Tension over the evolving situation with 2019-nCoV escalated on the global stage in recent days, as countries around the world implemented heightened measures to contain the epidemic, while experts began for the first time to publicly sound the alarm that the new coronavirus might go pandemic.
The world faces uncertainty over which of two outcomes will emerge in coming weeks and months: either control and eventual extermination of 2019-nCoV in humans, as happened with SARS, or the coronavirus going endemic and/or pandemic and troubling humanity over a much longer period of time.
We report on this situation in depth below, but briefly:
- The latest studies suggest most transmissions of 2019-nCoV are symptomatic, even though asymptomatic transmission is possible
- There’s still no true clarity on the case fatality rate, despite the widely cited 2% CFR number. One new study from China puts the CFR at 6.5%.
- Hubei is still melting down, with 56% growth in confirmed cases over the last two days, caseloads swamping all available medical facilities, and critical shortages of important supplies
- The situation in Hubei is even worse than official statistics suggest, with widespread cremation of deceased pneumonia cases who are not counted as confirmed cases, according to a censored report from an independent Chinese magazine. However, it remains unclear whether these reporting problems are marginal or very large
- In China outside Hubei, the quarantine appears to be taking effect and is slowing or halting growth in case numbers, raising the possibility the epidemic could be exterminated like SARS
- The Chinese political situation appears to be volatile, but with little indication of what this could mean
- The growth of case numbers outside China has been reduced even more, so that extermination in first world countries seems quite possible
- Possible wider outbreaks in third world countries are a point of greater concern for global public health authorities, but so far none have been confirmed
- The situation is still evolving rapidly, and a lot of important questions have yet to be answered
Researchers beginning to home in on 2019-nCoV’s properties
A cohort study of the first 425 cases from Chinese physicians in Wuhan was recently published in the New England Journal of Medicine, and included estimates of the size of the initial zoonotic outbreak, and the virus’s latent and incubation periods, Ro, and native doubling time. This is the first significant study to track cases by the onset of illness, and the largest cohort study to date, making it the best direct read on the disease’s properties. They estimate that the initial zoonotic outbreak was larger than previously believed, with almost 50 identified cases directly tied to the Huanan seafood market.
The NEJM cohort study suggests that the median serial interval of the disease is about seven days, as previously believed, and that the period from infection to symptoms averages only about four to five days, but can range up to a couple weeks. This would suggest that most infections are not asymptomatic, even though it is known to be possible.
It also reports that the timeline of the illness is long, with most hospitalized patients arriving in the hospital only after over a week has elapsed since the onset of symptoms.
2019 nCoV’s case fatality rate, one of the most important factors in determining the degree of damage humanity will sustain in a widespread epidemic or possible pandemic, remains very uncertain, with estimates still ranging over an order of magnitude from approximately 1% to as high as above 10%.
The NEJM study did not directly address CFR, while a recent model fitting study from the Chinese Academy of Sciences based on case counts, deaths, and recovery numbers estimated the virus’s current CFR at 6.5%.
Work continues on vaccines and therapies
Teams around the world are still working to develop and test therapies for 2019-nCoV. The search for existing antiviral drugs which may be effective against 2019-nCoV has landed on protease inhibitors as the most likely possible candidates, with three drugs from Abbvie (lopinavir and ritonavir) and Gilead (remdesivir) considered leading candidates.
Abbvie developed lopinavir and ritonavir as HIV therapies, while Gilead originally developed remdesivir for Ebola. All three are being shipped to Wuhan for early trials, and a team in Thailand has already reported early success with lopinavir and ritonavir in a small number of patients.
Many viruses contain proteases, which they use to separate functionally different viral proteins which are transcribed and translated together, and without which an infected cell cannot assemble new virions. Because all proteases share peptide bonds as their substrate, their active sites have certain similarities which makes protease inhibitors sometimes more portable from one virus to another than some other classes of antiviral drugs. If these proteasome inhibitors prove effective against 2019-nCoV, they are currently widely available enough, and simple enough to administer, that they could be rapidly deployed for most 2019-nCoV patients.
An American company, Moderna Therapeutics, based in Cambridge, MA, has announced it is working on an RNA vaccine for 2019-nCoV, which it says may be ready for a phase 1 human trial with healthy volunteers in as little as three months.
RNA vaccines, a recent arrival in the vaccine world, are much easier to manufacture than traditional vaccines, because instead of being fermented in a viral culture, they can be manufactured in the established manufacturing supply chain for nucleic acids, which is largely insensitive to which sequence is being manufactured. Accordingly, scaling up the manufacturing of a therapeutic nucleic acid can be nearly instantaneous, whereas scaling up traditional vaccines can take a long time. However, it is unclear if such a vaccine will actually be ready on the short timescale Moderna hopes, and how effective it would be.
Still not a bioweapon
All indications continue to show that 2019-nCoV is not a bioweapon.
We previously covered conspiracy theories about this based on the location of China’s premier virology institute, and a paper from India that found some sequence overlaps in hypervariable regions of 2019-nCoV and some HIV samples, but the conspiracies keep coming, including the theories that the use of HIV therapies for 2019-nCoV means 2019-nCoV is made from HIV, and the notion that the Chinese military made 2019-nCoV two years ago and for some reason posted the sequence of its top secret bioweapon on the internet.
Needless to say, these theories are still not true, and 2019-nCoV is still not a bioweapon, but we’ll have more detailed coverage of these conspiracy theories soon.
Hubei still in meltdown, with little clarity on how bad it is or when it will stop
In Hubei itself, the situation is still in a state of total meltdown, with conditions worsening, little insight into exactly how bad they are, and recent revelations putting the reliability of information into doubt.
The number of confirmed cases has continued to escalate, with the latest case number at over 11,000 confirmed cases in Hubei. The growth has been slowing, in percentage terms, but as we discussed previously, it’s still not possible to confirm whether the reduction has been due to a reduction in the actual growth rate in the epidemic, or a slowdown in the growth of ascertainment, or both.
The unimpeded rate of growth according to the latest models is about 10% per day, and the confirmed case numbers in Hubei are still growing about 25% per day. With estimates of ascertainment still low, upper range estimates of the real number of cases in Hubei now top out in the hundreds of thousands of cases. The epidemic has attained a gigantic scope.
The Chinese government’s quarantine measures have only escalated. The city continues to be effectively closed to most movement, with every public space and business other than medical facilities and a minority of supermarkets closed down, along with all transit, all routes in and out of Hubei, and a continued de facto ban on private vehicle travel.
Sixty million Hubei residents remain effectively trapped in their homes, including a large number of tourists and visitors. With the shortage of masks, gloves, and goggles, heartrending photos of improvised safety equipment made from water bottles, fruit, and other supplies circulate on social media. Meanwhile, those who venture out in public report being harassed by flying police drones, which warn pedestrians over loudspeakers to return to their homes.
While the first of two purpose-specific hospitals in Wuhan has been completed, and the hospital, now christened “Mountain Fire God Hospital,” has brought a thousand extra hospital beds online only two days behind schedule, the scale of the epidemic continues to completely swamp medical facilities in Hubei.
It has been widely reported that the Chinese government’s capacity to test sick patients for possible 2019-nCoV infection is falling far short of demand, leading public health authorities to resort to quarantining those with fever and cough symptoms without even checking whether they have 2019-nCoV. These patients are quarantined either at home or in large open buildings like factories converted to emergency use.
This latter measure, reminiscent of measures taken around the world during the 1918 flu pandemic, raises the disturbing possibility that cold and flu patients may be quarantined together with 2019-nCoV patients and contract the disease from them in large numbers.
The Chinese government is still censoring news of how bad it really is
Yesterday, a bombshell report in the independent Chinese magazine Caijing revealed that large numbers of suspected 2019-nCoV fatalities have been sent directly to morgues without being tested for 2019-nCoV or added to official counts, identified only as suffering from cryptic pneumonia.
The lengthy feature was censored by the Chinese government almost immediately after publication, but survives on archive sites.
Caijing quotes one hospital as saying that, under instruction from local government, they have been logging as confirmed only those cases admitted to the hospital and administered PCR tests, which due to the shortage of testing supplies is less than 10% of suspected cases.
Those who die without a confirmed diagnosis never make it onto the confirmed case roster, because no testing supplies are available for the dead. At several hospitals, and the wait for a bed was almost four days long.
At another hospital, Caijing reported that a major new addition of beds from conversion of another facility into a coronavirus ward was stymied by a lack of protective clothing for medical workers, leaving the new beds largely empty.
With the shortage of beds and testing capacity, thousands of 2019-nCoV patients suffer and sometimes die in Hubei without meaningful medical treatment, their cases largely unreported in the official numbers. Without any confirmation of how many such cases there are, it is difficult to know if the underestimate in official case and death numbers is marginal or highly significant, but one attending physician told Caijing his ward has seen more deaths than patient releases, the inverse of what is seen in official statistics.
A baffling shortage of tests leads to systematic under-diagnosis & further spread
Caijing reported that of Wuhan’s ten major hospitals with the capability to test for 2019-nCoV with the PCR test, one major hospital had the testing capacity for no more than 100 PCR tests per day, while another reported only having 10 tests per day. They quote one physician, who is supervising a ward of 600 serious cases but unable to test any of them, as saying he did not understand why testing capacity was lacking. The Wuhan Health and Medical Commission said on January 27 that it had the capacity for 2000 tests per day and would scale up from there.
It remains totally unclear why, weeks after the epidemic began to explode in size, testing capacity would remain such a bottleneck. PCR tests are not technically complicated, and in theory an undergraduate student in a pedestrian lab can design and order primers and perform such a test independently, if needed.
Developed-world hospitals routinely maintain PCR testing facilities with a capacity of thousands of tests per day. These types of machines require only a different pair of primers in order to convert from testing for one virus to another, and a tablespoon of primer which costs a very modest sum of money to make and can be shipped overnight from vendors like IDT may contain enough material for a thousand tests. And China, in recent years, has become a global contender in nucleic acid biotechnology, with native sequencing provider BGI going toe to toe with US sequencing giant Illumina on many metrics.
So China should be able to do as many PCR tests as are needed. Whether the shortage in testing capacity is mainly a matter of problems in case tracking, bottlenecks in steps of the process other than the PCR reaction itself, or simple incompetence, remains to be seen, as does the length of time before this bizarre unforced error is corrected.
Potential signs of containment in ex-Hubei mainland China, with uncertainty
Elsewhere in China, the situation seems significantly less dire. Every Chinese province faces cases, with over a dozen provinces facing hundreds each, but the latest case numbers show only a 15% growth in the number of cases in the top 13 provinces outside Hubei over the last two days. This means that unless ascertainment is actually falling (or the books are being cooked), the quarantine is successfully reducing the number of cases in provinces outside Hubei. In fact, the absolute number of new confirmed cases in recent reports has actually fallen in recent days.
While this situation is bad, it is nowhere near as bad as in Wuhan, and in particular, the capacity of hospital beds and PCR testing seems adequate so far, according to official reports. Whether those reports are accurate or have problems similar to those in Hubei, and if so, how serious, remains unknown.
Major Chinese cities remain under a form of flexible quarantine, with most citizens in deeply affected cities like Guangzhou sheltering in place, although not to the extent seen in Hubei. Public spaces remain closed through most of China, and the national new year holiday has been extended through at least February 9.
Reports from our contacts in Beijing and Shanghai continue to indicate that food supplies and prices are nearly normal, although sporadic reports from elsewhere have suggested shortages and supermarket closures in some neighborhoods.
If the following conditions hold, then the future of the epidemic in ex-Hubei mainland China seems likely to parallel the experience of SARS on a larger scale:
- Official statistics are at least somewhat closer to reality in major Chinese cities than they are in Hubei
- Public health system remains intact
- Cases are consistently identified and quarantined in hospitals
- Capacity remains adequate
- The quarantine of Hubei prevents large numbers of cases from migrating
If all of the above is true, then we’d expect to see case numbers dropping slowly to zero as the value of R is pushed below one by public health measures and kept there. If public health measures reduce R to .4, as in the case of SARS, and if the serial interval is seven days, then new case numbers would drop approximately a factor of forty each month, allowing the epidemic to be effectively exterminated in most of China within a couple of months. This is the best-case scenario for China outside Hubei, but it remains impossible to confirm for now.
One potential challenge to this scenario will be the disruption to the quarantine over the next week as travelers across China return to their homes from the new year holiday, and as workplaces across China reopen. If statistics confirm recent hints at a reduction in case numbers, the question will still remain whether the trend continues as the effects of this migration and reopening of businesses are seen.
Chinese anger rises on social media
In the midst of the suffering and chaos in Hubei and across the country, with the true depth of the situation uncertain, anger against the local and national governments has been building to a fever pitch.
Particular fury has been vented against the Hubei Red Cross and its relationship with the Hubei local government, with accusations of both incompetence and racketeering circulating widely.
There have also been limited and unconfirmed reports of instability in the national government. This raises the dual possibilities of hurried reforms enabling improvements in the capacity to respond to the emergency, or political instability worsening matters further.
2019-nCoV may soon be contained on the global stage, as attention fixes on Germany, the third world
In the world outside mainland China, the case total stands at 182 according to the latest update on the Johns Hopkins portal, up only 11% from two days ago. It appears that the number of cases arriving from China has been significantly reduced by travel restrictions, and that most imported cases are not leading to significant propagation, at least so far.
Since the WHO’s declaration of a Public Health Emergency of International Concern, the USA has followed suit with its own declaration. Other governments have diverted and screened travelers from China, scrambled private jets to bring their citizens back from Wuhan, quarantined those citizens when they arrived, recalled their diplomats, banned Chinese travelers, and even closed borders. 3M has put protective masks on global allocation, cutting supplies to nonemergency uses, while airlines around the world have stopped flying to China.
In the USA, the government has banned non-citizen travelers from China, quarantined Americans arriving from Hubei, and is continuing to screen all arrivals from China.
Delta, United, and American have announced a suspension of all flights to and from China, with the last flights trickling in over the coming days.
The US government has announced it is building special quarantine facilities for travelers arriving from China who exhibit symptoms, in the housing complexes of military bases. And, unfortunately, significant open racism against Chinese people in the USA has emerged in relation to the epidemic.
The response of case numbers to these efforts appears to be significant. Although the USA has seen one transmission between family members, and the German workplace transmission case has expanded to a cluster of cases including at least one third-generation transmission, reports continue to suggest that most identified imported cases have not yet yielded significant transmission.
The situation appears broadly similar to what happened with SARS. In the USA, for example, of the five imported cases over a week old, only one has transmitted, and only intrafamilially. It appears that in the first world, imported cases are not leading to self-sustaining local outbreaks.
The situation in the third world remains less clear. Confirmed cases in Thailand, Malaysia, Vietnam, the UAE, Russia, the Philippines, and Cambodia are being monitored closely for signs they will lead to local outbreaks.
Some African countries facing suspected cases or expecting them have notified the WHO they would like assistance preparing local testing capacity, as few hospitals in many countries on the continent have PCR facilities.
Countries with limited capacity may face self-sustaining epidemics even if China and the first world successfully lock down the spread of 2019-nCoV, and if they do, a catastrophic situation like the one in Hubei province could develop in one or more of them in just a couple months.
Major outstanding questions to watch
As the situation evolves, there will be several important questions to watch, including:
- Whether 2019-nCoV becomes globally contained outside China, or an ex-China country has a large outbreak
- Whether the signs of containment in China outside Hubei hold
- What news arrives about the accuracy of epidemic statistics from China
- When the situation in Hubei stops blowing up, and how badly has it already blown up
- Whether capacity gaps in PCR testing and hospital beds in Hubei ease up
- Whether the political situation in China undergoes an upheaval