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      How will country-based mitigation measures influence the course of the COVID-19 epidemic?

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          Abstract

          Governments will not be able to minimise both deaths from coronavirus disease 2019 (COVID-19) and the economic impact of viral spread. Keeping mortality as low as possible will be the highest priority for individuals; hence governments must put in place measures to ameliorate the inevitable economic downturn. In our view, COVID-19 has developed into a pandemic, with small chains of transmission in many countries and large chains resulting in extensive spread in a few countries, such as Italy, Iran, South Korea, and Japan. 1 Most countries are likely to have spread of COVID-19, at least in the early stages, before any mitigation measures have an impact. What has happened in China shows that quarantine, social distancing, and isolation of infected populations can contain the epidemic. 1 This impact of the COVID-19 response in China is encouraging for the many countries where COVID-19 is beginning to spread. However, it is unclear whether other countries can implement the stringent measures China eventually adopted. Singapore and Hong Kong, both of which had severe acute respiratory syndrome (SARS) epidemics in 2002–03, provide hope and many lessons to other countries. In both places, COVID-19 has been managed well to date, despite early cases, by early government action and through social distancing measures taken by individuals. The course of an epidemic is defined by a series of key factors, some of which are poorly understood at present for COVID-19. The basic reproduction number (R0), which defines the mean number of secondary cases generated by one primary case when the population is largely susceptible to infection, determines the overall number of people who are likely to be infected, or more precisely the area under the epidemic curve. For an epidemic to take hold, the value of R0 must be greater than unity in value. A simple calculation gives the fraction likely to be infected without mitigation. This fraction is roughly 1–1/R0. With R0 values for COVID-19 in China around 2·5 in the early stages of the epidemic, 2 we calculate that approximately 60% of the population would become infected. This is a very worst-case scenario for a number of reasons. We are uncertain about transmission in children, some communities are remote and unlikely to be exposed, voluntary social distancing by individuals and communities will have an impact, and mitigation efforts, such as the measures put in place in China, greatly reduce transmission. As an epidemic progresses, the effective reproduction number (R) declines until it falls below unity in value when the epidemic peaks and then decays, either due to the exhaustion of people susceptible to infection or the impact of control measures. The speed of the initial spread of the epidemic, its doubling time, or the related serial interval (the mean time it takes for an infected person to pass on the infection to others), and the likely duration of the epidemic are determined by factors such as the length of time from infection to when a person is infectious to others and the mean duration of infectiousness. For the 2009 influenza A H1N1 pandemic, in most infected people these epidemiological quantities were short with a day or so to infectiousness and a few days of peak infectiousness to others. 3 By contrast, for COVID-19, the serial interval is estimated at 4·4–7·5 days, which is more similar to SARS. 4 First among the important unknowns about COVID-19 is the case fatality rate (CFR), which requires information on the denominator that defines the number infected. We are unaware of any completed large-scale serology surveys to detect specific antibodies to COVID-19. Best estimates suggest a CFR for COVID-19 of about 0·3–1%, 4 which is higher than the order of 0·1% CFR for a moderate influenza A season. 5 The second unknown is the whether infectiousness starts before onset of symptoms. The incubation period for COVID-19 is about 5–6 days.4, 6 Combining this time with a similar length serial interval suggests there might be considerable presymptomatic infectiousness (appendix 1). For reference, influenza A has a presymptomatic infectiousness of about 1–2 days, whereas SARS had little or no presymptomatic infectiousness. 7 There have been few clinical studies to measure COVID-19 viraemia and how it changes over time in individuals. In one study of 17 patients with COVID-19, peak viraemia seems to be at the end of the incubation period, 8 pointing to the possibility that viraemia might be high enough to trigger transmission for 1–2 days before onset of symptoms. If these patterns are verified by more extensive clinical virological studies, COVID-19 would be expected to be more like influenza A than SARS. For SARS, peak infectiousness took place many days after first symptoms, hence the success of quarantine of patients with SARS soon after symptoms started 7 and the lack of success for this measure for influenza A and possibly for COVID-19. The third uncertainty is whether there are a large number of asymptomatic cases of COVID-19. Estimates suggest that about 80% of people with COVID-19 have mild or asymptomatic disease, 14% have severe disease, and 6% are critically ill, 9 implying that symptom-based control is unlikely to be sufficient unless these cases are only lightly infectious. The fourth uncertainty is the duration of the infectious period for COVID-19. The infectious period is typically short for influenza A, but it seems long for COVID-19 on the basis of the few available clinical virological studies, perhaps lasting for 10 days or more after the incubation period. 8 The reports of a few super-spreading events are a routine feature of all infectious diseases and should not be overinterpreted. 10 What do these comparisons with influenza A and SARS imply for the COVID-19 epidemic and its control? First, we think that the epidemic in any given country will initially spread more slowly than is typical for a new influenza A strain. COVID-19 had a doubling time in China of about 4–5 days in the early phases. 3 Second, the COVID-19 epidemic could be more drawn out than seasonal influenza A, which has relevance for its potential economic impact. Third, the effect of seasons on transmission of COVID-19 is unknown; 11 however, with an R0 of 2–3, the warm months of summer in the northern hemisphere might not necessarily reduce transmission below the value of unity as they do for influenza A, which typically has an R0 of around 1·1–1·5. 12 Closely linked to these factors and their epidemiological determinants is the impact of different mitigation policies on the course of the COVID-19 epidemic. A key issue for epidemiologists is helping policy makers decide the main objectives of mitigation—eg, minimising morbidity and associated mortality, avoiding an epidemic peak that overwhelms health-care services, keeping the effects on the economy within manageable levels, and flattening the epidemic curve to wait for vaccine development and manufacture on scale and antiviral drug therapies. Such mitigation objectives are difficult to achieve by the same interventions, so choices must be made about priorities. 13 For COVID-19, the potential economic impact of self-isolation or mandated quarantine could be substantial, as occurred in China. No vaccine or effective antiviral drug is likely to be available soon. Vaccine development is underway, but the key issues are not if a vaccine can be developed but where phase 3 trials will be done and who will manufacture vaccine at scale. The number of cases of COVID-19 are falling quickly in China, 4 but a site for phase 3 vaccine trials needs to be in a location where there is ongoing transmission of the disease. Manufacturing at scale requires one or more of the big vaccine manufacturers to take up the challenge and work closely with the biotechnology companies who are developing vaccine candidates. This process will take time and we are probably a least 1 year to 18 months away from substantial vaccine production. So what is left at present for mitigation is voluntary plus mandated quarantine, stopping mass gatherings, closure of educational institutes or places of work where infection has been identified, and isolation of households, towns, or cities. Some of the lessons from analyses of influenza A apply for COVID-19, but there are also differences. Social distancing measures reduce the value of the effective reproduction number R. With an early epidemic value of R0 of 2·5, social distancing would have to reduce transmission by about 60% or less, if the intrinsic transmission potential declines in the warm summer months in the northern hemisphere. This reduction is a big ask, but it did happen in China. School closure, a major pillar of the response to pandemic influenza A, 14 is unlikely to be effective given the apparent low rate of infection among children, although data are scarce. Avoiding large gatherings of people will reduce the number of super-spreading events; however, if prolonged contact is required for transmission, this measure might only reduce a small proportion of transmissions. Therefore, broader-scale social distancing is likely to be needed, as was put in place in China. This measure prevents transmission from symptomatic and non-symptomatic cases, hence flattening the epidemic and pushing the peak further into the future. Broader-scale social distancing provides time for the health services to treat cases and increase capacity, and, in the longer term, for vaccines and treatments to be developed. Containment could be targeted to particular areas, schools, or mass gatherings. This approach underway in northern Italy will provide valuable data on the effectiveness of such measures. The greater the reduction in transmission, the longer and flatter the epidemic curve (figure ), with the risk of resurgence when interventions are lifted perhaps to mitigate economic impact. Figure Illustrative simulations of a transmission model of COVID-19 A baseline simulation with case isolation only (red); a simulation with social distancing in place throughout the epidemic, flattening the curve (green), and a simulation with more effective social distancing in place for a limited period only, typically followed by a resurgent epidemic when social distancing is halted (blue). These are not quantitative predictions but robust qualitative illustrations for a range of model choices. The key epidemiological issues that determine the impact of social distancing measures are what proportion of infected individuals have mild symptoms and whether these individuals will self-isolate and to what effectiveness; how quickly symptomatic individuals take to isolate themselves after the onset of symptoms; and the duration of any non-symptomatic infectious period before clear symptoms occur with the linked issue of how transmissible COVID-19 is during this phase. Individual behaviour will be crucial to control the spread of COVID-19. Personal, rather than government action, in western democracies might be the most important issue. Early self-isolation, seeking medical advice remotely unless symptoms are severe, and social distancing are key. Government actions to ban mass gatherings are important, as are good diagnostic facilities and remotely accessed health advice, together with specialised treatment for people with severe disease. Isolating towns or even cities is not yet part of the UK Government action plan. 15 This plan is light on detail, given the early stages of the COVID-19 epidemic and the many uncertainties, but it outlines four phases of action entitled contain, delay, research, and mitigate. 15 The UK has just moved from contain to delay, which aims to flatten the epidemic and lower peak morbidity and mortality. If measures are relaxed after a few months to avoid severe economic impact, a further peak is likely to occur in the autumn (figure). Italy, South Korea, Japan, and Iran are at the mitigate phase and trying to provide the best care possible for a rapidly growing number of people with COVID-19. The known epidemiological characteristics of COVID-19 point to urgent priorities. Shortening the time from symptom onset to isolation is vital as it will reduce transmission and is likely to slow the epidemic (appendices 2, 3) However, strategies are also needed for reducing household transmission, supporting home treatment and diagnosis, and dealing with the economic consequences of absence from work. Peak demand for health services could still be high and the extent and duration of presymptomatic or asymptomatic transmission—if this turns out to be a feature of COVID-19 infection—will determine the success of this strategy. 16 Contact tracing is of high importance in the early stages to contain spread, and model-based estimates suggest, with an R0 value of 2·5, that about 70% of contacts will have to be successfully traced to control early spread. 17 Analysis of individual contact patterns suggests that contact tracing can be a successful strategy in the early stages of an outbreak, but that the logistics of timely tracing on average 36 contacts per case will be challenging. 17 Super-spreading events are inevitable, and could overwhelm the contact tracing system, leading to the need for broader-scale social distancing interventions. Data from China, South Korea, Italy, and Iran suggest that the CFR increases sharply with age and is higher in people with COVID-19 and underlying comorbidities. 18 Targeted social distancing for these groups could be the most effective way to reduce morbidity and concomitant mortality. During the outbreak of Ebola virus disease in west Africa in 2014–16, deaths from other causes increased because of a saturated health-care system and deaths of health-care workers. 19 These events underline the importance of enhanced support for health-care infrastructure and effective procedures for protecting staff from infection. In northern countries, there is speculation that changing contact patterns and warmer weather might slow the spread of the virus in the summer. 11 With an R0 of 2·5 or higher, reductions in transmission by social distancing would have to be large; and much of the changes in transmission of pandemic influenza in the summer of 2009 within Europe were thought to be due to school closures, but children are not thought to be driving transmission of COVID-19. Data from the southern hemisphere will assist in evaluating how much seasonality will influence COVID-19 transmission. Model-based predictions can help policy makers make the right decisions in a timely way, even with the uncertainties about COVID-19. Indicating what level of transmission reduction is required for social distancing interventions to mitigate the epidemic is a key activity (figure). However, it is easy to suggest a 60% reduction in transmission will do it or quarantining within 1 day from symptom onset will control transmission, but it is unclear what communication strategies or social distancing actions individuals and governments must put in place to achieve these desired outcomes. A degree of pragmatism will be needed for the implementation of social distancing and quarantine measures. Ongoing data collection and epidemiological analysis are therefore essential parts of assessing the impacts of mitigation strategies, alongside clinical research on how to best manage seriously ill patients with COVID-19. There are difficult decisions ahead for governments. How individuals respond to advice on how best to prevent transmission will be as important as government actions, if not more important. Government communication strategies to keep the public informed of how best to avoid infection are vital, as is extra support to manage the economic downturn.

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          Most cited references8

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          Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus–Infected Pneumonia

          Abstract Background The initial cases of novel coronavirus (2019-nCoV)–infected pneumonia (NCIP) occurred in Wuhan, Hubei Province, China, in December 2019 and January 2020. We analyzed data on the first 425 confirmed cases in Wuhan to determine the epidemiologic characteristics of NCIP. Methods We collected information on demographic characteristics, exposure history, and illness timelines of laboratory-confirmed cases of NCIP that had been reported by January 22, 2020. We described characteristics of the cases and estimated the key epidemiologic time-delay distributions. In the early period of exponential growth, we estimated the epidemic doubling time and the basic reproductive number. Results Among the first 425 patients with confirmed NCIP, the median age was 59 years and 56% were male. The majority of cases (55%) with onset before January 1, 2020, were linked to the Huanan Seafood Wholesale Market, as compared with 8.6% of the subsequent cases. The mean incubation period was 5.2 days (95% confidence interval [CI], 4.1 to 7.0), with the 95th percentile of the distribution at 12.5 days. In its early stages, the epidemic doubled in size every 7.4 days. With a mean serial interval of 7.5 days (95% CI, 5.3 to 19), the basic reproductive number was estimated to be 2.2 (95% CI, 1.4 to 3.9). Conclusions On the basis of this information, there is evidence that human-to-human transmission has occurred among close contacts since the middle of December 2019. Considerable efforts to reduce transmission will be required to control outbreaks if similar dynamics apply elsewhere. Measures to prevent or reduce transmission should be implemented in populations at risk. (Funded by the Ministry of Science and Technology of China and others.)
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            SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients

            To the Editor: The 2019 novel coronavirus (SARS-CoV-2) epidemic, which was first reported in December 2019 in Wuhan, China, and has been declared a public health emergency of international concern by the World Health Organization, may progress to a pandemic associated with substantial morbidity and mortality. SARS-CoV-2 is genetically related to SARS-CoV, which caused a global epidemic with 8096 confirmed cases in more than 25 countries in 2002–2003. 1 The epidemic of SARS-CoV was successfully contained through public health interventions, including case detection and isolation. Transmission of SARS-CoV occurred mainly after days of illness 2 and was associated with modest viral loads in the respiratory tract early in the illness, with viral loads peaking approximately 10 days after symptom onset. 3 We monitored SARS-CoV-2 viral loads in upper respiratory specimens obtained from 18 patients (9 men and 9 women; median age, 59 years; range, 26 to 76) in Zhuhai, Guangdong, China, including 4 patients with secondary infections (1 of whom never had symptoms) within two family clusters (Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). The patient who never had symptoms was a close contact of a patient with a known case and was therefore monitored. A total of 72 nasal swabs (sampled from the mid-turbinate and nasopharynx) (Figure 1A) and 72 throat swabs (Figure 1B) were analyzed, with 1 to 9 sequential samples obtained from each patient. Polyester flock swabs were used for all the patients. From January 7 through January 26, 2020, a total of 14 patients who had recently returned from Wuhan and had fever (≥37.3°C) received a diagnosis of Covid-19 (the illness caused by SARS-CoV-2) by means of reverse-transcriptase–polymerase-chain-reaction assay with primers and probes targeting the N and Orf1b genes of SARS-CoV-2; the assay was developed by the Chinese Center for Disease Control and Prevention. Samples were tested at the Guangdong Provincial Center for Disease Control and Prevention. Thirteen of 14 patients with imported cases had evidence of pneumonia on computed tomography (CT). None of them had visited the Huanan Seafood Wholesale Market in Wuhan within 14 days before symptom onset. Patients E, I, and P required admission to intensive care units, whereas the others had mild-to-moderate illness. Secondary infections were detected in close contacts of Patients E, I, and P. Patient E worked in Wuhan and visited his wife (Patient L), mother (Patient D), and a friend (Patient Z) in Zhuhai on January 17. Symptoms developed in Patients L and D on January 20 and January 22, respectively, with viral RNA detected in their nasal and throat swabs soon after symptom onset. Patient Z reported no clinical symptoms, but his nasal swabs (cycle threshold [Ct] values, 22 to 28) and throat swabs (Ct values, 30 to 32) tested positive on days 7, 10, and 11 after contact. A CT scan of Patient Z that was obtained on February 6 was unremarkable. Patients I and P lived in Wuhan and visited their daughter (Patient H) in Zhuhai on January 11 when their symptoms first developed. Fever developed in Patient H on January 17, with viral RNA detected in nasal and throat swabs on day 1 after symptom onset. We analyzed the viral load in nasal and throat swabs obtained from the 17 symptomatic patients in relation to day of onset of any symptoms (Figure 1C). Higher viral loads (inversely related to Ct value) were detected soon after symptom onset, with higher viral loads detected in the nose than in the throat. Our analysis suggests that the viral nucleic acid shedding pattern of patients infected with SARS-CoV-2 resembles that of patients with influenza 4 and appears different from that seen in patients infected with SARS-CoV. 3 The viral load that was detected in the asymptomatic patient was similar to that in the symptomatic patients, which suggests the transmission potential of asymptomatic or minimally symptomatic patients. These findings are in concordance with reports that transmission may occur early in the course of infection 5 and suggest that case detection and isolation may require strategies different from those required for the control of SARS-CoV. How SARS-CoV-2 viral load correlates with culturable virus needs to be determined. Identification of patients with few or no symptoms and with modest levels of detectable viral RNA in the oropharynx for at least 5 days suggests that we need better data to determine transmission dynamics and inform our screening practices.
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              Feasibility of controlling COVID-19 outbreaks by isolation of cases and contacts

              Summary Background Isolation of cases and contact tracing is used to control outbreaks of infectious diseases, and has been used for coronavirus disease 2019 (COVID-19). Whether this strategy will achieve control depends on characteristics of both the pathogen and the response. Here we use a mathematical model to assess if isolation and contact tracing are able to control onwards transmission from imported cases of COVID-19. Methods We developed a stochastic transmission model, parameterised to the COVID-19 outbreak. We used the model to quantify the potential effectiveness of contact tracing and isolation of cases at controlling a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-like pathogen. We considered scenarios that varied in the number of initial cases, the basic reproduction number (R 0), the delay from symptom onset to isolation, the probability that contacts were traced, the proportion of transmission that occurred before symptom onset, and the proportion of subclinical infections. We assumed isolation prevented all further transmission in the model. Outbreaks were deemed controlled if transmission ended within 12 weeks or before 5000 cases in total. We measured the success of controlling outbreaks using isolation and contact tracing, and quantified the weekly maximum number of cases traced to measure feasibility of public health effort. Findings Simulated outbreaks starting with five initial cases, an R 0 of 1·5, and 0% transmission before symptom onset could be controlled even with low contact tracing probability; however, the probability of controlling an outbreak decreased with the number of initial cases, when R 0 was 2·5 or 3·5 and with more transmission before symptom onset. Across different initial numbers of cases, the majority of scenarios with an R 0 of 1·5 were controllable with less than 50% of contacts successfully traced. To control the majority of outbreaks, for R 0 of 2·5 more than 70% of contacts had to be traced, and for an R 0 of 3·5 more than 90% of contacts had to be traced. The delay between symptom onset and isolation had the largest role in determining whether an outbreak was controllable when R 0 was 1·5. For R 0 values of 2·5 or 3·5, if there were 40 initial cases, contact tracing and isolation were only potentially feasible when less than 1% of transmission occurred before symptom onset. Interpretation In most scenarios, highly effective contact tracing and case isolation is enough to control a new outbreak of COVID-19 within 3 months. The probability of control decreases with long delays from symptom onset to isolation, fewer cases ascertained by contact tracing, and increasing transmission before symptoms. This model can be modified to reflect updated transmission characteristics and more specific definitions of outbreak control to assess the potential success of local response efforts. Funding Wellcome Trust, Global Challenges Research Fund, and Health Data Research UK.
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                Author and article information

                Contributors
                Journal
                Lancet
                Lancet
                Lancet (London, England)
                Elsevier Ltd.
                0140-6736
                1474-547X
                9 March 2020
                21-27 March 2020
                9 March 2020
                : 395
                : 10228
                : 931-934
                Affiliations
                [a ]Department of Infectious Disease Epidemiology, MRC Centre for Global Health Analysis, Imperial College London, London W2 1PG, UK
                [b ]Department of Population Health Sciences, Utrecht University, Utrecht, Netherlands
                [c ]National Institute for Public Health and the Environment ( RIVM), Bilthoven, Netherlands
                [d ]Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK
                Article
                S0140-6736(20)30567-5
                10.1016/S0140-6736(20)30567-5
                7158572
                32164834
                6e889620-b3aa-417b-aaf0-3dc6474562d8
                © 2020 Elsevier Ltd. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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