Boast, A. COVID and Hydroxychloroquine, Don't Forget the Bubbles, 2020. Available at:
There has been lots of media attention around hydroxychloroquine use for COVID-19 in recent days, largely stemming from this press release where Donald Trump discussed its effectiveness.
However, as many have since pointed out, the evidence is very limited, and care needs to be taken when trying new drugs in a clinical context, even in a pandemic. There are many risks associated with using a drug for a new indication, particularly in patients who are otherwise unwell.
What is hydroxychloroquine?
Hydroxychloroquine is a prescription medication currently used in both adults and children for autoimmune diseases including lupus and for the treatment of malaria.
What is the evidence so far?
The evidence for hydroxychloroquine can be divided into two types – in vitro (in the test tube) and in vivo (in people).
In vitro evidence
The in vitro evidence for hydroxychloroquine is promising. It works in two ways:
- Direct inhibition of SARS-CoV-2
- Immune modulation
Severe disease occurs in COVID-19 due to the pro-inflammatory cascade and cytokine sstorm causing acute respiratory distress syndrome (ARDS). The inflammatory cytokine interleukin-6 (IL-6) has been particularly implicated in this pathway, and there is evidence to show that hydroxychloroquine has anti-inflammatory effects decreasing the production of a number of cytokines including IL-6.
In vivo evidence
The evidence for hydroxychloroquine in COVID-19 is currently limited to a few small prospective studies in adults. These studies have many methodological limitations increasing the risk of bias, and more randomised controlled trials are required before commenting on its efficacy. There are also concerning reports of cardiac toxicity with hydroxychloroquine use, which highlights the importance of only using new drugs in the context of clinical trials.
What evidence is there in children?
In short – none!
So far there have been no clinical trials of hydroxychloroquine in children. As it is already used in children with other conditions, we do know that is safe in the ‘well’ child and have some information about appropriate dosing. However, if it is prescribed to children with moderate to severe disease COVID-19, we cannot assume that the distribution around the body and clearance (pharmacokinetics) and its interaction with the body (pharmacodynamics) is the same.
Where to from here?
As per the World Health Organisation experimental therapies should not be used outside of registered clinical trials. The future use of hydroxychloroquine in children with COVID-19 is therefore dependent on whether clinical trials are conducted.
Why is this important?
For any new therapeutic agent to be used in children it requires the same rigorous assessment in clinical trials in adults. Often due to ethical issues and the inherent challenges of performing clinical trials with children, these studies do not occur. This is a huge issue in paediatrics in general, as almost all new drugs are only tested thoroughly in adults.
Paediatricians are often forced to prescribe drugs ‘off label’ (use of drugs for a different age group, indication, dosage, frequency or route) or ‘unlicensed’ (where a drug is used despite it not being approved by the licencing body such as Therapeutic Goods Australia). Many commonly used drugs are actually prescribed ‘off label’ including ondansetron, salbutamol and even paracetamol. There are well-documented risks of adverse effects with off-label and unlicensed prescribing. Without clinical trials there is no other option.
It would be great if hydroxychloroquine was the wonder-drug we were all waiting for, with the in vitro data certainly promising. However, further clinical trials to assess its efficacy and safety are required, particularly before its use in children.
Liu J, Cao R, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6:16.
Mackenzie AH. Dose refinements in long-term therapy of rheumatoid arthritis with antimalarials. Am J Med. 1983;75(1a):40-5.
Yao X, Ye F, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of SARS-CoV-2. Clin Infect Dis. 2020.
Chen Z, Hu J, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv. 2020. **PREPRINT
Chen J, Liu L, et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19. J Zhejiang Univ (Med Sci). 2020;49(1):0-.
Gautret P, Lagier JC, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020:105949.
Coomes EA, Haghbayan H. Interleukin-6 in COVID-19: A Systematic Review and Meta-Analysis. medRxiv. 2020:2020.03.30.20048058. **PREPRINT
Savarino A, Boelaert JR, et al. Effects of chloroquine on viral infections: an old drug against today’s diseases? Lancet Infect Dis. 2003;3(11):722-7.