The new coronavirus that has frightened the whole world
Published
Hacettepe University Hospitals
2019 Coronavirus Outbreak – Current Situation and First Impressions
Dr. Ahmet Görkem Er, Dr. Serhat Ünal
On 29.12.2019, some recent pneumonia cases were linked to the Huanan Seafood Market, and on 31.12.2019 the existence of a new outbreak was announced to the world by the Wuhan Health Commission, the National Health Commission of the People's Republic of China and the Chinese Center for Disease Control and Prevention. On 08.01.2020, the existence of a new coronavirus as the cause of this new outbreak was officially announced by the Chinese Center for Disease Control and Prevention(1).
A Brief History of Coronaviruses
In 1965, Tyrrell and Bynoe isolated a virus in tissue culture from a patient with a common cold, and in the following years the hepatitis virus in mice and the gastroenteritis virus in pigs were also found to have the same morphology under electron microscopy(2, 3). This new virus was named coronavirus because its surface projections gave it the appearance of a crown(4). Coronaviruses are single-stranded, positive-sense, enveloped RNA viruses. The family Coronaviridae is placed in the order Nidovirales and consists of the subfamilies Coronavirinae and Torovirinae; they infect mammals and birds and can cause various respiratory, enteric, neurological and hepatic diseases(5). The subfamily Coronavirinae is divided into four genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus. While HCoV-229E, HCoV-OC43 and HCoV-NL63, which cause classic common cold symptoms in humans, are placed in the genus Alphacoronavirus; HKU1-CoV, also a cause of the classic common cold, SARS-CoV, identified in 2003 and responsible for Severe Acute Respiratory Syndrome (SARS), and MERS-CoV, identified in 2012 and responsible for Middle East Respiratory Syndrome (MERS), are placed in the genus Betacoronavirus (5, 6).
SARS and MERS Outbreaks
It appears that we are faced with a new coronavirus outbreak in a new decade(7). SARS-CoV and MERS-CoV, which caused outbreaks in the 2000s and 2010s, are of zoonotic origin like other coronaviruses; it has been determined that SARS-CoV crossed to humans from exotic animals and MERS-CoV from camels, causing epidemics. Both pathogens are thought to be of bat origin. It is also known that both viruses tend to infect intrapulmonary epithelial cells rather than upper respiratory tract epithelial cells(7). The SARS epidemic began in mid-November 2002 in Guangdong province of the People's Republic of China; in March 2003, following severe pneumonia cases in Singapore, Hong Kong and Hanoi, it was announced to the world by the World Health Organization (WHO)(8). The outbreak spread worldwide, cases were seen in 29 countries, the number of probable cases was given as 8096 and the number of deaths as 774, and the fatality rate was determined as 7-17%(5). The MERS epidemic was identified in September 2012; according to WHO data, as of January 2020, 2494 laboratory-confirmed cases had been detected in 27 countries, and the total number of deaths was determined as 858. MERS cases continue to be seen today(9, 10).
2019 Novel Coronavirus Outbreak
The 2019 coronavirus outbreak was first presented, together with the genetic structure of the virus, as a brief report by Zhu et al. on 24.01.2020. In this study, the virus was isolated from four respiratory samples taken from three cases, the effect of the virus on cells was evaluated by making a human airway epithelial cell culture, cells showing a cytopathic effect were examined by electron microscopy, and viral genome sequencing was performed. In this case series, in which two cases recovered and one case died of respiratory failure, it was shown that the virus isolated from the cases and named 2019-nCoV belongs to the subgenus Sarbecovirus of the genus Betacoronavirus, and that the virus, which had a cytopathic effect in cell culture, had 86.9% nucleotide sequence similarity in phylogenetic analysis to the bat-origin SARS-like CoV (bat-SL-CoVZC45, MG772933.1) (11).
Huang et al. also, on 24.01.2020, shared the clinical characteristics of 41 laboratory-confirmed patients admitted to hospital. In this study, it was stated that 30 of the patients (73%) were male, 13 (32%) had an underlying disease and 27 had been exposed to the Huanan Seafood Market, and the median age was found to be 49.0 [41.0 – 58.0]. All patients needing oxygen, the most common symptoms being fever (98%), cough (76%), dyspnea (55%) and myalgia or fatigue (44%), 13 patients (32%) being admitted to intensive care and a total of 6 patients (15%) dying were noted in the study as important findings (12).
The first family cluster in the literature was presented by Chan et al. This study, in which person-to-person transmission was demonstrated, provides important data regarding the spread of the outbreak. In this study, a family of six with no history of visiting the Huanan Seafood Market or eating wild animals traveled from Shenzhen to Wuhan. Two members of the family visited a hospital in Wuhan, and on follow-up after returning to Shenzhen, 2019-nCoV was detected in 5 members of the family, one of whom was asymptomatic. In another family member who had no history of going to Wuhan and lived in Shenzhen, lower back pain and fatigue developed 3 days after the family members returned to Shenzhen, and 2019-nCoV was also detected in this patient, who was evaluated after developing a complaint of fever(13).
While the number of patients in the region was increasing rapidly, a letter to the editor providing information that the incubation period of the disease could be less than three days was published on 28.01.2020. In this letter, it was stated that a person who stayed in the same hotel room for three days with his father returning from Wuhan to Vietnam, and who had no other epidemiological link to the outbreak, developed dry cough, fever, vomiting and diarrhea within 3 days after contact with his father and was infected with 2019-nCov (14).
In response to the rapid spread of the outbreak during this period, a group of measures was taken by the People's Republic of China. On 10.01.2020 the Chinese Center for Disease Control and Prevention shared the genome sequence of the virus with the world, and a new PCR kit was prepared for diagnosis. The emergency response level was raised on 15.01.2020 to Level 1, the highest level. On 16.01.2020, restrictions were placed on the departure from Wuhan of people with a body temperature above 37.3°C, and although not recommended by the WHO, quarantine began to be implemented from 23.01.2020 and 24.01.2020, first in the city of Wuhan and then throughout Hubei province(1, 10).
The most comprehensive study examining the early spread dynamics of the outbreak was published by Li et al. on 29.01.2020. In this study of 425 laboratory-confirmed patients, the mean age was found to be 59, and 56% of the patients were male. Before 01.01.2020, 55% of the patients had a history of exposure to the Huanan Seafood Market, whereas this rate was found to have fallen to 6% after 12.01.2020. This shows that person-to-person transmission has become the main driving force in the spread of the outbreak. In addition, while no disease was seen in any health care workers at the beginning, it was stated that 7% of the patients after 12.01.2020 were health care workers. This rate being lower than in the SARS and MERS epidemics was attributed to rapid spreaders defined as super-spreaders not yet having been seen in this outbreak. The mean incubation period was found to be 5.2 days (4.1 – 7.0) and the basic reproduction number (R0) 2.2 (1.4 – 3.9)(1, 15).
On 30.01.2020, a letter to the editor was published stating that asymptomatic patients could also be carriers, which required infection control measures to be reconsidered. In this letter, it was stated that an index case, a Chinese citizen reported to be asymptomatic during a visit to Germany, infected four people in Germany(16). However, it was later learned that the authors of the letter to the editor had not spoken with the index case and thought the index case was asymptomatic based on the statements of the four patients in Germany, and that when Robert Koch Institute officials reached the index case by phone, the index case turned out to have been fatigued during the trip to Germany and to have used paracetamol(17). In light of current information, there is no clear evidence in the literature of carriage by asymptomatic patients.
On 31.01.2020, a modeling study by Wu et al. was published evaluating the magnitude of the current epidemic and the possible effect of the social and personal measures taken since January 2020. In this study, the transportation options from Wuhan to outside mainland China between 01.12.2019 and 25.01.2020 were first evaluated and R0 was calculated taking the number of cases into account. The continuous zoonotic force that was effective in the spread of the outbreak was examined with different models. The spread dynamics were sought to be understood by assuming that the serial interval of the outbreak was the same as in the SARS outbreak in Hong Kong and that the incubation period of 2019-nCoV was the same as that of SARS-CoV and MERS-CoV. Accordingly, in the scenario in which the lowest continuous zoonotic force was assessed, R0 was found to be 2.68 (2.47 – 2.86), and the number of cases in mainland China, which was 5,993 at the time of the study, was calculated to actually be 75,815 (37,304 – 130,330). It was also pointed out that if intercity transmission could not be reduced, the peak of the outbreak would be in April 2020. It was stated that if intercity transmission could be reduced by 50%, the outbreak could subside, and that large-scale quarantine measures could have only a minimal effect on the spread of the outbreak, since patients were already present in large cities(10).
While various protective measures against the spread of the outbreak are being taken and forecasting models are being developed, efforts are also being made to improve pharmacological approaches. Today there is no treatment or vaccine protocol with proven efficacy against coronavirus infections. Huang et al. stated in their study that they started the lopinavir/ritonavir combination as antiviral treatment in 38 (93%) of their patients infected with 2019-nCoV(12). Chu et al. used this combination in SARS patients and reported that ARDS and death were seen less often in the treatment group than in historical control patients (2.4% and 28.8%, p<0.001)(18). The MIRACLE trial is also investigating the combination of lopinavir/ritonavir and interferon-β1b for MERS; the trial has not yet concluded(19). In addition, a study in mice has been published in which remdesivir was used for both prophylaxis and treatment, showing that the remdesivir/interferon-β combination had a better antiviral effect than the lopinavir/ritonavir combination and that prophylactic remdesivir use reduced the replication of MERS-CoV and its ability to cause disease(20).
Ramaiah et al., in their study in which immune markers for a vaccine to be developed against 2019-nCoV were expressed and which they shared as a preprint, stated that they found eight high-affinity CD4 T cell epitopes in the S, E, M and N proteins of the virus and that these immunodominant epitopes could be used for immunization (21). Deep learning platforms are also seen to be used in developing pharmacological approaches; Richardson et al., as a result of their analyses with BenevolentAI, stated that baricitinib, used in the treatment of rheumatoid arthritis, is a potential drug candidate because it would reduce both the endocytosis of the virus via the ACE2 receptor and inflammation via the JAK ½ pathway(22, 23).
The Situation in Our Country
A probable case definition is given in the 2019-nCoV guideline published by the Ministry of Health of the Republic of Türkiye. According to this guideline, without overlooking that the clinical course may be atypical in immunocompromised patients, patients with acute respiratory tract illness of any severity or acute severe respiratory tract infection are considered probable cases if, within the last 14 days, they have had close contact with a confirmed case of 2019-nCoV infection, or have been in any health care facility in a country where hospital-associated 2019-nCoV infection has been reported, or have been in the People's Republic of China, or have worked in units where patients with 2019-nCoV infection are treated regardless of their residence or travel history; and cases that meet this case definition are considered confirmed cases if confirmed by molecular methods(6).
Probable cases must be reported promptly to the Provincial Health Directorate, the case notification form must be filled in, and standard, contact and droplet isolation precautions must be taken. It has been stated that, for health personnel who will come closer than 1 meter to confirmed or probable cases, gloves, a non-sterile gown, a medical mask, a face shield, goggles, liquid soap and alcohol-based hand sanitizer should be provided by the health center as personal protective equipment, and that an N95/FFP2 mask should be used only during procedures that cause aerosolization, such as aspiration and intubation(6).
Conclusion
At the time this review was written (08.02.2020), the WHO Novel Coronavirus Situation Report 19 stated that the number of confirmed cases worldwide was 34,886(24). 724 deaths have been attributed to 2019-nCoV infection, and the death toll is expected to exceed that of the SARS epidemic within the next few hours. No cases have yet been seen in Turkey. 2019-nCoV infection has global pandemic potential, and considering the 2003 SARS outbreak, the 2009 influenza (H1N1) pandemic, the 2011 Escherichia coli outbreak in Germany, the 2012 MERS outbreak, the 2014 Ebola outbreak and the 2016-2017 Zika virus pandemics, it is clear that an increasingly globalized world has become far more vulnerable to outbreaks (5, 25-28). Learning lessons from current outbreaks, preparing for new ones and keeping national pandemic response guidelines continuously up to date are considered an absolute necessity.
References
1. Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N Engl J Med. 2020.
2. McIntosh K, Becker WB, Chanock RM. Growth in suckling-mouse brain of "IBV-like" viruses from patients with upper respiratory tract disease. Proc Natl Acad Sci U S A. 1967;58(6):2268-73.
3. Witte KH, Tajima M, Easterday BC. Morphologic characteristics and nucleic acid type of transmissible gastroenteritis virus of pigs. Arch Gesamte Virusforsch. 1968;23(1):53-70.
4. Tyrrell DA, Almeida JD, Cunningham CH, Dowdle WR, Hofstad MS, McIntosh K, et al. Coronaviridae. Intervirology. 1975;5(1-2):76-82.
5. Bennett J, Dolin R, Blaser MJ. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 8th Edition ed. Philadelphia, PA: Elsevier/Saunders; 2014.
6. Ministry of Health of the Republic of Türkiye. 2019-nCoV Disease Guide for Healthcare Workers. 2020.
7. Perlman S. Another Decade, Another Coronavirus. New England Journal of Medicine. 2020.
8. Zhao Z, Zhang F, Xu M, Huang K, Zhong W, Cai W, et al. Description and clinical treatment of an early outbreak of severe acute respiratory syndrome (SARS) in Guangzhou, PR China. J Med Microbiol. 2003;52(Pt 8):715-20.
9. World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV). 2020.
10. Wu JT, Leung K, Leung GM. Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: a modelling study. Lancet. 2020.
11. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020.
12. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020.
13. Chan JF, Yuan S, Kok KH, To KK, Chu H, Yang J, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 2020.
14. Phan LT, Nguyen TV, Luong QC, Nguyen TV, Nguyen HT, Le HQ, et al. Importation and Human-to-Human Transmission of a Novel Coronavirus in Vietnam. N Engl J Med. 2020.
15. Wong G, Liu W, Liu Y, Zhou B, Bi Y, Gao GF. MERS, SARS, and Ebola: The Role of Super-Spreaders in Infectious Disease. Cell Host Microbe. 2015;18(4):398-401.
16. Rothe C, Schunk M, Sothmann P, Bretzel G, Froeschl G, Wallrauch C, et al. Transmission of 2019-nCoV Infection from an Asymptomatic Contact in Germany. N Engl J Med. 2020.
17. Study claiming new coronavirus can be transmitted by people without symptoms was flawed.2020. Available from: https://www.sciencemag.org/news/2020/02/paper-non-symptomatic-patient-transmitting-coronavirus-wrong.
18. Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59(3):252-6.
19. Arabi YM, Alothman A, Balkhy HH, Al-Dawood A, AlJohani S, Al Harbi S, et al. Treatment of Middle East Respiratory Syndrome with a combination of lopinavir-ritonavir and interferon-beta1b (MIRACLE trial): study protocol for a randomized controlled trial. Trials. 2018;19(1):81.
20. Sheahan TP, Sims AC, Leist SR, Schafer A, Won J, Brown AJ, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun. 2020;11(1):222.
21. Ramaiah A, Arumugaswami V. Insights into Cross-species Evolution of Novel Human Coronavirus 2019-nCoV and Defining Immune Determinants for Vaccine Development. bioRxiv. 2020:2020.01.29.925867.
22. Genovese MC, Kremer J, Zamani O, Ludivico C, Krogulec M, Xie L, et al. Baricitinib in Patients with Refractory Rheumatoid Arthritis. N Engl J Med. 2016;374(13):1243-52.
23. Richardson P, Griffin I, Tucker C, Smith D, Oechsle O, Phelan A, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. The Lancet.
24. World Health Organization. Novel Coronavirus(2019-nCoV) Situation Report – 19. 2020.
25. Kockerling E, Karrasch L, Schweitzer A, Razum O, Krause G. Public Health Research Resulting from One of the World's Largest Outbreaks Caused by Entero-Hemorrhagic Escherichia coli in Germany 2011: A Review. Front Public Health. 2017;5:332.
26. Girard MP, Tam JS, Assossou OM, Kieny MP. The 2009 A (H1N1) influenza virus pandemic: A review. Vaccine. 2010;28(31):4895-902.
27. Kaner J, Schaack S. Understanding Ebola: the 2014 epidemic. Global Health. 2016;12(1):53.
28. Kobres PY, Chretien JP, Johansson MA, Morgan JJ, Whung PY, Mukundan H, et al. A systematic review and evaluation of Zika virus forecasting and prediction research during a public health emergency of international concern. PLoS Negl Trop Dis. 2019;13(10):e0007451.