The new coronavirus that has frightened the whole world (14/02/2020)

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 declared 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 give it a crown-like appearance(4). Coronaviruses are single-stranded, positive-sense, enveloped RNA viruses. The Coronaviridae family belongs to the order Nidovirales and consists of the subfamilies Coronavirinae and Torovirinae; by infecting mammals and birds, these viruses can cause various respiratory, enteric, neurological and hepatic diseases(5). The Coronavirinae subfamily 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, belong to the genus Alphacoronavirus; HKU1-CoV, another cause of the 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), belong to the genus Betacoronavirus (5, 6).

SARS and MERS Outbreaks

It appears that, in a new decade, we are once again facing a new coronavirus outbreak(7). SARS-CoV and MERS-CoV, which caused outbreaks in the 2000s and 2010s, are, like other coronaviruses, of zoonotic origin; it has been determined that SARS-CoV passed from exotic animals to humans and MERS-CoV from camels to humans, causing epidemics. Both pathogens are thought to have originated in bats. Both viruses are also known to tend to infect intrapulmonary epithelial cells rather than the epithelial cells of the upper respiratory tract(7). The SARS epidemic began in the Guangdong province of the People's Republic of China in mid-November 2002; it was announced to the world by the World Health Organization (WHO) in March 2003 after severe pneumonia cases were seen in Singapore, Hong Kong and Hanoi(8). The outbreak spread worldwide, cases were seen in 29 countries, the number of probable cases was reported as 8096 and the number of deaths as 774, and the case fatality rate was determined to be 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 to be 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 summary 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 using human airway epithelial cell culture, cells showing cytopathic effects were examined by electron microscopy, and viral genome sequencing was performed. In this case series, in which two cases recovered and one died of respiratory failure, it was shown that the virus isolated from the cases, named 2019-nCoV, belongs to the subgenus Sarbecovirus of the genus Betacoronavirus, and that the virus, which had a cytopathic effect in cell culture, showed 86.9% nucleotide sequence similarity in phylogenetic analysis to a bat-derived 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, 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 49.0 [41.0 – 58.0]. The study reported as important findings that all patients required oxygen, that the most common symptoms were fever (98%), cough (76%), dyspnea (55%) and myalgia or fatigue (44%), that 13 patients (32%) were admitted to intensive care and that a total of 6 patients (15%) died (12).

The first family cluster in the literature was presented by Chan et al. This study, which demonstrated person-to-person transmission, 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 after returning to Shenzhen, 2019-nCoV was detected in 5 members of the family, one of whom was asymptomatic. Another family member who lived in Shenzhen and had no history of traveling to Wuhan developed back pain and fatigue 3 days after the family members returned to Shenzhen, and 2019-nCoV was also detected in this patient, who was evaluated because of a complaint of fever(13).

As the number of patients in the region increased rapidly, a letter to the editor was published on 28.01.2020 providing information that the incubation period of the disease may be under three days. This letter reported that a person who stayed in the same hotel room for three days with his father, who had returned 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).

Owing to the rapid spread of the outbreak during this period, the People's Republic of China took a series of measures. 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 also raised on 15.01.2020 to Level 1, the highest level. On 16.01.2020, restrictions were placed on people with a body temperature above 37.3°C leaving Wuhan, and, although not recommended by the WHO, quarantine began on 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 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 driver of the spread of the outbreak. In addition, while no healthcare workers were affected at the beginning, it was reported that 7% of patients after 12.01.2020 were healthcare workers. The fact that this rate is lower than in the SARS and MERS epidemics was attributed to the fact that rapid spreaders defined as super-spreaders have not yet 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 suggesting that asymptomatic patients could also be carriers, which required infection control measures to be reconsidered. This letter 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 revealed that the authors of the letter to the editor had not spoken with the index case and had assumed the index case was asymptomatic based on the statements of the four patients in Germany; when officials of the Robert Koch Institute reached the index case by telephone, it was learned that the index case had felt fatigued during the trip to Germany and had taken paracetamol(17). In light of current information, there is no clear evidence in the literature of carriage by asymptomatic patients.

On 31.01.2020, Wu et al. published a modeling study evaluating the size of the current epidemic and the possible effect of social and personal measures taken since January 2020. In this study, 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 affecting the spread of the outbreak was examined with different models. Spread dynamics were investigated on the assumption that the serial interval of the outbreak was the same as that of 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 with the lowest continuous zoonotic force, R₀ was found to be 2.68 (2.47 – 2.86), and it was calculated that the number of cases in mainland China, which was 5,993 at the time of the study, was in fact 75,815 (37,304 – 130,330). It was also indicated that if intercity transmission could not be reduced, the epidemic would peak in April 2020. It was stated that if intercity transmission could be reduced by 50%, the epidemic could die out, and that large-scale quarantine measures would have only a minimal effect on the spread of the outbreak, since there were already patients in large cities(10).

While various protective measures are being taken against the spread of the outbreak and prediction models are being developed, pharmacological approaches are also being refined. Currently, there is no treatment or vaccine protocol of proven efficacy for coronavirus infections. In their study, Huang et al. stated 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 less common in the treatment group than in historical control patients (2.4% and 28.8%, p<0.001)(18). The MIRACLE study is also investigating the lopinavir/ritonavir and interferon-β1b combination for MERS; the study has not yet concluded(19). In addition, a study has been published in which remdesivir was used in mice for both prophylaxis and treatment; it showed that the remdesivir/interferon-β combination had a better antiviral effect than the lopinavir/ritonavir combination and that prophylactic use of remdesivir reduced MERS-CoV replication and its ability to cause disease(20).

In their preprint study describing immune markers for a vaccine to be developed against 2019-nCoV, Ramaiah et al. 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; as a result of analyses carried out with BenevolentAI, Richardson et al. 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 guide published by the Ministry of Health of the Republic of Türkiye. According to this guide, without overlooking that the clinical course may be atypical in immunocompromised patients, patients with an acute respiratory 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 2019-nCoV case, or have been in any healthcare 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 2019-nCoV patients are treated regardless of residence or travel history; cases meeting this definition are considered confirmed cases if confirmed by molecular methods(6).

Probable cases must be promptly reported to the Provincial Health Directorate, the case report form must be filled in, and standard, contact and droplet isolation precautions must be taken. It has been stated that for healthcare personnel who will come closer than 1 meter to confirmed or probable cases, the healthcare center must provide gloves, a non-sterile gown, a medical mask, a face shield, goggles, liquid soap and alcohol-based hand sanitizer 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 the number of confirmed patients worldwide as 34,886(24). There have been 724 deaths due 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 Türkiye. 2019-nCoV infection has the potential for a global pandemic, 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 the globalized world has become much more open 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 seen as an essential requirement.

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.