It’s hard to stay away from the coronavirus pandemic, even though Doc Gumshoe basically has no information that’s any different from what’s flooding into your inboxes or TV screens or, for those of us who are still members of the ancient fellowship of newspaper readers, the pages of our daily newspapers. But a few topics demand some Gumshoe-like sleuthing.
Can hydroxychloroquine combat the coronavirus?
The possibility that hydroxychloroquine may deliver at least some benefit to individuals infected with the coronavirus needs to be examined carefully. From some quarters comes unquestioning approval – it’s the best possible news about COVID 19, and the call is for all hands to put this near-miracle to work saving huge numbers of innocent lives. And from other quarters, diametrically opposed views are being expressed – hydroxychloroquine, along with chloroquine, has not been shown to be effective, and giving patients large doses of this drug will do nothing but put their lives at risk.
Hydroxychloroquine (HCQ), trade-named Plaquenil, from Mylan (MYL), is widely used as an antimalarial drug, although some malaria pathogens have developed resistance to HCQ. It is also used to treat systemic lupus and, in some cases, rheumatoid arthritis. And it is also one of the very few drugs that are at least partially effective against Sjögren’s syndrome.
A clinical trial in Wuhan, China reported evidence of benefit in some patients with COVID 19 treated with HCQ. A total of 62 patients hospitalized with COVID 19 were randomized to receive what was considered standard treatment, or standard treatment plus 400 mg HCQ tablets for five days. Standard treatment included oxygen therapy, antiviral and antibacterial drugs, and immunoglobulin. The primary endpoint was time to clinical recovery, which was defined as a return to normal body temperature and cough relief, maintained for more than 72 hours.
The patients in the group receiving HCQ experienced a shorter time to return to normal body temperature than controls – 2.2 days in the cohort receiving HCQ versus 3.2 days for controls. Time to cough relief was also shorter in the HCQ cohort – 2.0 days versus 3.1 days. Both outcomes were considered to be highly significant – P = 0.0008 for return to normal body temperature and P = 0.0016 for cough relief.
Four of the 62 patients, all in the control group, progressed to severe illness. Overall, a larger proportion of patients receiving HCQ experienced improvement in pneumonia symptoms compared with those in the control group – 80.6% versus 54.8%.
In the meantime, there has been considerable public controversy about HCQ in the treatment of COVID 19. For example, a primary care physician in the New York suburbs has been using HCQ as part of a three-drug cocktail for patients infected with the virus, the other two drugs being the antibiotic azithromycin and zinc sulfate, which is thought (by some) to bolster immune response. This physician, Dr Vladimir Zelenko, has treated hundreds of patients with COVID 19, mostly in a community of 35,000 Hasidic Jews called Kiryas Joel.
Dr Zelenko has claimed that 100% of the patients that he treated with this combination had survived the virus with no hospitalizations and no need for a ventilator. His claims have been taken up and disseminated by a number of prominent figures, including Sean Hannity, the Fox News personality; also by Mark Meadows, who is the incoming White House Chief of Staff. The notorious Rudy Giuliani lavished praise on Dr Zelenko for “thinking of solutions, just like the President,” and posted a tweet calling HCQ “100% effective in treating COVID 19.” And the president of Brazil, Jair Bolsonaro, has stated that HCQ is a definite “cure” for COVID 19.
President Trump has been highly enthusiastic about HCQ. For weeks he has been claiming that it is “very effective,” and perhaps the “biggest game changer in the history of medicine.” The president has had public run-ins with Dr Anthony S. Fauci, head of the National Institute of Allergy and Infectious Diseases. In a television appearance, after Mr Trump once again evinced a high degree of confidence in HCQ, a reporter turned to Dr Fauci and asked him what he thought of HCQ. Mr Trump interrupted the reporter, saying that Dr Fauci had been asked that question many, many times and there was no need to ask the question again, effectively silencing Dr Fauci.
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Most medical experts are a great deal more cautious about HCQ, and in particular, about combining HCQ with azithromycin – a combination that can result in grave adverse reactions, particularly in persons with a range of heart conditions. Joint guidance issued by the American Heart Association and the American College of Cardiology specifically warns that using those two drugs together has been known to prolong the QT interval in the cardiac cycle. This can fairly quickly provoke torsade de pointes, a fatal cardiac arrhythmia.
Some of the HCQ boosters have also talked up the supposed effectiveness of chloroquine, HCQ’s precursor, which is also used as an antimalarial, although it is effective only against some malarial strains. The effectiveness of chloroquine against COVID 19 is a matter of speculation for which there is no supporting evidence.
Those critics of the enthusiastic proclamations about HCQ point out that those studies cited in support of its effectiveness demonstrate limited benefit at best – somewhat faster recovery time, and some improvement in pneumonia symptoms, as compared with trial subjects not receiving HCQ. In particular, the patients in the study mostly had very mild cases of the coronavirus. This does not mean that the drug is useless – only that it’s not a panacea, as its most enthusiastic supporters appear to be claiming.
Dr Jeremy Faust, an emergency physician at Harvard Medical School and Brigham and Women’s Hospital in Boston, has warned against the notion of relying on HCQ as a preventive medication. He said, “Patients with lupus, arthritis, and other conditions are already on hydroxychloroquine. And we are diagnosing them with COVID 19 left and right!”
Another possible coronavirus antagonist?
This one is familiar to any healthcare worker who deals with infectious diseases. It is the bacillus Calmette-Guerin (BCG), developed more than a century ago as a means of preventing tuberculosis, which was an active global threat throughout the world at that time. Since tuberculosis has been largely controlled in the developed world, BCG inoculation is seldom employed in those parts of the planet. However, BCG continues to be widely used in the developing world, and not only to minimize tuberculosis infections. The bacillus has been shown to have a number of other beneficial effects. It sharply reduces the incidence of respiratory infections, and also has been found to minimize infant deaths from a range of diseases.
The means by which BCG accomplishes these benefits appears to be that it encourages or trains the immune system to recognize a range of hostile invaders, including viruses, bacteria, and parasites. Up to this point, there is no evidence that BCG will work this way in preventing infection by the coronavirus, but clinical trials are now underway or in the planning stage to determine whether BCG will prevent COVID 19.
The bacillus was discovered in the 1800s following the observation that “milkmaids” – women who milked cows – did not develop tuberculosis. This will no doubt remind people of the similar observation that milkmaids also did not develop smallpox, which led to the development of a vaccine for smallpox based on the pathogen that caused cowpox, a mild and temporary infection in humans. Small doses of the cowpox pathogen conferred lifelong immunity to smallpox. The word “vaccine” is derived from the Latin for cow – “vacca.”
Two French scientists, Dr Albert Calmette and Dr Camille Guerin, cultured material from cow’s udders, based on the fact that the milkmaids would have had direct contact with the udders while performing their tasks. From this material they cultured mycobacterium bovis, a form of tuberculosis that infects cattle. Drs Calmette and Guerin worked with this culture for several years until they came upon a strain of the culture that could infect laboratory animals, but did not produce disease symptoms. However, it did foster immunity against tuberculosis. This became the bacillus Calmette Guerin, which was first used in humans in 1921, and became widely adopted after World War II.
BCG is now used mostly in the developing world or in areas where tuberculosis is still prevalent. The vaccine is currently given to about 100 million infants per year.
There have been a number of studies supporting the position that BCG has benefits beyond preventing tuberculosis. A trial in 2,320 babies in West African reported that death rates in low- birth-weight babies were dramatically reduced after vaccination with BCG, and infectious disease rates in these babies were cut by more than 40%. Other studies have yielded similar results. A 25-year observational study in more than 150,000 children in 33 countries reported that children who received the BCG vaccine had a 40% lower rate of lower respiratory tract infections, while a study in the elderly showed reduced incidence of acute upper respiratory infections in patients vaccinated with BCG.
Clinical trials of BCG, specifically looking for data about its effectiveness in inhibiting COVID 19 infections, have been initiated in Australia and the Netherlands. And Dr Denise Faustmann, director of immunobiology at Massachusetts General Hospital, is currently seeking funding to start a trial of BCG in healthcare workers.
Some BCG skeptics point out that there will be a specific vaccine against the coronavirus before long, and that it would be a waste of resources to try to adopt a vaccine that it not directly targeting the virus. But the BCG proponents point out that BCG is available right now, and could save many lives before a specific vaccine became available.
What’s the latest on Gilead’s remdesivir?
Remdesivir was thought to be a highly promising treatment for the coronavirus. As perhaps you remember, the first time I took notice of the disease caused by this virus (at that time not yet named COVID 19), I mentioned Gilead’s (GILD) drug remdesivir, which had been developed as treatment for the Ebola virus, but was not found to be as effective against Ebola as other agents. However, remdesivir had been shown to have antiviral activity against both SARS and MERS, both caused by coronaviruses.
What in particular focused attention on remdesivir was the case of a 35-year-old man in the state of Washington who had recently returned from visiting his family in Wuhan. On January 20th, test results for what was then usually called the 2019-n-CoV came back positive. The patient’s symptoms worsened considerably, and on hospital day 7, the treating physicians decided to start treatment with remdesivir. His symptoms improved immediately, and there were immediate plans to conduct clinical trials with remdesivir.
Some results of the first clinical trial have just become available, and, while remdesivir probably delivers some patient benefit, it’s not a miracle drug by any stretch of the imagination.
The patients in the trial all had severe symptoms. All patients in the trial had oxygen saturation of less than 94%, and at the beginning of the trial, 34 patients were receiving supplementary oxygen, whether by means of a ventilator or in the course of normal respiration. A total of 61 patients received at least one dose of remdesivir. Of these, 40 patients received a full 10 day course of remdesivir.
About two-thirds of those 40 patients (68%) experienced improvement in terms of need for oxygen support. Of the 34 patients receiving ventilation, 20 were either extubated or were off supplemental oxygen after 18 days of follow up.
Overall mortality in the group was 13%. In patients receiving ventilation, mortality was 18%, and in those not receiving ventilation, mortality was 5%.
A total of 32 patients experienced side effects during the trial, including increased liver enzymes, diarrhea, rash, kidney involvement, and episodes of low blood pressure.
This trial was classified as a compassionate use trial. There was no control group, and neither a placebo nor a drug against which to evaluate remdesivir. It is not possible to know for certain whether mortality would have been higher if the patients had not been receiving remdesivir.
… and another piece of remdesivir news
This comes from another clinical trial, still in progress. The trial is being conducted at the University of Chicago College of Medicine, and 125 patients with COVID 19 were recruited for the trial. Of these, 113 had severe disease.
According to Kathleen Mullane, the infectious disease specialist overseeing the remdesivir studies for the Chicago hospital to which these patients were admitted, even though the protocol called for a treatment period of 10 days, most patients did not require the full course, and left treatment after 6 days. Only three of the patients required the full 10-day course. Dr Mullane added that the patients’ fevers usually subsided quickly, many after only one day of treatment, and many patients were able to come off ventilators after one day of treatment. In the total cohort of 125 patients, there were two fatalities.
As in the previously-described trial, there was no control group and neither a placebo nor another drug against which to compare remdesivir, so we can’t exactly proclaim that remdesivir is going to be the magic bullet . But the overall results are positive and hopeful.
There will certainly be more clinical trials with remdesivir, and Doc Gumshoe will be on the lookout.
And now, let us tear ourselves away from coronavirus-related matter and look at other doings in health care.
Zantac (ranitidine) will be banished from the market at the FDA’s request
Ranitidine (Zantac) is an antacid drug that works by blocking the generation of a histamine in the stomach. This histamine, labeled histamine-2 (H2), stimulates cells in the lining of the stomach to release acid. Acid release in the stomach is a natural and essential part of the digestive process, but excess stomach acid can be painful, and acid stomach contents can push their way past the duodenum into the esophagus, causing inflammation and ulceration, and the sensation called heartburn. In some cases, stomach acid can lead to cancer of the esophagus. Reducing the generation of stomach acid can help to avoid these outcomes. Zantac, made by Sanofi, is also sold under its generic name as ranitidine, made by Apotex and other manufacturers.
The reason for the FDA’s action is that some ranitidine samples have been found to have unacceptably high levels of N-nitrosodimethylamine (NDMA), which in some cases can be carcinogenic. The FDA emphasized that NDMA was not found in ranitidine samples originally tested by the FDA. NDMA is commonly present, at very low levels, in the normal human diet, but at higher concentrations, it can be carcinogenic.
The FDA’s rationale for asking all ranitidine to be removed from the market is that it has been established that the NDMA content in ranitidine increases over time, especially when stored at higher than room temperatures.
Dr Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, summed up the FDA’s decision as follows:
“The FDA is committed to ensuring that the medicines Americans take are safe and effective. We make every effort to investigate potential health risks and provide our recommendations to the public based on the best available science. We didn’t observe unacceptable levels of NDMA in many of the samples that we tested. However, since we don’t know how or for how long the product might have been stored, we decided that it should not be available to consumers and patients unless its quality can be assured.”
The implication of the FDA’s comments is that NDMA is not present at significant levels in ranitidine when first packaged. However, the concentration may increase to potentially harmful levels during storage.
The FDA urged persons who had been taking ranitidine and who needed to continue their condition to consider using one of the many other over-the-counter products in its place. To date, the FDA’s testing has not found NDMA in famotidine (Pepcid, from Merck), cimetidine (Tagamet, from Glaxo SmithKline), esomeprazole (Nexium, from AstraZeneca), lansoprazole (Prevacid, from Takeda) or omeprazole (Prilosec, from Procter & Gamble).
Detecting Parkinson’s by the sense of smell
This story begins with a woman named Joy Milne, who, after about 10 years of marriage, noticed that her husband had developed a new odor, “a kind of nasty, yeasty smell,” as she put it. For several years, she attributed this odor to poor hygiene on her husband’s part. Her husband at that time was a physician, and she assumed that the small came from some substance her husband had come into contact with at the hospital where he worked.
Over the next few years, Joy realized that it wasn’t just her husband’s odor that had changed. His behavior had also changed. When his behavior shifted from being merely a bit odd to being, on occasion, totally out of control, they sought professional medical help. And it was then that her husband was diagnosed with Parkinson’s.
For many more years, they tried to deal with the situation as best they could, but as her husband’s condition deteriorated, they joined a support group for persons with Parkinson’s.
When Joy walked into a meeting attended by several persons with Parkinson’s, she immediately recognized that they shared her husband’s strange smell. Was it possible that individuals with Parkinson’s had a characteristic smell?
Joy shared this perception with her husband, and they agreed that expert opinion on the subject was needed. So they consulted a Parkinson’s researcher at the University of Edinburgh named Tilo Kunath. Initially, Dr Kunath dismissed the notion that Parkinson’s might be identified by a special characteristic odor. But then he learned that dogs could identify persons with cancer, and decided that perhaps the Parkinson’s smell connection deserved serious investigation.
Dr Kunath devised a simple test to see whether there was any substance to Joy’s claim that she had detected a characteristic Parkinson’s smell. He got back in touch with Joy Milne, who would be crucial participant in the study. She was identified as a “Super Smeller” in the paper describing the study. This is from the opening paragraph of that paper, published on March 20, 2019 in the American Chemical Society’s journal. (Trivedi DK. ACS Cent. Sci. 2019, 5, 4, 599-606)
“Physicians in ancient times, including Hippocrates, Galenus, and Avicenna, used odor as a diagnostic tool. Although the olfactory skills of physicians are not routinely used in modern medicine, it is well documented that a number of conditions, predominantly metabolic and infectious diseases, are associated with a unique odor, but there is scant evidence for odors as symptoms of neurodegenerative disorders. To the best of our knowledge, this is the first study that demonstrates the use of sebum as biofluid to screen for Parkinson’s disease (PD). … Joy Milne, a Super Smeller whose husband Les was diagnosed with PD in 1986, has demonstrated a unique ability to detect PD by odor. Joy has an extremely sensitive sense of smell, and this enables her to detect and discriminate odors not normally detected by those of average olfactory ability. Preliminary tests with T-shirts and medical gauze indicated the odor was present in areas of high sebum production, namely, the upper back and forehead, and not present in armpits.”
The study recruited 64 participants, 43 of whom had been diagnosed with Parkinson’s, along with 31 controls. Each participant was given a T-shirt and asked to take it home, wear it overnight, and return it. Each subject was also swabbed on the upper back with a medical gauze. These gauzes were then stored at a subfreezing temperature until they could be analyzed at the University of Manchester in the UK.
Dr Kunath gave Joy the T-shirts to test using her Super Smeller gifts. She was asked to evaluate the smell from each T-shirt and assess the likelihood that the subject who had worn the T-shirt had Parkinson’s, and if so, how severe the disease was.
According to Dr Kunath, she was incredibly accurate. In her scoring of the 64 study subjects, she was judged to have made only one mistake. She identified a man in the control group – the group supposedly without Parkinson’s – as having the disease. But the “mistake” turned out not to have been a mistake. A few months later the man in the control group was diagnosed with Parkinson’s. It turned out that Super Smeller Joy Milne had spotted the man as having Parkinson’s months ahead of his official diagnosis.
Based on the results of that initial test, confirming that Parkinson’s could indeed be detected by its odor, the research team went to work to attempt to identify what particular substances might be present in the sebum of Parkinson’s patients that enabled the Super Smeller to detect the presence of the disease. Here’s another excerpt from the paper the team published:
“Sebum is a waxy, lipid-rich biofluid excreted by the sebaceous glands in the skin, overproduction of which known as seborrhea, is a known non-motor symptom of PD. PD skin has recently been shown to contain phosphorylated α-synuclein, a molecular hallmark of PD. Identification and quantification of the compounds that are associated with this distinctive PD odor could enable rapid, early screening of PD as well as provide insights into molecular changes that occur as the disease progresses and enable stratification of the disease in the future.”
The research team identified at least three specific compounds that were found to be up-regulated in the sebum of persons with Parkinson’s. These were hippuric acid, eicosane, and octadecanal; the smell of a mixture of these compounds was described as “very strong” and “musky.”
The researchers concluded that their study highlighted the potential of comprehensive analysis of sebum from Parkinson’s patients could be used as a non-invasive screen for Parkinson’s, perhaps facilitating earlier detection, with a goal of initiating earlier treatment. Research along these lines is continuing.
For this, the researchers acknowledge their debt of thanks to the Super Smeller, Joy Milne, and also to her husband, who in the last days of his life encouraged Joy to pursue the lead. Or, we could put it, to “follow her nose.”
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Doc Gumshoe is determined not to spend all his time looking into everything connected with our present plague, but when things of interest come up, you may expect comment in these posts. However, there’s a whole lot more in the world of health to keep an eye on, and I promise that I will do just that. Thanks for all the comments – keep them coming! Best to all, Michael Jorrin (aka Doc Gumshoe)