Coronaviruses (CoV) have been identified as human pathogens since the 1960’s. Coronaviruses infect humans and many other vertebrates . Illness in humans is mostly respiratory or gastrointestinal infections, however symptoms can range from the common cold to more severe lower respiratory infections such as pneumonia [1]. A broad range of coronaviruses are found in bats, which might play a crucial role in the virus evolution of alpha– and betacoronavirus lineages in particular. However, other animal species can also act as an intermediate host and animal reservoir.
Zoonotic coronaviruses have emerged in recent years to cause human outbreaks, such as the Severe Acute Respiratory Syndrome (SARS) in 2003 and the Middle East Respiratory Syndrome (MERS) since 2012.
Coronaviruses are enveloped positive stranded RNA viruses in the order of Nidovirales [2]. With their characteristic surface, the virions have a crown-like appearance under the electron microscope, which is why the viruses are named after the Latin word corona, meaning ‘crown’ or ‘halo’. The subfamily Orthocoronavirinae of the family Coronaviridae is further classified into four coronavirus (CoV) genera: Alpha-, Beta-, Delta– and Gammacoronavirus. Betacoronavirus genus is further separated in five subgenera (Embecovirus, Hibecovirus, Merbecovirus, Nobecovirus and Sarbecovirus). Coronaviruses were identified in the mid-1960s and are known to infect humans and a variety of animals (including birds and mammals). Epithelial cells in the respiratory and gastrointestinal tract are the primary target cells. Due to these characteristics, viral shedding occurs via these systems and transmission can occur through different routes: fomites, airborne or faecal-oral.
To date, seven coronaviruses have been shown to infect humans. Common human coronaviruses Betacoronavirus HCoV-OC43 and HCoV-HKU1 as well as Alphacoronavirus HCoV-229E cause common colds but also severe lower respiratory tract infections in the youngest and oldest age groups; while Alphacoronavirus HCoV-NL63 is considered to be an important cause of (pseudo) croup and bronchiolitis in children [3].
Additional zoonotic coronaviruses have emerged and caused outbreaks in humans: SARS-CoV (2002, Betacoronavirus, subgenus Sarbecovirus), and MERS-CoV (2012, Betacoronavirus, subgenus Merbecovirus). In late 2019, a novel coronavirus related to a cluster of pneumonia cases in Wuhan, China (2019-nCoV) was identified. The 2019-nCoV is closely related to SARS-CoV and genetically clusters within Betacoronavirus subgenus Sarbecovirus [4-6].
Human infections with common coronaviruses are mostly mild and asymptomatic, but severe and fatal infections have been observed. Occasionally, the viruses are able to cause more significant lower respiratory tract infections in humans with pneumonia; this is more likely in immunocompromised individuals, people with cardiopulmonary illnesses, as well as the elderly and young children [3,7,8].
SARS-CoV was identified and caused large outbreaks in 2002–2003; the virus affected 8 096 people causing severe pulmonary infections in different countries globally [7,9,10]
MERS-CoV was identified in 2012 in Saudi-Arabia. Clinical presentation following MERS-CoV infection can range from asymptomatic to symptomatic. Symptoms can include fever, cough and shortness of breath, with pneumonia as a common clinical diagnosis. Symptoms can progres in severe cases to acute respiratory distress syndrome (ARDS), septic shock and multi-organ failure resulting in death. In addition, the gastrointestinal tract can be involved with gastrointestinal symptoms, such as diarrhoea. The clinical course is more severe in immunocompromised patients [8,9].
As regards the 2019-nCoV, epidemiological and serological information is still lacking, limiting our ability to describe the full disease spectrum caused by this virus. Currently, 20–25% of laboratory-confirmed cases have severe clinical presentations [11]. Symptoms reported to date in patients infected with 2019-nCoV include mainly fever and difficulty breathing, with radiological findings of pneumonia [12]. However, severe and even critically ill patients with ARDS have also been reported.
During the emergence of Severe Acute Respiratory Syndrome-related coronavirus (SARS-CoV) in 2002–2003, the virus affected 8 096 people causing severe pulmonary infections, with 774 deaths (case-fatality ratio: 10%) [7,13].
For MERS-CoV, dromedary camels are important animal reservoirs of the virus and are considered the main intermediate animal host source for human MERS-CoV infections. The majority of human cases have been observed in the Arabian Peninsula, reported from healthcare-associated outbreaks in Saudi Arabia, the United Arab Emirates and South Korea [14-16], while small numbers of imported cases have been reported from various countries. Transmission to patients sharing a room or ward with a MERS patient, to healthcare workers and to family visitors has occurred during healthcare-associated outbreaks [17]. No sustained human-to-human transmission or community outbreaks outside of close contacts have been documented for MERS. The analysis of transmission patterns is supported by molecular epidemiological studies, which are able to identify relatedness of viruses despite no obvious risk factors for transmission [18]. The case-fatality ratio of MERS-CoV infections is estimated to be 35% [9].
For the 2019-nCoV, the first reported cluster of hospitalised patients with pneumonia was reported on 31 December 2019, from Wuhan, China [19]. Subsequently, reports of cases increased sharply, mainly in China, as well as reports of travel-related cases, with exposure to Wuhan [6,20]. Human-to-human transmission also occurs, as indicated by infection in persons without exposure to wet markets but with exposure to people with respiratory symptoms and by infections among healthcare workers[11].
A broad range of coronaviruses are found in bats, which might play a crucial role in the virus evolution of alpha– and betacoronavirus lineages in particular. However, other animal species can also act as host and animal reservoir.
The incubation period of coronaviruses ranges from 2–14 days. SARS-CoV had an incubation period between 3–10 days and MERS-CoV up to 14 days.
In humans, the transmission of coronaviruses between an infected individual and others can occur via respiratory secretions. This can happen either directly through droplets from coughing or sneezing, or indirectly through touching contaminated objects or surfaces as well as close contact, such as touching or shaking hands and then y touching your nose, eyes or mouth. Nosocomial transmission has been described as an important driver in the epidemiology of SARS and MERS.
For SARS-CoV, bats were the likely origin of the virus, which further spread to Himalayan palm civets, Chinese ferret badgers and raccoon dogs at the wet markets of Guangdong, China. People handling or consuming these animals were infected and further spread the virus through human-to-human transmission.
For MERS-CoV, human-to-human infections related to healthcare settings have been responsible for the majority of cases. Although the precise routes of human-to-human transmission (e.g. droplet, airborne or ingestion) are still unclear, close contact is known to facilitate transmission. Contact with infected animals can also be a route of infection; zoonotic infections due to the consumption of raw camel milk, or other camel products related to MERS-CoV infections have also been reported [9].
For the 2019-nCoV, the source of infection, animal host and reservoir are currently unknown [6,20].
In humans, MERS-CoV has been detected in respiratory tract specimens (such as sputum, nasopharyngeal swab, endotracheal aspirate), as well as in urine, faeces and blood [8]. Viral shedding has been detected for three weeks or longer after infection [10]. Interim guidance documents for the testing of MERS-CoV has been developed by WHO [17].
For the novel coronavirus 2019-nCoV, WHO and ECDC developed interim guidance for laboratory testing to support EU/EEA Member States, as prompt case confirmation is necessary to ensure rapid and effective contact tracing, implementation of infection prevention and control measures according to national recommendations, and collection of relevant epidemiological and clinical information [21,22]. For the 2019-nCoV it is important to note that one negative result in a patient with strong epidemiological or clinical suspicion for disease should be confirmed with a second specific RT-PCR test targeting a different gene and/or a clinical sample from a different anatomical site.
Coinfection with other respiratory pathogens that can also cause lower respiratory disease such as viruses (influenza, respiratory syncytial and metapneumovirus), bacteria (Haemophilus, Bordetella etc) cannot be excluded, Therefore strongly suspected patients should be thoroughly investigated.
The clinical manifestations of MERS-CoV infections range from asymptomatic infection to severe pneumonia, often complicated by ARDS, septic shock, and multi-organ failure leading to death. High-risk groups include those with advanced age and co-morbid conditions, particularly immunosuppression [23,24].
There is currently no specific treatment or vaccine against coronavirus-caused respiratory illness. Supportive care is the mainstay of management for all patients including the ones confirmed with SARS, MERS or 2019-nCoV. Oxygen, IV fluids and possible mechanical ventilation may be warranted for all patients with severe clinical presentation. Several antiviral treatments including ribavirin, interferons and the anti-HIV combination lopinavir/ritonavir or remdesivir are under investigation for use against MERS-CoV infection and have been initiated against the 2019-nCoV [25,26].
In the past, systematic implementation of public health measures such as active case finding, prompt isolation of cases and quarantine of contacts, as well as strict application of infection control practices have been successful in controlling outbreaks, such as the SARS outbreak of 2003 [27].
Only SARS is currently notifiable in the EU [28]; the case definition laid down in Commission implementing decision (EU) 2018/945 of 22 June 2018 can be found in Annex 1.
Cases of MERS-CoV and the 2019-nCoV infection should be immediately reported to the Early Warning and Response System (EWRS) in accordance with Decision No 1082/2013 on serious cross-border threats to health[29].
In addition, WHO has developed a case definition for the reporting of MERS-CoV and the 2019-nCoV, which emerged in December 2020 [30] under IHR (2005) [31,32].
In the large healthcare associated outbreaks of MERS-CoV in Saudi Arabia, transmission was mostly attributed to poor implementation of infection prevention and control protocols. Therefore, prompt identification of cases, contact tracing and strict application of IPC protocols in healthcare settings remain the mainstays of control of MERS-CoV spread, along with avoidance of contact with animals (e.g. drinking raw camel milk) [33].
Regarding the 2019-nCoV, several vital pieces of information on the infectivity, spectrum of clinical presentation and environmental persistence remain unknown. Knowledge gathered from the response to the above-mentioned SARS-CoV and MERS-CoV outbreaks is being used as a surrogate to assist in informing the control of the currently evolving outbreak that is occurring mainly in China. As such, prompt identification of cases, isolation and contact tracing is currently the mainstream advice for containing possible secondary transmission from imported cases [11].
ECDC has published a document on public health management of persons having had contact with novel coronavirus cases in the European Union on its website.
In order to reduce the risk of the spread of coronavirus infections, basic preventative measures are advised for the public, including: good respiratory hygiene and respiratory etiquette; frequent careful hand washing; avoiding touching one’s eyes, mouth and nose; sanitary disposal of oral and nasal discharges as well as avoiding contact with sick people.
Zoonotic infections due to the consumption of raw camel milk, or other camel products related to MERS-CoV infections have been reported. Adequate food and hand hygiene minimise the risk of transmission through such animal products. Therefore, all relevant camel products should be properly cooked, pasteurised or heat-treated before consumption. In unpasteurised camel milk, MERS-CoV remains infectious beyond 72 hours after introduction to the milk but infectious viruses could not be found after pasteurisation [34]. The persistence of the virus in the outdoor environment is not clear.
During the SARS and MERS outbreaks, infection of healthcare staff was a significant concern. Strict infection prevention and control procedures (IPC) are critical for occupational safety and for the control of those pathogens.
MERS-CoV has been cultured from air and from surfaces and medical equipment up to several days after contact with a positive patient. MERS-CoV remains viable on plastic and metal surfaces for 48 hours at 20°C and 40% relative humidity, which represent common environmental conditions in a hospital ward or regular indoor space. The virions are sensitive to heat, lipid solvents, non-ionic detergents, oxidising agents and ultraviolet light [34]. Viability decreases at higher temperatures or higher levels of relative humidity [34].
Specific guidance for the IPC procedures when caring for a suspect or confirmed MERS-CoV infected patient are available from WHO [35].
For aerosol-generating procedures, such as tracheal intubation, broncho-alveolar lavage and manual ventilation, airborne precautions are recommended. The guidance recommends that the procedure should be performed in an adequately ventilated room with the number of persons in the room limited to a minimum.
For the novel coronavirus 2019-nCoV, while there are still important gaps in the information relevant to determining appropriate prevention and control measures (e.g. virus persistence in the environment), guidance for IPC has been developed by WHO drawing upon the experience with the SARS and MERS outbreaks in the past [6,35].
1. Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Seminars in Immunopathology. 2017 July 01;39(5):529-39.
2. Viruses ICoTo. ICTV 9th Report 2011 [14 January 2020]. Available from: https://talk.ictvonline.org/ictv-reports/ictv_9th_report/positive-sense-rna-viruses-2011/w/posrna_viruses/223/coronaviridae-figures.
3. Yin Y, Wunderink RG. MERS, SARS and other coronaviruses as causes of pneumonia. Respirology. 2018;23(2):130-7.
4. Wuhan City Health Committee (WCHC). Wuhan Municipal Health Committee’s report on unexplained viral pneumonia 2020 [14 January 2020]. Available from: http://wjw.wuhan.gov.cn/front/web/showDetail/2020010509020.
5. WHO. WHO Statement Regarding Cluster of Pneumonia Cases in Wuhan, China Geneva2020 [updated 9 January 202014 January 2020]. Available from: https://www.who.int/china/news/detail/09-01-2020-who-statement-regarding-cluster-of-pneumonia-cases-in-wuhan-china.
6. WHO. Novel Coronavirus – China Geneva2020 [updated 12 January 202014 January 2020]. Available from: https://www.who.int/csr/don/12-january-2020-novel-coronavirus-china/en/.
7. WHO. SARS (Severe Acute Respiratory Syndrome) Geneva [14 January 2020]. Available from: https://www.who.int/ith/diseases/sars/en/.
8. Hui DS, Azhar EI, Kim Y-J, Memish ZA, Oh M-d, Zumla A. Middle East respiratory syndrome coronavirus: risk factors and determinants of primary, household, and nosocomial transmission. The Lancet Infectious Diseases. 2018;18(8):e217-e27.
9. European Centre for Disease Prevention and Control (ECDC). Rapid risk assessment: Severe respiratory disease associated with Middle East respiratory syndrome coronavirus (MERS-CoV), 22nd update. 2018.
10. Corman, V. M., et al. (2015). “Viral Shedding and Antibody Response in 37 Patients With Middle East Respiratory Syndrome Coronavirus Infection.” Clinical Infectious Diseases 62(4): 477-483.
11. WHO. Statement on the meeting of the International Health Regulations (2005) Emergency Committee regarding the outbreak of novel coronavirus (2019-nCoV) 2020 [updated 23 January 2020]. Available from: https://www.who.int/news-room/detail/23-01-2020-statement-on-the-meeting-of-the-international-health-regulations-(2005)-emergency-committee-regarding-the-outbreak-of-novel-coronavirus-(2019-ncov).
12. European Centre for Disease Prevention and Control (ECDC). Risk assessment: Outbreak of acute respiratory syndrome associated with a novel coronavirus, Wuhan, China; first update 2020 [updated 22 January 2020]. Available from: https://www.ecdc.europa.eu/en/publications-data/risk-assessment-outbreak-acute-respiratory-syndrome-associated-novel-coronavirus.
13. European Centre for Disease Prevention and Control (ECDC). Facts about severe acute respiratory syndrome (SARS) Stockholm2018 [14 January 2020]. Available from: https://www.ecdc.europa.eu/en/severe-acute-respiratory-syndrome/facts.
14. Oboho IK, Tomczyk SM, Al-Asmari AM, Banjar AA, Al-Mugti H, Aloraini MS, et al. 2014 MERS-CoV outbreak in Jeddah—a link to health care facilities. New England Journal of Medicine. 2015;372(9):846-54.
15. Cowling BJ, Park M, Fang VJ, Wu P, Leung GM, Wu JT. Preliminary epidemiologic assessment of MERS-CoV outbreak in South Korea, May–June 2015. Euro surveillance: bulletin Europeen sur les maladies transmissibles= European communicable disease bulletin. 2015;20(25).
16. Kim K, Tandi T, Choi JW, Moon J, Kim M. Middle East respiratory syndrome coronavirus (MERS-CoV) outbreak in South Korea, 2015: epidemiology, characteristics and public health implications. Journal of Hospital Infection. 2017;95(2):207-13.
17. WHO. Laboratory testing for Middle East Respiratory Syndrome Coronavirus. Interim guidance 2018 [24 January 2020]. Available from: https://www.who.int/csr/disease/coronavirus_infections/mers-laboratory-testing/en/.
18. Corman VM, Albarrak AM, Omrani AS, Albarrak MM, Farah ME, Almasri M, et al. Viral Shedding and Antibody Response in 37 Patients With Middle East Respiratory Syndrome Coronavirus Infection. Clinical Infectious Diseases. 2015;62(4):477-83.
19. Wuhan City Health Committee (WCHC). Wuhan Municipal Health and Health Commission’s briefing on the current pneumonia epidemic situation in our city 2019 [updated 31 December 201914 January 2020]. Available from: http://wjw.wuhan.gov.cn/front/web/showDetail/2019123108989.
20. European Centre for Disease Prevention and Control (ECDC). Novel coronavirus in China 2020 [24 January 2020]. Available from: https://www.ecdc.europa.eu/en/novel-coronavirus-china.
21. European Centre for Disease Prevention and Control (ECDC). Laboratory testing of suspect cases of 2019 nCoV using RT-PCR 2020 [17 January 2020]. Available from: https://www.ecdc.europa.eu/en/publications-data/laboratory-testing-suspect-cases-2019-ncov-using-rt-pcr.
22. WHO. Laboratory testing for 2019 novel coronavirus (2019-nCoV) in suspected human cases 2020 [17 January 2020]. Available from: https://www.who.int/health-topics/coronavirus/laboratory-diagnostics-for-novel-coronavirus.
23. Arabi YM, Balkhy HH, Hayden FG, Bouchama A, Luke T, Baillie JK, et al. Middle East respiratory syndrome. New England Journal of Medicine. 2017;376(6):584-94.
24. WHO. Clinical management of severe acute respiratory infection when Middle East respiratory syndrome coronavirus (MERS-CoV) infection is suspected. Interim guidance 2019 [updated January 2019]. Available from: https://www.who.int/csr/disease/coronavirus_infections/case-management-ipc/en/.
25. Sheahan TP, Sims AC, Leist SR, Schäfer A, Won J, Brown AJ, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nature Communications. 2020 2020/01/10;11(1):222.
26. WHO. Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected 2020 [17 January 2020]. Available from: https://www.who.int/internal-publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected.
27. Bell DM, World Health Organization Working Group on I, Community Transmission of S. Public health interventions and SARS spread, 2003. Emerging infectious diseases. 2004;10(11):1900-6.
28. COMMISSION IMPLEMENTING DECISION (EU) 2018/945 of 22 June 2018 on the communicable diseases and related special health issues to be covered by epidemiological surveillance as well as relevant case definitions, (2018).
29. Decision No 1082/2013/EU of the European Parliament and of the Council of 22 October 2013 on serious cross-border threats to health and repealing Decision No 2119/98/EC 2013 [17 January 2020]. Available from: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A32013D1082.
30. WHO. Surveillance case definitions for human infection with novel coronavirus (nCoV) 2020 [17 January 2020]. Available from: https://www.who.int/internal-publications-detail/surveillance-case-definitions-for-human-infection-withnovel-coronavirus-(ncov).
31. WHO. Middle East respiratory syndrome coronavirus: Case definition for reporting to WHO 2017 [23 January 2020]. Available from: https://www.who.int/csr/disease/coronavirus_infections/case_definition/en/.
32. WHO. International Health Regulations (2005), 3rd Ed. 2016 [17 January 2020]. Available from: https://www.who.int/ihr/publications/9789241580496/en/.
33. Mackay IM, Arden KE. MERS coronavirus: diagnostics, epidemiology and transmission. Virol J. 2015 Dec 22;12:222.
34. van Doremalen N, Bushmaker T, Munster VJ. Stability of Middle East respiratory syndrome coronavirus (MERS-CoV) under different environmental conditions. Eurosurveillance. 2013;18(38):20590.
35. WHO. Infection prevention and control during health care for probable or confirmed cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection. Interim guidance 2019 [updated October 2019]. Available from: https://www.who.int/csr/disease/coronavirus_infections/ipc-mers-cov/en/.
Clinical criteria
Any person with fever or a history of fever
AND
At least one of the following three:
AND
At least one of the following four:
AND
No alternative diagnosis which can fully explain the illness
Laboratory criteria
Laboratory criteria for case confirmation
At least one of the following three:
Laboratory criteria for a probable case
At least one of the following two:
Epidemiological criteria
At least one of the following three:
Case classification for the inter-epidemic period
Also applies during an outbreak in a non-affected country or area
A. Possible case
Any person meeting the clinical criteria with an epidemiological link
B. Probable case
Any person meeting the clinical criteria with an epidemiological link and meeting the laboratory criteria for a probable case
C. Nationally confirmed case
Any person meeting the clinical and the laboratory criteria for case confirmation where the testing has been performed at a national reference laboratory
D. Confirmed case
Any person meeting the clinical and the laboratory criteria for case confirmation where the testing has been performed at a WHO SARS verification and reference laboratory
Case classification during an outbreak
Applies during an outbreak in a country/area where at least one person has been laboratory confirmed by a WHO SARS verification and reference laboratory
A. Possible case
Any person meeting the clinical criteria
B. Probable case
Any person meeting the clinical criteria with an epidemiological link to a nationally confirmed or a confirmed case
C. Nationally confirmed case
Any person meeting the clinical and the laboratory criteria for case confirmation where the testing has been performed at a national reference laboratory
D. Confirmed case
One of the following three:
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