The treatment of viral pneumonia is supportive care. The arrival of COVID-19 has not changed that basic principle. Due to the scope of the crisis, there is massive interest in finding other possible treatments. I will review the evidence for those various treatments, starting today with chloroquine and hydroxychloroquine, but I think we will end up back where we started: the treatment of viral pneumonia is supportive care.
By now, because of widespread media coverage and the antics of a certain politician, everyone has heard that chloroquine might cure COVID-19. But what does the evidence really tell us?
There is some laboratory (in vitro) evidence that chloroquine could be effective in inhibiting SARS-CoV-2 (the virus that I will from now on refer to by its clinical name, COVID-19). (Wang 2020) However, in vitro data needs to be treated incredibly carefully. Chloroquine has been shown to have in vitro activity against influenza, but there is a double blind RCT showing no effect in patients (for prevention). (Paton 2011) It also has in vitro effects on Dengue, but no clinical benefit. (Tricou 2010) Similar in vitro effects have been shown against ebola, and again were not replicated in any in vivo animal studies. (Touret 2020)
There are at least 16 clinical trials that have been done in China (although only with a total of 100 patients so far). This includes RCTs, such as this one, but as far as I can tell, none of them are actually finished. People are relying on a research letter and a news briefing that reported that in the initial patients enrolled in these trials, chloroquine was superior to control in “inhibiting the exacerbation of pneumonia, improving lung imaging findings, promoting a virus negative conversion, and shortening the disease course.” (Gao 2020) This sounds promising, but it is hard to make any treatment recommendations based on a press briefing. None of the scientific details are available to review. We should wait to see the published results.
As far as I can tell, there is only one clinical trial published at this point:
Gautret P, Lagier J, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents. 2020; [article]
This is an observational study of patients 12 years and older with documented COVID-19 admitted to a single hospital in France, with a control group from other hospitals around France. They excluded patients with an allergy or contraindication to chloroquine or hydroxychloroquine, G6PD deficiency, QT prolongation, pregnancy, and breastfeeding. The patients were pretty healthy, with only 20% having pneumonia, and 17% being asymptomatic. At the primary centre, all patients were given 200 mg of oral hydroxychloroquine three times a day. Patients at the other centers did not receive hydroxychloroquine. (This is clearly not an ideal control, as there are lots of reasons that care might differ between hospitals, especially when one of those hospitals is organizing a trial, while the others aren’t.) They originally enrolled 42 patients. However, 6 were excluded from the main site, mostly because of death or transfer to the ICU, while no patients were excluded from the controls. (They didn’t do an intent-to-treat analysis). This means the sickest patients were excluded from the treatment group, so we should expect their results to look better. The patients were not similar at baseline (most of the controls didn’t have the quantitative PCR test done at enrollment and the demographics of the groups were significantly different), and they also weren’t treated the same throughout the trial (eg. the treatment group was swabbed more often than the no treatment group). In other words, there are many sources of bias in this trial.Their primary endpoint was viral clearance on day 6, which occured in 70% of the treatment group and 13% of the controls (p=0.001). Some patients also happened to get azithromycin, and those patients happened to have 100% viral clearance on day 6. They make no mention of harm or adverse events in the paper (although there are already multiple reports of people overdosing on these dangerous medications because of widespread reporting that it might help with COVID-19. See here, here, and here.)
This study is a mess, and clearly should not drive clinical practice. It is the kind of study we wouldn’t even notice in normal times, but the pandemic is causing people to throw out scientific principles. This is an observational trial with significant sources of bias. It doesn’t assess any patient oriented or clinical outcomes. And it doesn’t look at the group of patients we are most concerned about (they included asymptomatic patients here). At best, these results represent and an association at high risk of bias. The study raises a hypothesis. When combined with other data, it might be reasonable to proceed with an RCT, but based on historical examples, changing clinical practice at this point is more likely to do harm than good. With regards to azithromycin, the results are so weak I am not sure it’s even worth considering it a hypothesis.
There is no reason to be using chloroquine at this point. I will update the blog when the Chinese RCTs are published. There is also a very large RCT underway through the WHO (SOLIDARITY) and many other RCTS (eg NCT04303507 and NCT04308668).
There is a systematic review published, but it only includes “one narrative letter, one in-vitro study, one editorial, expert consensus paper, two national guideline documents”. (Cortegiani 2020) They conclude that there is reasonable pre-clinical justification for a clinical trial, but that chloroquine and hydroxychloroquine should be considered experimental, and there is no justification for widespread clinical use.
A pandemic is not an excuse for sloppy science. It is ridiculous that pharmacies are out of these drugs, so that they are not available to patients who actually need them. It is ridiculous that patients have died because they thought this drug might prevent COVID-19, fueled by irresponsible media coverage and unscientific statements from a world leader. Science still applies in 2020. We need to do better.
Cortegiani A, Ingoglia G, Ippolito M, Giarratano A, Einav S. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19 Journal of Critical Care. 2020;
Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies BST. 2020; 14(1):72-73. PMID: 32074550
Gautret P, Lagier J, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents. 2020
Paton NI, Lee L, Xu Y, et al. Chloroquine for influenza prevention: a randomised, double-blind, placebo controlled trial The Lancet Infectious Diseases. 2011; 11(9):677-683.
Touret F, de Lamballerie X. Of chloroquine and COVID-19 Antiviral Research. 2020; 177:104762-.
Tricou V, Minh NN, Van TP, et al. A Randomized Controlled Trial of Chloroquine for the Treatment of Dengue in Vietnamese Adults PLoS Negl Trop Dis. 2010; 4(8):e785-.
Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro Cell Res. 2020; 30(3):269-271.