The growing coronavirus epidemic

coronavirusAn unprecedented amount of information is emerging on the new coronavirus, provisionally called 2019-nCoV, that originated in China and is spreading globally. As of this writing there are 8,236 confirmed cases (8,124 in China) with 171 deaths (Click the link for real-time updates).

What was the origin of the virus?

The virus was first isolated by infection of cells in culture with broncho-alveolar wash from a patient in Wuhan with pneumonia. The infected cells showed cytopathic effects, and staining of cells with an antibody to coronavirus NP protein, which is conserved among coronaviruses, revealed intracellular staining.

The complete genome sequence of this isolate was determined (29,891 bases) and comparison with genomes of other coronaviruses revealed that it is most closely related (96.2% identity) with viral RNA from a Rhinolophus affinis bat obtained in Yunnan Province in 2013. This finding means that both viruses have a common ancestor in bats. Recall that SARS-CoV also originated in bats. Many coronaviruses circulate in bats and more are likely to cross into humans in the future.

How the virus entered humans from bats is unknown. At the onset of the outbreak in Wuhan, it was suggested that transmission occurred at the Huanan Fish Market, because the initial infected individuals all had been in the market, which sells exotic meats as well as fish. However an epidemiological analysis of the first 41 hospital admitted cases indicates otherwise. Specifically, the first case, which occurred on 1 December 2019, had no contact with the Huanan Fish Market. Furthermore, none of the other 40 patients had contact with that first patient, and 13 had no contact with the Huanan Fish Market. There are two implications of these observations. First, the Huanan Fish Market was likely not the origin of the outbreak. Where the virus entered humans is currently unknown. It is possible that the initial infections occurred in a different market, or even outside of the city. At some point the virus might have been brought into the Huanan market from where it spread further. Analysis of wildlife products from markets for viral sequences might help pinpoint the origin of this zoonosis.

We do not know if the virus entered humans directly from a bat, or via an intermediary animal, such as palm civets which were involved in crossover of SARS-CoV from bats.

The second implication of the epidemiological observations noted above is that the first infections did not occur on 21 December, as previously reported, but much earlier. The first patient on 1 December was likely infected during November. The virus might have been circulating as early as October, as suggested by evolutionary analysis of genome sequences from multiple patients. The virus could have been causing cases of pneumonia even in November, which were overlooked in the background of this disease observed in winter months. More extensive spread of the virus earlier than previously thought could account for the sudden surge of cases in January.

How transmissible is infection with 2019-nCoV?

Preliminary studies based on the first 425 confirmed cases have placed the reproductive index, R0, at 2.2 (range 1.4 to 3.9). The R0 is the number of people, on average, who are infected by a single infected person. In comparison, the R0 for SARS-CoV was about 3. Outbreaks can be halted when the R value is brought to less than 1. Transmissibility is determined by the length of time that a virus-shedding patient has contact with other patients. Rapid identification and isolation of infected patients can shorten this period and lower the R value.

In SARS-CoV infected patients, virus shedding largely coincides with the peak of disease symptoms. Given the severity of the disease, many patients were in hospitals and transmitted the infection there. Consequently patient isolation and infection control were essential for halting the outbreak. There appear to be many more mild infections with 2019-nCoV, and there is greater chance for community spread of infection versus hospital spread. Community acquired infections, such as influenza, pose a great challenge for control. Identifying every infected patient to break the chains of transmission will be difficult.

The relationship between disease severity and transmission is nicely summarized in this article:

…if this virus transmits efficiently, its seemingly lower pathogenicity as compared with SARS, possibly combined with super-spreader events in specific cases, could allow large-scale spread. In this manner, a virus that poses a low health threat on the individual level can pose a high risk on the population level, with the potential to cause disruptions of global public health systems and economic losses.

We do not yet know whether 2019-nCoV is transmitted to other individuals during the incubation period – the time before disease signs and symptoms appear. If it is, it will make control even more difficult. The mean incubation period has been estimated at 5.2 days (range 4.1 to 7.0), supporting the use of a 14-day observation or quarantine period for individuals who have been exposed to infection.

Can infection be prevented or cured?

A number of experimental vaccines for 2019-nCoV have been announced, but it is unlikely that they will be available to halt the current outbreak. Nevertheless, they should be pursued should the virus become endemic in humans (unlike SARS-CoV, which has not been seen since).

Antiviral drugs would be useful for treatment of very sick patients. Remdesvir, a nucleotide analog with potent antiviral activity against a wide range of RNA viruses, including ebolaviruses, MERS-CoV, and SARS-CoV, should be tested for efficacy against 2019-CoV. It has been shown to be superior to a combination of lopinavir, ritonavir, and interferon beta, which is being evaluated for treatment of MERS-CoV and 2019-CoV infections in humans. With multiple 2019-nCoV virus isolates available, it will be possible to test other existing antivirals or identify new ones.

Final thoughts

The CDC estimates that so far this season (in the USA) there have been at least 15 million influenza illnesses, 140,000 hospitalizations and 8,200 deaths from the disease. There are no travel bans in place to prevent spread of seasonal influenza. Those in place in China, and being considered elsewhere, are an attempt to halt the global spread of 2019-nCoV. I doubt they will be effective, as the virus has already spread to 21 countries outside of China, and it is very difficult to prevent the travel of every infected individual. The question now is how extensive the epidemic will be. Will it reach the extent of pandemic influenza? (in 2009, 60 million cases in the US alone). What will the case fatality rate be? (It was 0.02-0.4% for 2009 H1N1 influenza virus, 9.5% for SARS-CoV.) It is too early to answer these questions, but we learn more every week.

{ 10 comments… add one }
  • Kevin Carney 31 January 2020, 9:36 am

    Your 30 Jan TWiV blogpost is at the forefront of accurate and scientifically sophisticated reporting on the emerging coronavirus epidemic and TWiV 584 is essential listening for an introduction to the subject. The TWiV posts and podcasts also put the current epidemic in perspective e.g. your comparison of coronavirus with flu and S Perlman’s TWiV 538 discussion of the epidemiology of SARS vs HIV. The TWiV fights panic with knowledge. How rare.

  • Virus Watcher 31 January 2020, 11:29 am

    There are still two great unknowns:

    Base Reprodution Rate R0 (1.5 to 5 )
    Case Fatality Rate ( 0.01% to 10% )

    To obtain better estimated of those two parameters must be given the highest research priority now.

    Best point to start is to follow the progress of the cases “exported” outside china which are already very closely monitored.

    I am concerned about CFR because with SARS it took on avg. 3 weeks from symptom onset to death. So we must not set the number of deaths in relation to the current case numbers but to the case numbers 3 weeks ago, which is about ten times less cases (assuming doubling of cases every 5 day). Also number of discharged patients still less than number of deaths.

  • Virus Watcher 31 January 2020, 11:37 am

    “So we must not set the number of deaths in relation to the current case numbers but to the case numbers 3 weeks ago, which is about ten times less cases (assuming doubling of cases every 5 day). Also number of discharged patients still less than number of deaths.”

    On the other hand, it is not unreasonable to assume that the currently reported numbers are only a small fraction of actual cases (may be also off by a factor of about ten) so the two biases might roughly cancel each other out.

  • nyc 31 January 2020, 8:30 pm

    Nice summary, thx. When you say “the first case … had no contact with the Huanan Fish Market,” is that based on the line “No epidemiological link was found between the first patient and later cases” in the Lancet report? Thx again.

  • Virus Watcher 1 February 2020, 6:31 am

    The very latest Lancet Paper published today estimates R0 as 2.6 .

    This research is extremely valuable because it is based not on the published chinese figures but by modelling exported cases outside china and air traffic patterns.

    Case doubling time is estimated to 6.4 days.

    As of Jan. 25 the paper estimates about 25000 cases in the Wuhan region (Figure 2)

    So now we can do a resonably non-biased estimate of the CFR.

    The time from symptom onset to death with other viral pneumpnia ARDS-related conditions (notably for SARS it was reported as 21 days [1]) is about three weeks on average.

    So we have to set the current number of reported deaths (about 200 as of jan.31) to the number of cases three weeks ago (january 10).
    We know from the paper there were 25000 cases on jan. 25, so calculating back via the doubling time (6.4 days) there were roughly 6000 cases on jan.10

    This leads to case fatality rate = 200 / 6000 = 3% (i.e. worse than 1918 spanish flu)

    This is assuming there is no under-reporting of fatal cases of course in which case CFR would be even higher.

    [1] Mark Elliott, Stefano Nava, “Non-invasive Ventilation and Weaning: Principles and Practice”

  • John Harris 3 February 2020, 11:00 am

    HIV 1 protease is an aspartic protease. I will guess this aspartic protease is the target for all of the HIV 1 protease inhibitors.

    Is it possible to read from the sequence of the 2019 CoV the specific type of protease it encodes?

    Suppose the 2019 CoV protease is something other than an aspartic protease. If so, then perhaps there already exists a protease inhibitor that more specifically targets this other type of viral protease.

    The hope would be that it might outperform the HIV 1 protease inhibitors that are currently being tried.

  • Weijunjie Zhang 18 February 2020, 12:42 pm

    My name is name is Mr. Weijunjie Zhang, i am originally from wuhu china. i am successful business man that deal on antiques. i was married but lost my wife and daughter 8 years ago. sadly enough i contacted the coronavirus and i have been fighting hard to survive it, but i was unlucky. medical report shpws that i only have few weeks to live, and i have no family to will all my properties to. now i want to will it to the ophans, ophanage home an the less privileged because i have just limited time to live.

    My asset is worth more than (12.9 million Chinese Yuan) and that is twelve million nine hundred thousand yuan.
    I really need you if you are interested to help me give the money to the ophanage home there and also to the less privilege, and you can take 40% out of the money as your time wasted and inconveniences.
    Kindly contact me now via my email address:weijunjiezhang567@outlook.com
    if you are interested. it’s really urgent and i have not much time to live.
    Thank you for paying time to read and understand my request.

    Yours faithfully
    Weijunjie zhang
    signed..

Leave a Comment