed and spread dengue. A. aegypti mosquitoes can lay eggs in standing water as small as a bottle cap, pipes, broken pots or anywhere that collects water.

According to the World Health Organization, most persons who get dengue never show symptoms. But those who do can get high fever, body aches, nausea and rash. Most recover in a couple weeks.

Some infections are so severe they can require hospitalization or even, in rare instances, result in mortality. Severe dengue occurs in about 1 in 20 infections and is more likely with repeat infections. Symptoms include vomiting, restlessness, rapid breathing and bloody gums and nose, or blood in the stool. Infants, elderly people and pregnant women are at increased risk for severe disease, according to the CDC.

Following infection with dengue, the patient develops immunity to the virus, but only for a few years. The immunity is specific to one of the four different types of dengue virus. There is no specific treatment for dengue; care of the disease focuses on managing the symptoms as well as possible.

The same A. aegypti species that caries dengue is notorious for triggering historic epidemics of deadly diseases such as yellow fever and Zika.

While mosquitoes carrying dengue can infect people, infected people – including those who show no symptoms – can also introduce the virus to local mosquito populations. And once infectious, a mosquito can transmit the virus for the rest of its short life. This helps sustain dengue’s spread.

Climate change has contributed to the spread of several diseases besides dengue. Mosquito and tick populations have increased, and the result has been the increasing prevalence of West Nile virus and Lyme disease as well as other diseases. Treatment for some of these diseases is available and effective. West Nile, however, is exceptionally difficult to treat. Prevention is the best strategy, and the most effective prevention strategy is to control the mosquito population. This strategy also applies to dengue, and in areas where dengue has appeared, there have been efforts to kill the mosquitoes that transmit the disease.

I acknowledge that what I have communicated to you is not good news, but neither is it catastrophic news. Dengue is not at present a major threat in the more northern latitudes. But dengue’s prevalence is definitely increasing, and as that prevalence grows, the healthcare world will sharpen its focus on developing effective treatment. Not that long ago there was no such thing as an effective antiviral drug. The threat of the human immunodeficiency virus (HIV) spurred research, and the development of an effective drug to treat the coronavirus has opened new pathways for research on ways to attack viruses. I anticipate positive developments.

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A brief post-script: about a week ago the NYTimes devoted a half-page to an article about a new test for Alzheimer’s that predicted the test “with 90% accuracy.” This is evidently the Preclivity AD2 test from C2N. The Times does not mention the test by name or identify the maker, but the article clearly states what the test does, which is to measure the concentration of the form of tau peptide that sprouts into tangles in the brains of people with AD, namely p-tau 217.

According to the company, “The PrecivityAD2 blood test simultaneously quantifies specific plasma amyloid beta and tau peptide concentrations to calculate the Aβ42/40 Ratio and p-tau217/np-tau217(p-tau217 Ratio). As far as I have been able to determine, the AD2 test is the only test that provides that information. Why the NYTimes would describe the test in detail, naming the authors of the JAMA study describing the test, but not identifying either the name of the test or the name of the company that developed the test escapes me, unless the Times was being wary about giving advance publicity to the test before it received official recognition.

From my perspective, Doc Gumshoe provides information, not publicity.

Best to all, Michael Jorrin (aka Doc Gumshoe)

[ed note: Michael Jorrin, who I dubbed “Doc Gumshoe” many years ago, is a longtime medical writer (not a doctor) and shares his commentary with Gumshoe readers once or twice a month. He does not generally write about the investment prospects of topics he covers, but has agreed to our trading restrictions.  Past Doc Gumshoe columns are available here.]