(photo courtesy of pixabay.com and David Mark)
This report is shocking and unsettling. It comes from Premier, described as a “healthcare improvement company” by Medscape Medical News in an article that quotes a tweet from a nurse as saying she’d rather die than be intubated and put on a ventilator without these drugs. The list of drugs that are developing shortages is long and includes such familiar items as albuterol and ibuprofen. The shortage appears to be worst for drugs essential to, specifically, paralyze and sedate patients who are on ventilators. I am shocked, shocked I tell you, that it has come to this. It is as if “A black pool opened up at my feet. I dived in. It had no bottom.” (from a detective novel I read a long time ago: Google says it’s “Murder My Sweet” by Raymond Chandler)
(photo courtesy of pixabay.com and Alexas Fotos)
If it’s true, it’s an outrage, and Jared Kushner is responsible: he is behind the scenes “directing” our government’s response to this pandemic. Just another form of the corruption and incompetence that is paralyzing and killing us: nepotism.
Disappointing Results From Trial of hydroxychloroquine/azithromycin in Paris: a brief paper review
(photo courtesy of pixabay.com and David Mark)
Jerome Groopman reports in the New Yorker that a study published on Tuesday from Paris shows no clinical benefit or improved viral clearance from the use of the famous drug combination so talked about lately. Here is a link to the pdf of this pre-print (not peer-reviewed) paper.
When the study was published on March 28, the author reported only half a million cases; as of an hour ago, the world has 998,000 people who have been confirmed to have fallen ill.
The new study prospectively (beforehand) looked at eleven consecutive (one after the next) patients, two advantages that the Marseilles study did not boast. Eight of ten patients studied (the one who died was excluded) were still shedding virus in nasopharyngeal swabs at days five to six after treatment initiation (start). No apparent clinical improvement was seen.
While this study reported negative results with a stronger design, it is unclear as to why they did not wait a few more days to see if there was “late” improvement in viral shedding. As noted before, the first Chinese series reported in 191 patients gave an average duration of shedding at 20 days. The Marseilles study reported clearance at 5-6 days in all six patients with the drug combination.
A good “rule of thumb” for statistical interpretation of things in which the underlying distribution (the spread of possible results) is unknown: seven out of seven consecutive tests need to be positive, with no negative results, in order to believe in something to a 95% “confidence level”. With eleven consecutive tests, you can only have one negative result if you want to be mildly confident in the positive finding. This is known as nonparametric statistics. Based on this, I say the Marseilles study is not good enough.
At this moment, the TV (MSNBC) tells me that cases worldwide stand at 1,002,000. Metaphors like “speeding train” come to mind. There is a momentum to this pandemic that is truly astounding. It doesn’t look as if any drug or combination is going to be useful in the near future.
(photo courtesy of pixabay.com and David Mark)
Research that could support the compassionate use of chloroquine and azithromycin based on basic, preclinical, and clinical data is sorely lacking. A preprint literature search I found on Biorxiv located 19 studies that relate to this issue. Further clinical (experiments on humans) research will be difficult during this pandemic.
The clinical study that matters is this (a pdr version from IHU-Méditerranée Infection, Marseille, France, published on March 20). It included eighty patients, treating them all with hydroxychloroquine 200 mg three times a day and azithromycin 500 mg once followed by 250 mg daily for five days (also known as “Z-pack”– a prepackaged unit with seven azithromycin 250 mg tablets). There was no control group at all, and the authors relied on published data from other studies for comparison.
Patients in this study had a dramatically shortened period of virus shedding from their noses and throats: 83% had no virus detected by PCR (polymerase chain reaction) after day seven. Historical controls from another study of 191 patients in Wuhan were found to have a median duration of viral shedding of 20 days. One of the French patients died, but 54 died in Wuhan. This is impressive, to say the least, but there are many caveats.
For example, were patients pre-selected inadvertently? The 80 Marseilles patients all had mild to moderate disease at the beginning of treatment, except for one 86 year-old who went on to die. The 191 Wuhan patients were all consecutive admissions, many with severe disease. Treatments for the Wuhan patients were not described in the abstract. Quality of care was clearly better for the Marseilles patients, who were all isolated in separate isolation rooms. For these reasons, it would have been more appropriate to select controls from the Marseilles hospital; perhaps the predisposition to treat all patients with the drug combination there made this impossible.
There is little reason for not treating hospitalized patients with this drug combination when it is available. Outpatients are another matter. Hydroxychloroquine is in short supply at local outpatient pharmacies, although azithromycin is readily available (in fact, over a billion courses of “Z-pack” or its generic equivalent have been delivered, according to the Marseilles study).
This study is solely of hospital treatment at a well-equipped respiratory isolation medical center not under immediate threat of being overwhelmed with sick people. It was compared with treatment at a public hospital inundated with sick people. The results were used to justify early discharge for these patients in order to free up beds expected to be needed for newly admitted individuals. This is reasonable given that viral shedding, and therefore infectiousness, was stopped in about a week. Did the difference in hospital setting make a difference in the results? We don’t know, given that the Marseilles researchers didn’t attempt to collect any control patients at their own hospital; unfortunately, this is a key factor in case/control studies.
The authors of the Marseilles study also noted that a Chinese study of chloroquine treatment had negative results with 30 patients. Whether azithromycin made the difference is difficult to ascertain. Azithromycin by itself shows some signs of effectiveness against rhinoviruses but it is, like hydroxychloroquine, not approved for antiviral use.
There will be great difficulties in performing further research during a pandemic. We hope that those responsible for doing these studies will continue to accumulate patient data in a form that can be shared with other researchers. Part of these efforts will include obtaining informed consent from patients to share their data in a de-identified (with names and other identifying information removed) form.
I have to stop now to try and get some sleep. It is five AM here on the West Coast. I couldn’t sleep thinking about the post that I tried to write last night at nine PM that simply disappeared after I had put down 684 words. I tried to use Ctrl A, Ctrl C to copy those words, but my free WordPress word processor appeared to seize up and everything vanished. I was so frustrated that I gave up and went back to watching TCM, but after four hours of sleep I am back (not for long, I hope). The photo I selected for this post reflects my frustration and isolation.
(image courtesy of pixabay.com and Ri_Ya)
The SCMP (South China Morning Post) reported that scientists from Singapore, China, and the United States have identified a specific inhibitor of a bat gene that SARS-COV-2 requires for replication: carolacton. The paper was originally published on Biorxiv. The gene involved is key to the production of purine, a precursor to one of the RNA bases that the virus requires for its genome (its genetic blueprint). Apparently mammalian cells (like bats and humans, for example) are far more tolerant of purine synthesis inhibitors (drugs that stop the production of purine) than viruses.
If you have a yen for abstruse biology, visit Biorxiv.org; otherwise, I suggest you re-watch “Red Beard” or “Seven Samurai”, now featured on TMC as part of a retrospective of the famous Japanese actor (and swordsman) Toshiro Mifune.
(image courtesy of pixabay.com and Ri_Ya)
A story in today’s Washington Post describes the tragic tale of a 41-year-old ophthalmologist with three children on Long Island. He fell ill on March 14 with fever and cough, was hospitalized with dyspnea (shortness of breath), and by March 19 was on a ventilator. He has not improved with a course of the treatment touted by [redacted]: azithromycin and hydroxychloroquine. Then he failed to respond to Kevzar, an investigational drug originally intended for rheumatoid arthritis. His kidneys stopped working. Now he is ineligible to try remdesivir due to renal failure (kidneys not working).
To be clear, evidence was not presented that renal failure is a contraindication (reason for not using) to taking remdesivir. These are the criteria set by Gilead, the drug’s maker, to limit the number of patients eligible for trials of this drug. Presumably, the drug would be less likely to help him under these circumstances. There is also the issue of supply: over a thousand patients have already been treated with this not-yet-approved drug.
There is no publicly available outcomes data for remdesivir, in part because Gilead holds the patent and can claim that such information would be “proprietary” (a trade secret). On the other hand, there is widely circulated data on a French study of hydroxychloroquine and azithromycin which looks impressive until one checks the actual numbers. Only twenty patients were studied. This is inadequate given that, by now, thousands and thousands of patients have been treated with the drug combination, including people with renal failure and other comorbidities (additional diseases) and those in extremis (clearly dying).
The situation now is so dire that an obstetrician-gynecologist calling himself “The Honest Ob-Gyn” has circulated a video on FaceBook touting the results of the French study. He told his listeners to “tell your doctor” and by implication, to demand this treatment. He failed to mention the tiny number of patients in the study, and inaccurately claimed that the results (which he held up on a hand-drawn graph in the video) showed “clearance of virus from the blood”. In fact, the novel coronavirus doesn’t circulate in the blood in most cases, and is only shed from the respiratory epithelium (the lining of the nose, throat, bronchi, and lungs).
What is worse, hydroxychloroquine is currently unavailable to outpatients due to a run on the supply and the donation of hundreds of millions of doses to hospitals. There is plenty of azithromycin around, as this is widely prescribed for bronchitis (which is usually caused by other viruses) even though there is no evidence that it is effective even for ordinary, garden-variety acute bronchitis.
This FaceBuck video is now responsible for medical assistants asking their providers (the doctors and physician assistants they work for) why they are not prescribing these drugs! This in the context of no tests being readily available and the turnaround time for test results stretching out to ten days in routine cases. It has to be patiently and gently (adverbs of which I am not capable) explained to them what is wrong with this picture. This is one reason I retired: too many ignorant questions from people who don’t even know what questions to ask.
(image courtesy of pixabay.com and Ri_Ya)
Here’s a link to a Chinese study on Medrxiv that wasn’t retracted (yet– too late now).
Here’s the key findings:
In different infection periods, compared with the proportion after 1/31/2020, the proportion of asymptomatic patient among SARS-CoV-2 infected patient was higher(19% VS 1.5%). In different age groups, the proportion of asymptomatic patient was the highest(28.6%) in children group under 14, next in elder group over 70 (27.3%). Compared with mild and common Covid-19 patients, the mean latency of asymptomatic [sic] was longer (11.25 days VS 8.86 days), but the hospital length of stay was shorter (14.3 days VS 16.96 days) .
(image courtesy of pixabay.com and Ri_Ya)
Yesterday, I mentioned that the countries with the highest prevalence of blood type O might see some protection from the novel coronavirus. This study from China, published March 11 on Medrxiv, is the basis for this speculation. Peru has the second largest percentage of people in the world with this blood type (70%, with Chile at 86%). It also has a relatively stable, effective government. This contrasts with Brazil and Mexico, whose leaders are still downplaying the seriousness of this pandemic.
A report in the journal of the Americas Society/Council of the Americas published yesterday shows what is happening over the whole continent. The graph that counts gives us a picture of what is happening in Peru, and by contrast, Brazil. Peru has a shallowly increasing incidence of positive test results after the 100th case; Brazil has a steep curve, the worst in the continent. Colombia, Mexico, and Panama also show slow rises in cases. Cuba, with questionable data, has a similar, slow rise– I will discount their results because of the authoritarian dictatorship there. Chile seems to have had a middle-of-the-road curve.
Mexico appears to be doing relatively well, but I suspect that case finding is very poor there. Reports emerged this week of vacationers to Mexico returning to the US with infections (sorry, not sourced; you’ll have to Google it). Infrastructure is weak, and their leader AMLO (Andres Manuel Lopez Obrador) has been dismissive of the new virus’ impact. A national health emergency was declared on March 30, more than a month after their first case was reported on February 28. Nearly 50% of Mexicans live in poverty, and 82% disapproved of AMLO’s extensive travel within the country. On March 27, AMLO encouraged Mexicans to stay home, but the next day he started another journey, “which included a stop to meet—and shake hands—with the mother of U.S.-imprisoned drug cartel leader Joaquín “El Chapo” Guzman.”
Peru has been trying hard since its first case was announced March 6. A strict national quarantine and state of emergency was declared on March 15 and took effect on March 19, including a ban from the roads for private vehicles. The same day, 3 million poor families received payments of $100 each for two weeks of basic goods. President Vizcarra’s approval rating has soared 35% to 87%, and 95% support the lockdown. That very same day, the president announced that he had ordered 1.4 million test kits.
Details for all South and Central American countries are available in this report, so if this is something you are interested in, I encourage you to follow the link and look at what Chile has been up to. Whether the prevalence of type O blood in Chile and Peru will be protective remains to be seen; with many of its people having other types, there is plenty of room for damage. Fortunately for poor Peruvians, their government is trying hard.
Chile, with 86% of its people having type O blood, has done better than Brazil but not as well as the countries mentioned above. Thus, type O might be irrelevant to the larger picture– government response might be more important. What’s your blood type?
(image courtesy of pixabay.com and Ri_Ya)
Here’s a link directly to Das Coronavirus Update. It’s also available on YouTube, although I don’t recommend patronizing YouBube because of its morass of mis-information.
(image courtesy of pixabay.com and Ri_Ya)
Here’s the link to the story in NPR. It provides many details on the study and the Administration’s flawed attempt to cite it as a reason for the US developing its own test. The conclusion they drew is that the reasons why the study was retracted have not been revealed. According to the NPR:
Without access to the paper, nobody can assess the value of the work or determine whether it suffers from a scientific flaw. It’s also unknown if the paper was retracted for political reasons. That’s a possibility, though it was retracted well before U.S. officials started citing it in public in a way that disparaged the Chinese coronavirus test.
The study cited a 47% positivity rate in asymptomatic close contacts of ill patients. This number may well be accurate, although since the retraction, we cannot rely upon it. The revelation that asymptomatic people can carry and transmit the virus in a quarter to a third of cases puts this in perspective. The possibility is that many positive-tested patients are asymptomatic, and in this perspective, a 47% number is not so questionable.
The study may have been retracted for political reasons, namely the Chinese government’s attempts to cover up the fact that they have not included asymptomatic positive-testing people in their case counts. As of today, the Chinese will start to include such patients in their case counts. When they announced the coming change, they revealed that roughly 1,500 people were currently in quarantine for positive tests but lacking in symptoms (roughly a third of the total under isolation).
So it’s speculation, but I say that it’s possible that the retraction was not due to scientific inaccuracy, but for the way it made the Chinese government “look bad” or made them lose face. The Chinese are extremely sensitive, and they have an enveloping censorship that makes the true facts very hard to ascertain. The epidemic in China may have been much worse than they were willing to admit, and it may be continuing despite their best efforts.
Conrad Theodore Seitz 