Gareth S Kantor
In mid-February, reports from China1 suggested that the anti-malaria drug chloroquine might be an effective treatment for COVID-19 disease. A subsequent French clinical trial2 of the related drug hydroxychloroquine, which is used primarily to treat patients with the autoimmune disease lupus, has set off a global rush to stockpile both these drugs, fueled in part by Donald Trump’s comment that this is “a real chance to be one of the biggest game changers in the history of medicine”3.
The chloroquine and hydroxychloroquine clinical trials were small observational trials, and, despite Mr Trump’s pronouncements, many experts are unconvinced about the value of these drugs in the treatment of COVID-19 disease. In fact, there is little evidence, apart from in vitro (laboratory) experiments, that chloroquine, or any other available drug for that matter, is effective and safe in the prevention or treatment of COVID-19. This includes, for example, remdesivir, a drug just approved by the US FDA for compassionate use; the April 10th remdesevir study published in NEJM4 has several flaws, including small sample size, short or missing follow-up, missing data, and lack of a randomized control group, without which it’s almost impossible to tell whether it’s the drug or some other factor, or range of factors, that is responsible for any apparent outcome benefit. The same reservations apply to other drugs now being used in a desperate attempt to save the lives of thousands of critically ill patients.
The game has certainly changed for lupus sufferers; an unintended consequence is that these patients face difficulty obtaining medicine that is part of the established, effective treatment of their chronic illness.
It’s more difficult, and less common, to conduct randomised trials of “non-pharmaceutical interventions” (NPIs) but in the absence of effective medicines or a vaccine, public health interventions are currently the only way to reduce disease transmission and thus the number of deaths.
Compulsory stay-at-home policies and less complete bans on public gatherings are now in place in most countries, as well as closures of schools and non-essential businesses, face mask ordinances, and quarantining of individuals or entire geographic areas. On March 26th, President Ramaphosa imposed, and last week extended, South Africa’s 21-day lockdown.
The goal of the SA lockdown is to interrupt the chain of disease transmission. This meansreducing the average number of cases caused by each infected individual over their infectious period,the effective reproduction number, Rt, to less than 1.0.
Studies of pandemic influenza6 and the 1918-19 Spanish flu7,8 suggest that public health interventions introduced quickly after detection of a newly spreading infectious agent can reduce transmission. Data from the current pandemic is providing additional information to guide action.
Non-pharmaceutical interventions in Wuhan, China
In a study from Wuhan, China, the geographic origin of the COVID-19 pandemic, published April 10th in the journal JAMA9,10, the authors examined outcomes in over 32,500 patients with laboratory-confirmed SARS-CoV-2 infection, based on the number of infections per day per million people, effective reproduction numbers, and the proportion of severe disease, over 5 distinct time periods, each associated with different combinations and applications of public health actions (Table 1):
|TIME PERIOD||INTERVENTION||DAILY CASES PER MILLION PEOPLE||SEVERE OR CRITICAL CASES|
|Before January 10||No intervention||2.0||53.1%|
|January 10 – 22||Large migrations for the Chinese New Year holiday||45.9||35.1%,|
|January 23 – February 1||City lockdown, traffic restriction, home quarantine, cordons sanitaire[*]||162.6||23.5%|
|February 2 – 16||Intensified social distancing measures, centralized quarantine and treatment||77.9||15.9%|
|February 17 – March 8||Door-to-door and individual-to-individual community screening for symptoms in all residents.||17.2||10.3%|
Table 1, with Figures 1 and 2 below, show the association between this series of NPIs and reduction in the daily case rate from a peak of 162.6 per million people (January 23 – February 1) to 77.9 (February 2 – 16) and 17.2 (after February 16), while the proportion of severe or critical cases decreased from 35.1% to 10.3%.
Rt (Figure 1) dropped from almost 4 to close to 1.0 during the period when Wuhan was under cordons sanitaire, vehicle traffic was stopped, and quarantine of confirmed and presumed cases and their close contacts was enforced.
The JAMA article authors suggest that interventions in periods 4 and 5 might not have been necessary in subsequently reducing Rt below 1.0, although transmission did decrease further as additional measures were implemented.
Figure 1. The effective reproduction number Rt is defined as the mean number of secondary cases generated by a typical primary case at time t in a population, calculated for the whole period over a 5-day moving average. The darkened horizontal line indicates Rt = 1, below which sustained transmission is unlikely so long as anti-transmission measures are sustained, indicating that the outbreak is under control. Source: Association of Public Health Interventions With the Epidemiology of the COVID-19 Outbreak in Wuhan, China9.
As in other studies, significantly greater risk of acquiring COVID-19 was identified for males and for health care workers caring for patients with COVID-19. More concerning was the relatively high infection rate seen among children younger than 1 year (13.4 per million), falling between the rates for persons aged 20 – 39 years (12.7 per million) and those 40 – 59 years (19.4 per million). This may have important implications for managing daycare facilities for children in this age group.
2. The epidemic curve, key events and features, and public health interventions
during the COVID-19 outbreak in Wuhan, China. Chunyun is a period of
significant travel with extremely high traffic around the Chinese Lunar New
Year. Cordons sanitaire restrict movement of people outside of a defined area. Source:
Association of Public Health Interventions With the Epidemiology of the
COVID-19 Outbreak in Wuhan, China. JAMA9.
Lessons for South Africa?
In the context of the COVID-19 pandemic, randomised controlled studies of public health interventions are unlikely, though not impossible. Instead, as the disease inexorably spreads globally, countries are using different combinations and intensity of interventions at different points in the local trajectory of spread, which can be compared.
The JAMA paper, emerging from the epicenter of the global pandemic, provides evidence that cordons sanitaire, suspension of automobile traffic, and quarantine of all confirmed and potential cases and exposed persons can reduce Rt close 1.0 in the early stage of the pandemic.
The JAMA article authors suggest that interventions in periods 4 and 5 might not have been necessary in subsequently reducing Rt below 1.0, although transmission did decrease further as additional measures were implemented, but that is a more difficult conclusion to draw. If interventions had been reverse ordered, the same effect might have been seen. Also, the proportionate decrease in periods 4 and 5 looks greater than in periods 1 – 3. It’s not possible to say whether action #4 was riding on the coat tails of #3, but period 5 looks like it had additional effect.
Based on our relatively slow increase in COVID-19 cases, South Africa’s early lockdown, quarantining of the entire country and suspension of non-essential vehicle traffic seems to have been effective in terms of suppressing transmission, though low levels of testing limit confidence in this conclusion and other factors, such as innate immunity in our population, may be relevant.
Further interventions described in the paper and illustrated in Figure 2, such as quarantine facilities, may be needed, though compulsory actions may encounter legal and ethical challenges in South Africa, and have economic consequences.
After the 5-week lockdown is over, it may be necessary to introduce less strict “shelter-at-home” policies, replacing our mass quarantine of cities and the whole country, and to isolate geographic “hot spots” to limit spread to other regions. Such decisions will depend on many factors, including the availability of rapid testing and serological surveys (antibody tests) to accurately measure population immunity.
In the ongoing pandemic it will be crucial to access real-time data to guide real-time evaluation of pharmaceutical and non-pharmaceutical interventions. Accurate and continuous monitoring of key outcomes such as new infection rates and numbers, rates of severe disease including case fatality rates, and effective reproduction numbers will allow quality improvement methods to be used to evaluate these public health policies. Process measures such as health care staff absenteeism and physical distancing will be important guides to action.
By March 24 there were more than 500 potential treatments for COVID-19 registered in trials5, including Solidarity5, in which South Africa is participating, which have the potential, if well designed, to generate the solid evidence needed to justify widespread use of any particular remedy across the pandemic-afflicted world. But in the absence of effective medicines or a vaccine, non-pharmaceutical interventions are the only tools currently available for controlling COVID-19, and we now know the metrics of effectiveness. As it appears that South Africa and other countries will be living with this pandemic at least for the next 12 -18 months the evidence that NPIs can reduce COVID-19 transmission if applied effectively and measured appropriately is encouraging.
1. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020;14(1):72-73. doi:10.5582/bst.2020.01047
2. Gautret P, Lagier J-C, Parola P, 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. doi:10.1016/j.ijantimicag.2020.105949
3. Longo DL, Drazen JM. Data Sharing. N Engl J Med. 2016;374(3):276-277. doi:10.1056/NEJMe1516564
4. Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. April 2020:NEJMoa2007016. doi:10.1056/NEJMoa2007016
5. Global coalition to accelerate COVID-19 clinical research in resource-limited settings. Lancet. 2020;0(0). doi:10.1016/S0140-6736(20)30798-4
6. Peak CM, Childs LM, Grad YH, Buckee CO. Comparing nonpharmaceutical interventions for containing emerging epidemics. Proc Natl Acad Sci U S A. 2017;114(15):4023-4028. doi:10.1073/pnas.1616438114
7. Markel H, Lipman HB, Navarro JA, et al. Nonpharmaceutical interventions implemented by US cities during the 1918-1919 influenza pandemic. J Am Med Assoc. 2007;298(6):644-654. doi:10.1001/jama.298.6.644
8. Hatchett RJ, Mecher CE, Lipsitch M. Public health interventions and epidemic intensity during the 1918 influenza pandemic. Proc Natl Acad Sci U S A. 2007;104(18):7582-7587. doi:10.1073/pnas.0610941104
9. Pan A, Liu L, Wang C, et al. Association of Public Health Interventions With the Epidemiology of the COVID-19 Outbreak in Wuhan, China. JAMA. April 2020. doi:10.1001/jama.2020.6130
10. Hartley DM, Perencevich EN. Public Health Interventions for COVID-19. JAMA. April 2020. doi:10.1001/jama.2020.5910
Pierre Barker, Institute for Healthcare
[*] Cordon sanitaire is a defined quarantine area from which those inside are not allowed to leave).