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      COVID-19: towards controlling of a pandemic

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          Abstract

          During the past 3 weeks, new major epidemic foci of coronavirus disease 2019 (COVID-19), some without traceable origin, have been identified and are rapidly expanding in Europe, North America, Asia, and the Middle East, with the first confirmed cases being identified in African and Latin American countries. By March 16, 2020, the number of cases of COVID-19 outside China had increased drastically and the number of affected countries, states, or territories reporting infections to WHO was 143. 1 On the basis of ”alarming levels of spread and severity, and by the alarming levels of inaction”, on March 11, 2020, the Director-General of WHO characterised the COVID-19 situation as a pandemic. 2 The WHO Strategic and Technical Advisory Group for Infectious Hazards (STAG-IH) regularly reviews and updates its risk assessment of COVID-19 to make recommendations to the WHO health emergencies programme. STAG-IH's most recent formal meeting on March 12, 2020, included an update of the global COVID-19 situation and an overview of the research priorities established by the WHO Research and Development Blueprint Scientific Advisory Group that met on March 2, 2020, in Geneva, Switzerland, to prioritise the recommendations of an earlier meeting on COVID-19 research held in early February, 2020. 3 In this Comment, we outline STAG-IH's understanding of control activities with the group's risk assessment and recommendations. To respond to COVID-19, many countries are using a combination of containment and mitigation activities with the intention of delaying major surges of patients and levelling the demand for hospital beds, while protecting the most vulnerable from infection, including elderly people and those with comorbidities. Activities to accomplish these goals vary and are based on national risk assessments that many times include estimated numbers of patients requiring hospitalisation and availability of hospital beds and ventilation support. Most national response strategies include varying levels of contact tracing and self-isolation or quarantine; promotion of public health measures, including handwashing, respiratory etiquette, and social distancing; preparation of health systems for a surge of severely ill patients who require isolation, oxygen, and mechanical ventilation; strengthening health facility infection prevention and control, with special attention to nursing home facilities; and postponement or cancellation of large-scale public gatherings. Some lower-income and middle-income countries require technical and financial support to successfully respond to COVID-19, and many African, Asian, and Latin American nations are rapidly developing the capacity for PCR testing for COVID-19. Based on more than 500 genetic sequences submitted to GISAID (the Global Initiative on Sharing All Influenza Data), the virus has not drifted to significant strain difference and changes in sequence are minimal. There is no evidence to link sequence information with transmissibility or virulence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 1 the virus that causes COVID-19. SARS-CoV-2, like other emerging high-threat pathogens, has infected health-care workers in China4, 5 and several other countries. To date, however, in China, where infection prevention and control was taken seriously, nosocomial transmission has not been a major amplifier of transmission in this epidemic. Epidemiological records in China suggest that up to 85% of human-to-human transmission has occurred in family clusters 4 and that 2055 health-care workers have become infected, with an absence of major nosocomial outbreaks and some supporting evidence that some health-care workers acquired infection in their families.4, 5 These findings suggest that close and unprotected exposure is required for transmission by direct contact or by contact with fomites in the immediate environment of those with infection. Continuing reports from outside China suggest the same means of transmission to close contacts and persons who attended the same social events or were in circumscribed areas such as office spaces or cruise ships.6, 7 Intensified case finding and contact tracing are considered crucial by most countries and are being undertaken to attempt to locate cases and to stop onward transmission. Confirmation of infection at present consists of PCR for acute infection, and although many serological tests to identify antibodies are being developed they require validation with well characterised sera before they are reliable for general use. From studies of viral shedding in patients with mild and more severe infections, shedding seems to be greatest during the early phase of disease (Myoung-don Oh and Gabriel Leung, WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Special Administrative Region, China, personal communication).8, 9 The role, if any, of asymptomatic carriers in transmitting infection is not yet completely understood. 4 Presymptomatic infectiousness is a concern (Myoung-don Oh and Gabriel Leung, personal communication)8, 9 and many countries are now using 1–2 days of symptom onset as the start day for contact identification. A comprehensive report published by the Chinese Center for Disease Control and Prevention on the epidemiological characteristics of 72 314 patients with COVID-19 confirmed previous understanding that most known infections cause mild disease, with a case fatality ratio that ranged from 2·9% in Hubei province to 0·4% in the other Chinese provinces. 5 This report also suggested that elderly people, particularly those older than 80 years, and people with comorbidities, such as cardiac disease, respiratory disease, and diabetes, are at greatest risk of serious disease and death. The case definition used in China changed several times as COVID-19 progressed, making it difficult to completely characterise the natural history of infection, including the mortality ratio. 4 Information on mortality and contributing factors from outbreak sites in other countries varies greatly, and seems to be influenced by such factors as age of patients, associated comorbidities, availability of isolation facilities for acute care for patients who need respiratory support, and surge capacity of the health-care system. Individuals in care facilities for older people are at particular risk of serious disease as shown in the report of a series of deaths in an elderly care facility in the USA. 10 The pandemic of COVID-19 has clearly entered a new stage with rapid spread in countries outside China and all members of society must understand and practise measures for self-protection and for prevention of transmission of infection to others. STAG-IH makes the following recommendations. First, countries need to rapidly and robustly increase their preparedness, readiness, and response actions based on their national risk assessment and the four WHO transmission scenarios 11 for countries with no cases, first cases, first clusters, and community transmission and spread (4Cs). Second, all countries should consider a combination of response measures: case and contact finding; containment or other measures that aim to delay the onset of patient surges where feasible; and measures such as public awareness, promotion of personal protective hygiene, preparation of health systems for a surge of severely ill patients, stronger infection prevention and control in health facilities, nursing homes, and long-term care facilities, and postponement or cancellation of large-scale public gatherings. Third, countries with no or a few first cases of COVID-19 should consider active surveillance for timely case finding; isolate, test, and trace every contact in containment; practise social distancing; and ready their health-care systems and populations for spread of infection. Fourth, lower-income and middle-income countries that request support from WHO should be fully supported technically and financially. Financial support should be sought by countries and by WHO, including from the World Bank Pandemic Emergency Financing Facility and other mechanisms. 12 Finally, research gaps about COVID-19 should be addressed and are shown in the accompanying panel and include some identified by the global community and by the Research and Development Blueprint Scientific Advisory Group. Panel Research gaps that need to be addressed for the response to COVID-19 • Fill gaps in understanding of the natural history of infection to better define the period of infectiousness and transmissibility; more accurately estimate the reproductive number in various outbreak settings and improve understanding the role of asymptomatic infection. • Comparative analysis of different quarantine strategies and contexts for their effectiveness and social acceptability • Enhance and develop an ethical framework for outbreak response that includes better equity for access to interventions for all countries • Promote the development of point-of-care diagnostic tests • Determine the best ways to apply knowledge about infection prevention and control in health-care settings in resource-constrained countries (including identification of optimal personal protective equipment) and in the broader community, specifically to understand behaviour among different vulnerable groups • Support standardised, best evidence-based approach for clinical management and better outcomes and implement randomised, controlled trials for therapeutics and vaccines as promising agents emerge • Validation of existing serological tests, including those that have been developed by commercial entities, and establishment of biobanks and serum panels of well characterised COVID-19 sera to support such efforts • Complete work on animal models for vaccine and therapeutic research and development The STAG-IH emphasises the importance of the continued rapid sharing of data of public health importance in medical journals that provide rapid peer review and online publication without a paywall. It is sharing of information in this way, as well as technical collaboration among clinicians, epidemiologists, and virologists, that has provided the world with its current understanding of COVID-19.

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          Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention

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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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              Transmission of 2019-nCoV Infection from an Asymptomatic Contact in Germany

              To the Editor: The novel coronavirus (2019-nCoV) from Wuhan is currently causing concern in the medical community as the virus is spreading around the world. 1 Since identification of the virus in late December 2019, the number of cases from China that have been imported into other countries is on the rise, and the epidemiologic picture is changing on a daily basis. We are reporting a case of 2019-nCoV infection acquired outside Asia in which transmission appears to have occurred during the incubation period in the index patient. A 33-year-old otherwise healthy German businessman (Patient 1) became ill with a sore throat, chills, and myalgias on January 24, 2020. The following day, a fever of 39.1°C (102.4°F) developed, along with a productive cough. By the evening of the next day, he started feeling better and went back to work on January 27. Before the onset of symptoms, he had attended meetings with a Chinese business partner at his company near Munich on January 20 and 21. The business partner, a Shanghai resident, had visited Germany between January 19 and 22. During her stay, she had been well with no signs or symptoms of infection but had become ill on her flight back to China, where she tested positive for 2019-nCoV on January 26 (index patient in Figure 1) (see Supplementary Appendix, available at NEJM.org, for details on the timeline of symptom development leading to hospitalization). On January 27, she informed the company about her illness. Contact tracing was started, and the above-mentioned colleague was sent to the Division of Infectious Diseases and Tropical Medicine in Munich for further assessment. At presentation, he was afebrile and well. He reported no previous or chronic illnesses and had no history of foreign travel within 14 days before the onset of symptoms. Two nasopharyngeal swabs and one sputum sample were obtained and were found to be positive for 2019-nCoV on quantitative reverse-transcriptase–polymerase-chain-reaction (qRT-PCR) assay. 2 Follow-up qRT-PCR assay revealed a high viral load of 108 copies per milliliter in his sputum during the following days, with the last available result on January 29. On January 28, three additional employees at the company tested positive for 2019-nCoV (Patients 2 through 4 in Figure 1). Of these patients, only Patient 2 had contact with the index patient; the other two patients had contact only with Patient 1. In accordance with the health authorities, all the patients with confirmed 2019-nCoV infection were admitted to a Munich infectious diseases unit for clinical monitoring and isolation. So far, none of the four confirmed patients show signs of severe clinical illness. This case of 2019-nCoV infection was diagnosed in Germany and transmitted outside Asia. However, it is notable that the infection appears to have been transmitted during the incubation period of the index patient, in whom the illness was brief and nonspecific. 3 The fact that asymptomatic persons are potential sources of 2019-nCoV infection may warrant a reassessment of transmission dynamics of the current outbreak. In this context, the detection of 2019-nCoV and a high sputum viral load in a convalescent patient (Patient 1) arouse concern about prolonged shedding of 2019-nCoV after recovery. Yet, the viability of 2019-nCoV detected on qRT-PCR in this patient remains to be proved by means of viral culture. Despite these concerns, all four patients who were seen in Munich have had mild cases and were hospitalized primarily for public health purposes. Since hospital capacities are limited — in particular, given the concurrent peak of the influenza season in the northern hemisphere — research is needed to determine whether such patients can be treated with appropriate guidance and oversight outside the hospital.
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                Author and article information

                Contributors
                Journal
                Lancet
                Lancet
                Lancet (London, England)
                Elsevier Ltd.
                0140-6736
                1474-547X
                17 March 2020
                28 March-3 April 2020
                17 March 2020
                : 395
                : 10229
                : 1015-1018
                Affiliations
                [a ]Anthrologica, Oxfordshire, UK
                [b ]Instituto Nacional de Enfermedades Virales Humanas (INEVH) ”Julio Maiztegui” and CCWHO-OPS on Viral Haemorrhagic Fevers and Arboviruses, Buenos Aires, Argentina
                [c ]Karolinska Institute, Stockholm, Sweden
                [d ]Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London WC1E 7HT, UK
                [e ]Nigeria Centre for Disease Control, Abuja, Nigeria
                [f ]Infectious Disease Research Centre, Université Laval, Faculty of Medicine, Québec City, Canada
                [g ]National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
                [h ]Research and Innovation Center, King Saud Medical City, Ministry of Health, Riyadh, Saudi Arabia
                [i ]J W Lee Center for Global Medicine, SNU College of Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
                [j ]Institut Pasteur de Dakar, Dakar, Senegal
                [k ]Centers for Disease Control and Prevention, Atlanta, GA, USA
                [l ]Ministry of Health, Department of Diseases Control, Bangkok, Thailand
                [m ]Robert Koch Institute, Berlin, Germany
                Article
                S0140-6736(20)30673-5
                10.1016/S0140-6736(20)30673-5
                7270596
                32197103
                40b00fe2-6aab-4442-b336-167120cddf44
                © 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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