Dr. Didier Raoult of Marseilles and his co-workers have published another preprint on clinical results with the chloroquine/azithromycin combination that their earlier work has made famous. And I still don’t know what to think of it.
This is going to be a long post on the whole issue, so if you don’t feel like reading the whole thing, here’s the summary: these new results are still not from randomized patients and still do not have any sort of control group for comparison. The sample is larger, but it’s still not possible to judge what’s going on. And on further reading, I have doubts about Dr. Raoult’s general approach to science and doubts about Dr. Raoult himself. Despite this second publication, I am actually less hopeful than I was before. Now the details.
I. This Latest Study
The new manuscript calls this “an observational study”, but I don’t see how that’s right – this is interventional, and that’s the whole point. In it, the Marseilles team reports treatment of 80 patients. Median age was 52 years (range 20 to 86), nearly 1:1 male/female. Six of the patients were from the earlier study reported by the group, here with longer follow-up. The patients were grouped into those with upper respiratory symptom and those with lower (54% of them in that category), and comorbidities were noted (46 of the patients had at least one known risk factor) as well as days between onset of symptoms and hospital admission, and between admission and start of treatment. Interestingly, only 15% of the patients had a fever, and four of them were noted as asymptomatic carriers, which makes me wonder how they got them into the study in the first place. Patients were give a CT scan shortly after admission to look for pneumonia – the body of the article says that patients “systematically underwent” this test, but the data tables show that 20% of the subjects were not evaluated. Of those who were, 54% had radiologic pneumonia signs. Nasal swabs were taken daily (“with some exceptions”) and analyzed for viral RNA via RT-PCR. Cultures, meanwhile “were attempted in a random selection of patients”.
Patients received hydroxychloroquine (200mg t.i.d for ten days) and azithromycin (500mg on the first day, 200mg q.d. for the next four days). The patients with pneumonia and bad overall “national early warning scores” (22%) got additional antibiotic (ceftriaxone, dose and schedule not specified). Patients had an ECG before treatment and two days after starting treatment, looking for any signs of QT interval prolongation. Treatment was discontinued (or not started at all) depending on ECG results, and any other drugs that are associated with QT prolongation were discontinued. The paper says that symptomatic treatments, including oxygen, were added as needed.
The end points of this treatment were messy, probably unavoidably so:
Criteria for discharge changed over the course of the study. Initially, patients with two successive negative nasopharyngeal samples resulting from PCR assay (CT value ≥35) were discharged. From 18 March, patients with a single nasopharyngeal sample with a PCR CT value ≥34 were discharged to their homes or transferred to other units for continuing treatment, Ultimately, because of a crucial need to admit new, untreated inpatients, inpatients already receiving treatment with a PCR CT value <34, with good clinical outcome and good adherence to treatment were also discharged.
OK, that sets the stage. We’ll come back to the discharge numbers in a bit. The study’s results include all the patients who got the HCQ/AZ treatment for at least three days and were followed up for at least six. A lot of the data are included in the following chart
To see even more why that’s needed, let’s go out to Day 2. By this point, they’re still testing all 80 patients (the black bar) and now, what, about 64 of them are still positive (tan bar)? So of the 39 patients that started on Day 0 and the 26 that started on Day 1, only 6 more of them improved enough on the nasal swab to be called negative for viral RNA. In other words, 20% of the patients treated went clean during the first 24 hours, but less than 10% did over the second 24. The “number of patients” bars look pretty reasonable, but that’s before you look at who started treatment and on which day. And wouldn’t it be useful to see the progress of the individual patients day by day in that PCR test? How the most heavily viral-loaded ones did compared to the lighter ones, how the asymptomatic carriers did compared to the rest? We can’t. All we have are the aggregate numbers.
That takes us to Dr. Raoul’s other published work. For extended comment on this I refer the reader to this post by Leonid Schneider at For Better Science. To summarize, there are a number of papers published from his lab over the years that have some of the better-known publication sins: duplication of photomicrographs, photoshopped blots. One of these in 2006 was egregious enough that Raoult and several of his co-authors were banned from publishing in any ASM (American Society for Microbiology) journals for a year. He was angry enough about this that he has almost never published in an ASM journal since the incident.
I am a believer in the maxim that you should never ascribe to malice what can be explained by incompetence. When you see these sorts of things in a publication, it can be outright fabrication, or corner-cutting (not permissible either, of course), or sheer disorganization and sloppiness (which also not should be the case). Raoult publishes a lot of papers (hundreds of them), and I suppose one shouldn’t be surprised that there’s some junk in there. I don’t think he rises to the level of some serial fraudster. But neither does this stuff build confidence.
Credited to STM