Evidence-based, cost-effective interventions to suppress the COVID-19 pandemic: a rapid systematic review

Background: Countries vary in their response to the COVID-19 pandemic. Some emphasise social distancing, while others focus on other interventions. Evidence on the effectiveness and cost-effectiveness of these interventions is urgently needed to guide public health policy and avoid unnecessary damage to the economy and other harms. We aimed to provide a comprehensive summary of the evidence on epidemic control, with a focus on cost-effectiveness. Methods: MEDLINE (1946 to March week 3, 2020) and Embase (1974 to March 27, 2020) were searched using a range of terms related to epidemic control. Reviews, randomized trials, observational studies, and modelling studies were included. Articles reporting on the effectiveness or cost-effectiveness of at least one intervention were included and grouped into higher-quality (randomized trials) and lower-quality evidence (other study designs). Findings: We found 1,653 papers; 34 were included. Higher-quality evidence was only available to support the effectiveness of hand washing and face masks. Modelling studies suggested that these measures are highly cost-effective. For other interventions, only evidence from observational and modelling studies was available. A cautious interpretation of this body of lower-quality evidence suggests that: (1) the most cost-effective interventions are swift contact tracing and case isolation, surveillance networks, protective equipment for healthcare workers, and early vaccination (when available); (2) home quarantines and stockpiling antivirals are less cost-effective; (3) social distancing measures like workplace and school closures are effective but costly, making them the least cost-effective options; (4) combinations are more cost-effective than single interventions; (5) interventions are more cost-effective when adopted early and for severe viruses like SARS-CoV-2. For H1N1 influenza, contact tracing was estimated to be 4,363 times more cost-effective than school closures ($2,260 vs. $9,860,000 per death prevented). Conclusions: A cautious interpretation of this body of evidence suggests that for COVID-19: (1) social distancing is effective but costly, especially when adopted late and (2) adopting as early as possible a combination of interventions that includes hand washing, face masks, swift contact tracing and case isolation, and protective equipment for healthcare workers is likely to be the most cost-effective strategy.


INTRODUCTION
On March 11, 2020, the World Health Organization (WHO) characterized COVID-19 as a pandemic.Since then, the virus has infected exponentially more men and women worldwide.As of April 19, the WHO reports 2,241,359 confirmed cases and 152,551 deaths (WHO, 2020).This is more than double the deaths reported on April 6 (WHO, 2020b), indicating that the burden of COVID-19 is currently doubling approximately every 13 days.Countries have implemented a range of responses, and many are imposing nationwide school closures.These currently affect over 1.5 billion (almost 90%) of the world's students (WHO, 2020b).But closing school is costly-$10 to $47 billion for 4 weeks in the US alone (Lempel et al. 2009)-and could lead to a greater number of deaths than they prevent by creating unintended downstream effects, such as child-care obligations and losses in health-care workforce capacity (Bayham and Fenichel, 2020).Other countries have focused on other interventions, such as contact tracing and case isolation.These have been estimated to be 4,363 times more cost-effective than school closures for H1N1 influenza ($2,260 vs. $9,860,000 per death prevented) (Madhav et al. 2017).As states in the US and around the world are faced with the challenge of balancing public health interventions with economic (and other) considerations, evidence on the effectiveness and cost-effectiveness of these interventions is urgently needed to guide policy and avoid unnecessary harm.In this rapid systematic review, we aimed to provide a comprehensive summary of the evidence on epidemic control and to identify cost-effective interventions in the context of COVID-19.

METHODS
We performed preliminary searches to locate review articles, devise our search strategy, and identify potential shortcomings in the literature.A systematic review analyzed 7 studies, included only randomized trials, and concluded that the evidence was lacking for most non-pharmaceutical interventions (Smith et al. 2015).While we do not dispute this conclusion when looking only at randomized trials, we would argue that as urgent decisions of unknown cost-effectiveness are made in reaction to the COVID-19 pandemic, some evidence, even of lower quality, is better than no evidence at all.Therefore, we included a broad range of study designs in this review to provide a comprehensive summary of the peer-reviewed evidence.Reviews (all types), randomized trials, observational studies, and modelling studies were included.Articles reporting on the effectiveness or cost-effectiveness of at least one intervention were included.Articles in English, French, Spanish, and Portuguese were included.Studies of sexually transmitted infections (e.g.syphilis) and mosquito-borne diseases (e.g.dengue) were not included.Abstracts, case reports, and conferences proceedings were also excluded.MEDLINE (1946to April week 2, 2020) and Embase (1974( to April 17, 2020) ) were then searched using the terms "non-pharmaceutical interventions", "outbreak control", "outbreak interventions", "epidemic control", "epidemic interventions", "pandemic control", and "pandemic interventions" (last search: April 19, 2020).Screening of titles, abstracts, and full texts was carried out by a single investigator.Reference lists and PubMed related articles of included studies were reviewed for additional studies.For this rapid systematic review, we followed PRISMA guidelines (Moher et al. 2009), but we limited quality assessment to grouping studies into two categories: higher quality (randomized trials) and lower quality (other study designs).

Result of the search
A total of 2,742 papers were found in MEDLINE and Embase.Removing duplicates left 1,653.
We retained 622 based on title, 132 based on abstract, and 15 based on full text.We found 19 additional studies via reference lists and PubMed related articles searches.Therefore, a total of 34 studies were included (eFigure in the Supplement).Randomized trial evidence was only available for the effectiveness of hand washing and face masks (Jefferson et al. 2011;Smith et al. 2015;MacIntyre et al. 2015;Saunders-Hastings et al. 2017).For other interventions, only lower-quality evidence was available (observational and modelling studies).face masks (very cost-effective), preventive measures in hospitals (cost-effective), antiviral treatment (cost-effective), antiviral prophylaxis (cost-effective), low efficiency vaccination (costeffective if timed before cases peak), high efficiency vaccination (cost-effective if timed before cases peak), stockpiling antiviral medicine (cost-effective for high-income countries), quarantining confirmed cases at home (cost-effective for viruses with a case fatality rate of 1%, not cost-effective for viruses with a case fatality rate of 0.25%), self-isolation at home (costeffective with a case fatality rate of 1%, not cost-effective with a case fatality rate of 0.25%), and school closure (not cost-effective).For H1N1 influenza, contact tracing was estimated to be 4,363 times more cost-effective than school closures ($2,260 vs. $9,860,000 per death prevented) (Madhav et al. 2017).Indeed, Lempel et al. (2009) estimated that closing all schools in the US for 4 weeks would cost $10 to $47 billion (0.1-0.3% of GDP).Other systematic reviews found that school closures did not contribute to the control of the 2003 SARS epidemic in China, Hong Kong, and Singapore and would prevent only 2-4% of COVID-19 deaths (Viner et al. 2020); reduced the peak of epidemics by 29.65% on average and were more effective when timed early (Bin Nafisah et al. 2018); would be most effective if they caused large reductions in contact, if transmissibility was low (e.g. a basic reproduction number <2), and if attack rates were higher in children than in adults (Jackson et al. 2014); and appeared to be moderately effective in reducing the transmission of influenza and in delaying the peak of an epidemic, but were associated with very high costs (Rashid et al. 2015).Differences in publication date, virus transmissibility, and study selection may explain the discrepancies among these reviews.

Pasquini
Contact tracing and case isolation was one of the most cost-effective interventions, based on H1N1 data from Hubei, China (Wang et al. 2012).Pasquini-Descomps et al. (2017) computed that it cost less than $1,000 per disability-adjusted life year.In a simulation study, Hellewell et al. (2020) found that in most scenarios, highly effective contact tracing and case isolation would be enough to control a new outbreak of COVID-19 within 3 months.Timing was important: with five initial cases, there was a greater than 50% chance of achieving control, even at modest contact-tracing levels.However, at 40 initial cases, control was much less likely.Similarly, any delay from symptom onset to isolation decreased the probability of control, highlighting the need for swift action.In another modelling study, Chen et al. (2018) compared the effects of four interventions on the total attack rate and duration of a school influenza outbreak in Changsha, China.Case isolation was the most effective single intervention, and the addition of antiviral therapeutics, antiviral prophylaxis, vaccination prior to the outbreak, and school closure decreased the attack rate only slightly, and shortened outbreak duration by only 9 days.Saunders-Hastings et al. (2017) carried out a systematic review and meta-analysis of personal protective measures to reduce pandemic influenza transmission.They did not find any study evaluating respiratory etiquette (e.g.covering the mouth during coughing).Meta-analyses suggested that regular hand hygiene provided a significant protective effect (OR = 0.62; 95% CI 0.52-0.73).Face masks had a non-significant protective effect (OR = 0.53; 95% CI 0.16-1.71)which became significant (OR = 0.41; 95% CI 0.18-0.92)when randomized control trials and cohort studies were pooled with case-control studies (this also decreased heterogeneity).In an earlier systematic review, Jefferson et al. (2011)  Preventive measures in hospitals include use of personal protective equipment for healthcare workers in direct contact with suspected patients.Dan et al. (2009) estimated that this measure was cost-effective for H1N1 ($23,600 per death prevented).However, adopting a wider set of measures (full personal protective equipment, restricting visitors, and cancelling elective procedures) was much less cost-effective ($2,500,000 per death prevented).Similarly, Lee et al. (2011) found that increasing hand hygiene, use of protective apparel, and disinfection are the most cost-saving interventions to control a hospital outbreak of norovirus.Suphanchaimat et al. (2020) found that influenza vaccination for prisoners in Thailand was costeffective.The incremental cost-effectiveness ratio of vaccination (compared with routine outbreak control) was $1283 to $1990 per disability-adjusted life year.Prosser et al. (2011) also found that H1N1 vaccination in the US was cost-effective under many assumptions if initiated prior to the outbreak.Incremental cost-effectiveness ratios ranged from $8,000 to $52,000 per quality-adjusted life year for persons aged 6 months to 64 years without high-risk conditions.The authors noted that all doses (two for some children, one for adults) should be delivered before the peak of a hypothetical influenza season.Otherwise, vaccination may not be cost-effective.Khazeni et al. (2009) also found that earlier vaccination is more cost-saving.If vaccine supplies are limited, Lee et al. (2010) found that priority should be given to at-risk individuals, and to children within highrisk groups.
In another systematic review of economic evaluations, Pérez Velasco et al. (2012) examined 44 studies and found that combinations of pharmaceutical and non-pharmaceutical interventions were more cost-effective than vaccines and/or antivirals alone.Reducing non-essential contacts, using pharmaceutical prophylaxis, and closing schools was the most cost-effective combination for all countries.However, quarantine for household contacts was not cost-effective, even in low-and middle-income countries.A modelling study by Day et al. (2006) suggested that quarantine (of all individuals who have had contact with an infected individual) would be beneficial only when case isolation is ineffective, when there is significant asymptomatic transmission, and when the asymptomatic period is neither very long, nor very short.Perlroth et al. (2010) estimated the health outcomes and costs of combinations of 4 social distancing strategies and 2 antiviral medication strategies.For a virus with a case fatality rate of 1% and a reproduction number of 2.1 or greater, school closure alone was the least cost-effective intervention and cost $32,100 per case averted.Antiviral treatment ($18,200), quarantine of infected individuals ($15,300), and adult and child social distancing ($5,600) had increasing levels of cost-effectiveness.However, combining interventions was more cost-effective, and the most cost-effective combination included adult and child social distancing, school closure, and antiviral treatment and prophylaxis ($2,700 per case).However, the same combination without school closure was more cost-effective for milder viruses (case fatality rate below 1%, reproduction number 1.6 or lower).If antivirals are not available, the combination of adult and child social distancing and school closure was most effective.influenza pandemic (isolation or quarantine, school closure, public gathering ban).They found that every city adopted at least one of these interventions, and that 15 cities applied all three.The most common combination (school closure and public gathering bans) was implemented in 34 cities (79%) for a median duration of 4 weeks and was significantly associated with reductions in weekly excess death rate.Cities that implemented interventions earlier had greater delays in reaching peak mortality (Spearman r=−0.74,P<0.001), lower peak mortality rates (Spearman r=0.31,P=.02), and lower total mortality (Spearman r=0.37,P=.008).There was a significant association between increased duration of interventions and a reduced total mortality burden (Spearman r=−0.39,P=.005).
Ishola and Phin (2011) reviewed the literature on mass gatherings.They found 24 studies and cautiously concluded that there is some evidence to indicate that mass gatherings may be associated with an increased risk of influenza transmission.In a more recent systematic review, Rainey et al. (2016) found that mass gathering-related respiratory disease outbreaks were relatively rare between 2005 and 2014 in the US.They concluded that this could suggest-perhaps surprisingly-low transmission at most types of gatherings, even during pandemics.Similarly, in a US survey of 50 state health departments and 31 large local health departments, Figueroa et al.
(2017) found that outbreaks at mass gatherings were uncommon, even during the 2009 H1N1 pandemic.In a modelling study, Shi et al. (2010) found that mass gatherings that occur within 10 days before the epidemic peak can result in a 10% relative increase in peak prevalence and total attack rate.Conversely, they found that mass gatherings may have little effect when occurring more than 40 days earlier or 20 days later than the infection peak (when initial Ro = 1.5).Thus the timing of mass gatherings might explain the apparent lack of evidence in support of their ban.
Recently, Zhao et al. (2020) quantified the association between domestic travel out of Wuhan, China, and the spread of SARS-CoV-2.Using location-based data, they estimated that each increase of 100 in daily new cases and daily passengers departing from Wuhan was associated with an increase of 16.25% (95% CI: 14.86-17.66%) in daily new cases outside of Wuhan.Ryu et al. (2020) conducted a systematic review of international travel restrictions, screening of travelers, and border closure.They examined 15 studies and concluded that the evidence did not support entry screening as an effective measure, and that travel restrictions and border closures would have limited effectiveness in controlling pandemic influenza.In another systematic review, Mateus et al. ( 2014) concluded that the evidence did not support travel restrictions as an isolated intervention for the containment of influenza, and that restrictions would be "extremely limited" in containing the emergence of a pandemic virus.Chinazzi et al. (2020) used a global disease transmission model to project the impact of travel limitations on the spread of COVID-19.They estimated that the travel quarantine of Wuhan delayed the overall epidemic progression by 3 to 5 days in Mainland China, and reduced international case importations by nearly 80% until mid February.Modeling results also indicated that sustained 90% travel restrictions to and from China only modestly affect the epidemic trajectory unless combined with a 50% or higher reduction of transmission in the community.Travel limitations may be more effective when neighbouring countries fail to implement adequate outbreak control efforts (Bwire et al. 2016).

DISCUSSION
This rapid systematic review aimed to provide a comprehensive summary of the evidence on pandemic control, with a focus on cost-effective interventions in the context of COVID-19.
Randomized trial evidence was only available to support the effectiveness of hand washing and face masks.Modelling studies suggested that these measures are highly cost-effective.For other interventions, only evidence from observational and modelling studies was available.This lowerquality evidence suggests that overall, when timed appropriately, the following interventions are likely to be highly cost-effective: contact tracing and case isolation, protective equipment for healthcare workers, and vaccination prior to the outbreak (when available).Surveillance networks and protective equipment for healthcare workers are also likely to be cost-effective.Home quarantine for confirmed cases and stockpiling antivirals appear less cost-effective.The least costeffective interventions appear to be social distancing measures like workplace and school closures.
The evidence suggests that these are more cost-effective for severe viruses like SARS-CoV-2, and when timed early in the outbreak.Vaccination past the peak of infections and long-term school closures late in the outbreak appear less cost-effective, underscoring the importance of timing.

Limitations
This rapid systematic review has a number of limitations.First, randomized trial evidence was not available for most epidemic control interventions.Consequently, we included observational and modelling studies.Their results should be interpreted with caution.Still, as COVID-19 forces urgent decision-making, we submit that some evidence is better than none.Second, because of time constraints, our search was limited to two databases (MEDLINE and Embase).Only one investigator screened titles, abstracts, and the full text of papers.We performed limited quality assessment and we did not examine risk of bias.Third, most of the studies we have reviewed focused on H1N1 and other viruses, not SARS-CoV-2.Fourth, estimates of COVID-19 case fatality rate are subject to substantial uncertainties.We assessed the cost-effectiveness of interventions based on estimates of 1 to 2%.These are likely to change as more data emerge.Should the true rate be higher, all interventions would be more cost-effective.Conversely, should it be lower, costly interventions such as extended school closures may not be cost-effective.

Conclusions
Hand washing and face masks were the only measures supported by higher-quality evidence.Other interventions were supported by lower-quality evidence.In the context of COVID-19, a cautious interpretation suggests that (1) social distancing is effective but costly, especially when adopted late and (2) adopting as early as possible a combination of interventions that includes hand washing, face masks, swift contact tracing and case isolation, and protective equipment for healthcare workers is likely to be the most cost-effective strategy.
Halder et al. (2011)  also aimed to determine the most cost-effective interventions for a pandemic similar to H1N1.They found that a combination of interventions was most cost-effective.This combination included treatment and household prophylaxis using antiviral drugs and limited duration school closure.If antiviral drugs are not available, limited duration school closure was significantly more cost-effective compared to continuous school closure.Other social distancing strategies, such as reduced workplace attendance, were found to be costly due to productivity losses.Closing school for 2 to 4 weeks without other interventions did not cost much more than doing nothing but gave a significant 34% to 37% reduction in cases "if optimally timed".The authors examined timing in another study, in which the effectiveness of school closures were analyzed for durations of 2, 4 and 8 weeks(Halder et al. 2010).They found that the most appropriate strategy depended on the virus' severity and transmissibility.For mild viruses, they concluded that individual school closures should begin once daily new cases reach 10 to 50.For highly transmissible epidemics (reproduction number of 2 or above), they concluded that long duration school closure should begin as soon as possible and be combined with other interventions.Indeed, for such viruses, they found that school closure alone would be ineffective (~4% reduction in attack rate) and recommend "additional rigorous social distancing interventions."Studies on intervention effectiveness without cost-effectiveness analysisSmith et al. (2015) carried out a systematic review of non-pharmaceutical interventions to reduce the transmission of influenza in adults.Only randomized trials were included and 7 studies met all selection criteria.The authors found that positive significant interventions included professional oral hygiene intervention in the elderly and hand washing, and noted that home quarantine may be useful, but required further assessment.Jefferson et al. (2011) conducted a Cochrane systematic review of physical interventions to interrupt or reduce the spread of respiratory viruses.They found that the highest quality randomized cluster trials suggested this could be achieved by hygienic measures such as handwashing, especially around younger children.They recommended that the following effective interventions be implemented, preferably in a combined fashion, to reduce transmission of viral respiratory disease: frequent handwashing with or without adjunct antiseptics; barrier measures such as gloves, gowns and masks with filtration apparatus; and suspicion diagnosis with isolation of likely cases.Lee et al. (2009) carried out a systematic review of modelling studies quantifying the effectiveness of strategies for pandemic influenza response.They found that combinations of strategies increased the effectiveness of individual strategies and could reduce their potential negative impact.Combinations delayed spread, reduced overall number of cases, and delayed and reduced peak attack rate more than individual strategies.Pan et al. (2020) examined associations between public health interventions and the epidemiology of COVID-19 in Wuhan, China.Traffic restrictions, cancellation of social gatherings, and home quarantines were associated with reduced transmission, but were not sufficient to prevent increases in confirmed cases.These were reduced and estimates of the effective reproduction number fell below 1 only when additional interventions were implemented.Those included hospital-based measures (designated hospitals and wards, use of personal protective equipment, increased testing capacity and accelerated reporting, and timely medical treatment) and community-based interventions (quarantine of confirmed and presumptive cases and of close contacts in designated facilities).Markel et al. (2007) examined nonpharmaceutical interventions in US cities during the 1918-1919 As many authors have noted, the cost-effectiveness of interventions depends on virus severity.For SARS-CoV-2, Wu et al. (2020) estimated a case fatality rate of 1.4% in Wuhan, China, and a crude case fatality risk in areas outside Hubei of 0.85%.Russell et al. (2020) estimated a case fatality rate of 1.2% in China, and of 2.6% on the Diamond Princess cruise ship.Roussel et al. (2020) reported a mortality rate of 1.3% in OECD countries as of March 2, 2020.Onder al. (2020) reported a case fatality rate of 1% in Korea and rates in Italy ranging from 3.1% (February 24) to 7.2% (March 17).They point out that the high rates in Italy may be due to differences in population age, definition of COVID-19-related deaths, and testing strategies.Based on the above, our assessment of the cost-effectiveness of interventions is based on an estimate of 1 to 2% case fatality rate for COVID-19.The cost-effectiveness of interventions also depends on their timing.Taking this into account, we propose a 3-stage framework for pandemic control interventions, adapted from Madhav et al. (2017).This framework is illustrated in Figure 1.Stages are shown from left to right, and interventions are shown from top (most cost-effective) to bottom (least cost-effective).

Figure 1
Figure 1 shows the cost-effectiveness of interventions to control COVID-19 by stage of the pandemic.According to this framework, surveillance networks are highly cost-effective, should be established before the pandemic starts (stage 1), and maintained through stages 2 and 3.Vaccination, when available, should occur before the pandemic, or as early as possible.Antivirals can be stockpiled cost-effectively in high-income countries.As the pandemic starts (stage 2), early contact tracing and case isolation is the most cost-effective intervention.It may be sufficient to contain the outbreak.If the outbreak is not contained, hand hygiene, face masks, and protective equipment for healthcare workers are all highly cost-effective.If these measures are not sufficient, home quarantines, social distancing, and school closures are all effective, albeit increasingly costly measures.Assuming a 1 to 2% case fatality rate for COVID-19, these measures are likely to be cost-effective nonetheless, especially if implemented early.As COVID-19 spreads (stage 3), and especially past the peak, the costliest interventions can be replaced cost-effectively by a Day T, Park A, Madras N, Gumel A, Wu J.When is quarantine a useful control strategy for emerging infectious diseases?Am J Epidemiol.2006 Mar 1;163(5):479-85.Fähnrich C, Denecke K, Adeoye OO, Benzler J, Claus H, Kirchner G, Mall S, Richter R, Schapranow MP, Schwarz N, Tom-Aba D, Uflacker M, Poggensee G, Krause G. Surveillance and Outbreak Response Management System (SORMAS) to support the control of the Ebola virus disease outbreak in West Africa.Euro Surveill.2015 Mar 26;20(12).

Figueroa
Figueroa A, Gulati RK, Rainey JJ.Estimating the frequency and characteristics of respiratory disease outbreaks at mass gatherings in the United States: Findings from a state and local health department assessment.PLoS One.2017 Oct 27;12(10):e0186730.doi: 10.1371/journal.pone.0186730.