Worth the read.
Guest post by Rud Istvan,
ctm posted my longish scientific commentary written last Sunday on Monday. The situation is still rapidly evolving. Much more is now known than last Sunday. This updates my previous commentary and the general knowledge about Wuhan, adding new factual information plus additional research. For those interested, the WSJ online (paywalled, but I am a subscriber) has added a new coronavirus section tracking Wuhan daily news because of the importance to China and global supply chains. I rely on it here using today’s WSJ noon update.
A special h/t to previous commenters Robert of Texas and Nicolas McGinley, who added much to my previous post with many erudite comments.
Origins and precedents
Wuhan is the third known transmission of a respiratory tract coronavirus infection from bats via an intermediary mammal to humans:
SARS 2003: The following information is derived from a special WHO report. 916 deaths from 8422 total infections, mortality 10.9%. Not transmissible prior to onset of symptoms (cough, fever); main transmission days 4 and 5 after symptom onset. Mode of transmission mainly contact, with an R0 about 3. Bat corona via live civet intermediate to humans in a Chinese wet market.
MERS 2012: 779 deaths from 2229 total infections, mortality 35.5%. Not transmissible prior to symptom onset. Bat corona via live camel intermediate to humans in a Saudi Arabian camel market.
Wuhan 2020: to today at noon (2/13/20), about 1300 deaths in about 59000 diagnosed cases, with about 5000 full recoveries. The implications are discussed below. Bat corona via live pangolin to humans in Wuhan’s Huanan wet market (since permanently closed) in December 2019.
Wuhan transmission and clinical progression
Many more case reports are now giving a clear clinical picture.
Transmission route is either contact or inhalation (of real concern, because more flu like than cold like—even with annual flu shots influenza R0 remains about 2 because of flu vaccine issues covered in the previous post). Based on SARS and influenza, this means the likely Wuhan R0 is 3ish, so very contagious. The significant inhalation route is now shown by both the Diamond Princess cruise ship experiment (more below) and by the fact that ordinary surgical masks proved ineffective in the Wuhan hospital setting (JAMA, previous post).
Incubation period is 7-10 days from initial infection. The good news is that the 14-day quarantine adopted pretty much universally last week should therefore be effective (with a margin of safety) at Wuhan containment. But in most of Southeast Asia outside China, Japan, and Singapore, or in Africa should Wuhan spread there, 14-day quarantine will be difficult or impossible to maintain so the possibility of a pandemic remains.
The bad news is that Wuhan IS transmissible during some later part of the symptomless incubation period. The definitive clinical proof (there was comment debate about the reliability of previous post evidence from Japan and Germany) is an age 50’s UK male who attended an about 100 person sales conference in Singapore 1/20-1/22 2020. A single individual from Wuhan also attended this conference and was–per Singapore Wuhan containment policies– symptomless on arrival (no fever, no cough). That either symptomless or very early symptomatic individual transmitted Wuhan to the UK citizen in Singapore. The UK individual then flew to France for a 4-day family ski vacation 1/24-1/28 at Le Contamines-Montjoie. During the 4-day vacation the UK male remained symptomless (entire incubation time Singapore plus France at most 8 days) but transmitted Wuhan to 11 other individuals, 5 later diagnosed in UK (family and friends), 5 later diagnosed in France, and 1 later diagnosed in Spain. Clearly this case is NOTfamily close proximity contact transmission. This case may be a “super spreader” outlier, BUT it means a symptomless R0 as high as 11 cannot be ruled out, with a symptomless transmission period of several days. By comparison, the R0 for measles (absent vaccination) is 12-18, so a horrific Wuhan symptomless R0 of 11 is within the realm of actual possibility.
This is VERY bad news, as the formal CDC guidance on URI’s is that transmission risk is highest with peak symptoms (equating to peak virion shedding)–as was the case with SARS. Not so with Wuhan, reinforcing the public health necessity of strict 14-day quarantine.
Disease progression is standard common cold symptoms for 7-10 days with one exception–used since yesterday for clinical diagnosis in Hubei Province, as both the Chinese and the experimental CDC US test kits are showing significant problems with a high rate of false negatives. Common colds from over 120 distinct serotypes from all three viral families (RNA naked Rhino, RNA enveloped Corona, and DNA enveloped Adeno) all evidence the same three symptoms: runny nose, sore throat, and cough. Influenza adds two: fever and muscle ache. Wuhan clinically shows four: runny nose, sore throat, cough, AND fever—but NOT muscle ache. As of today, Hubei switched to clinical diagnosis and today’s ‘new’ diagnosed Wuhan cases were 14840. Yesterday, using only test kits, it was 1638. This is not a leap in cases; it is a leap in diagnostics.
Unfortunately, this new fact means Wuhan has previously (as suspected but now proven) been severely under diagnosed and reported. And that unfortunately means the 1300 attributed deaths were also severely underreported. More on presently inferable mortality comes in a following section.
Wuhan then makes a now well-established clinical bifurcation. In 75-80% of cases, by symptom day 10 there is a normal ‘corona cold’ recovery lasting a few days. (In my own case last week, 3 recovery days in total, days 9-12 from symptom onset.)
In 20-25% of cases, by symptom day 10 Wuhan progresses to lower respiratory tract pneumonia, where death may occur with or without ICU intervention. The percentage of these deep pneumonias that are viral as opposed to a secondary bacteria infection is not known, but the NEJM clinical case report from Washington State discussed in the following paragraph strongly suggests viral (like SARS), not secondary bacterial treatable with antibiotics.
The new NEJM case report is so important it is summarized here because it leads to a hopeful culminating section below. The Seattle Wuhan case evidenced x-ray diagnosed lower respiratory tract pneumonia from days 9-11 from symptom onset. Supplemental oxygen was started day 9. IV antibiotics were started day 10 to no effect, so discontinued after one day. Importantly (more below), experimental antiviral remdesivir started day 11 by IV under a compassionate use exception, and the deep viral pneumonia fully resolved (per x-ray diagnosis) within 24 hours!
Diamond Princess ‘lab’ experiment
On Sunday, reported cases were 69 out of about 3700 total ship passengers and crew. Japan was removing people from the ship to hospital isolation as soon as symptoms (fever) showed, so the cruise ship became a somewhat artificial (close quarters) symptomless R0 experiment.
As of today, the ship’s website reports that 218 passengers have been positively diagnosed from 713 tested, all removed to hospital isolation. About 3500 passengers and crew remain on board as the ‘experiment’ continues. This suggests symptomless Wuhan R0 is greater than 2 (37 new cases per day for four days among a symptomless about 3500- 3600) and could be, like SARS, 3ish. Except SARS transmission was after symptom onset; this is before.
Per its website, ship offered today to begin removing symptomless passengers to shore quarantine at their expense, or to remain quarantined on the ship at Princess expense. In either event, full cruise refunds have been made.
The news here is not good. We have mostly very poor data; both Hubei incidence and mortality were now provably severely under reported. But we do have one piece of usable comparable information. 1300 mortalities and 5000 recoveries amongst those who tested positive from the false negative test kits used until yesterday (the majority of cases have not yet resolved one way of the other). In the end, when the disease has run its course, there are only two outcomes: recovery or death. On the test kit basis, the mortality could be as high as 26%. That is horrible but not impossible since MERS was almost 36%.
My own ‘hunch’ is that Wuhan in the end will come in about 10% mortality; the mechanism is lower respiratory tract viral pneumonia just like 2003 SARS and the 1918 ‘Spanish flu’. There is no reason to think the mortality outcome would differ greatly from a very similar clinical mechanism.
For sure, not any time soon.
The degree of difficulty is explained by the structural nature of Wuhan and its reproduction method. It is an enveloped non-segmented positive sense single strand RNA of about 30kb (the largest of any virus). The genome reads from the 5’ end. It first codes for (along about 20kb) the RNA protease ‘polyprotein’ that hijacks the host cell and causes replication. The remaining ~10kb code for 4 viral proteins separately needed to finally reassemble viable Wuhan virions: S, the pronounced spike from the envelope that gives the corona virus its generic name and enables further cell infection; N, the nucleocapsid (the capsid protein around the RNA core); M, the envelope membrane protein, and E, the envelope protein that protrudes from M but not nearly as far as S.
The obvious vaccine antibody targets are primarily S and secondarily E. That is no different than H and N in influenza. Unfortunately also like influenza, in SARS it has been shown that both S and E undergo RNA transcription error mutation, and at higher rates than one might suspect from the specifics of RNA coronavirus. Thus, like influenza, it may not be possible to develop a general Wuhan vaccine, only one of limited effectiveness against circulating virus that Wuhan will then mutate around.
Here, the very new news is hopeful. Gilead Science developed remdesivir for enveloped non-segmented negative sense single strand Ebola virus. In emergency human clinical trials in Africa, it proved safe but not effective. It has shown good in vitro efficacy against SARS and MERS. And the single NEJM case report above has a definite positive proof of principle human outcome.
Based on this, China has announced a full-scale random double blind placebo controlled trial in 761 patients. As of this writing China reports successful synthesis of sufficient remdesivir active, so human testing begins today.
Of note for potential future Gilead/China intellectual property conflicts, China announced yesterday that it has applied for a patent to use remdesivir to treat human Wuhan. WUWT?
Updated WUWT conclusions
Is Wuhan a serious public health concern? Yes.
Is Wuhan a serious pandemic threat? Not yet.
If containment mainly to China via travel restrictions and 14-day quarantine can be enforced, it is probably not a pandemic threat ever to North America or Western Europe or Australia. Africa and Southeast Asia outside China, Japan, and Singapore need careful watching. And as with 2009 Swine flu, South America will be hit or miss.
Is 14-day quarantine effective? Yes.
Is a vaccine on the horizon? No.
Is a drug therapy on the horizon? Yes.