The Next Time

As we continue to fight the current covid pandemic caused by the SARS-CoV-2 virus, it’s not too early to begin thinking about the next pandemic.  I’ve been mulling this over for a while, and I was prompted to write this post by a twitter thread from Michael Baym.

Michael wrote about some work that he and Kaylee Mueller started, early in the pandemic, to develop a rapid colorimetric assay for covid.  They decided to curtail their work, however, when the personal risk of continuing to work in the lab seemed too great. But Michael is now wisely looking ahead, thinking about what science can do to respond even more quickly to the next pandemic.

Last February, as most of the world was just waking up to the threat posed by covid, I wrote a post with words of wisdom for pandemic preparedness. The words were written by a former Secretary of the US Department of Health and Human Services, Michael O. Leavitt, in 2007, who at that time was especially concerned about the potential for an influenza pandemic. He said: “Everything we do before a pandemic will seem alarmist. Everything we do after a pandemic will seem inadequate. This is the dilemma we face, but it should not stop us from doing what we can to prepare.”

So congratulations, and thanks, to Michael and all the others who are looking ahead. But really, all of us need to look and think ahead, using our hearts as well as our minds. 

Almost exactly a year ago, I was very worried about how hard this country would be hit by the pandemic.  I wrote:  “I think it is entirely possible, maybe even likely, that Europe will get hit harder by the coronavirus than China has been hit, and the US may get hit even harder than Europe.” 

I suggested that a number of epidemiological and sociopolitical issues would contribute to the United States being especially hard hit by the pandemic.  Among the former, “China’s outbreak started from a single point source in Wuhan … The US, meanwhile, has gotten many independent seeds both from China and from Europe … hundreds or even thousands of smoldering embers at first, most growing unseen and uncontained …”  Among the latter, “here in the US, we have deep social divisions, widespread skepticism of expertise (often fed by those divisions), an extremely complex political landscape with federal, state, & municipal layers of government … and many independent-minded people who are inclined to disregard advice and instructions—a wonderful attitude some of the time, but an exceptionally dangerous attitude during a pandemic.”

My worries about the next pandemic have been leaning to the problems of social division and disregard for evidence.  As terrible as this pandemic has been, the next one could be worse … even much worse.  How will people react if the next pandemic is 10 times more deadly than covid?  What if the next outbreak causes disproportionate mortality in kids or young adults?  Would the (mostly) right-wing denialists still refuse masks? Would anti-vaxxers (on the left & right) still oppose vaccination?

So, Michael Baym is right to be thinking ahead, as was Michael O. Leavitt. As a nation, we need to commit resources to support science (including the basic sciences that lead to breakthroughs in medicine) as well as our often neglected public-health system.  But we also need to find ways to come together as people, to overcome the sometimes willful ignorance, and to discuss things in a meaningful, non-conspiratorial way. 

Science and public-health workers can only do so much. The rest is up to all of us to protect ourselves, our families, and our communities from covid … and from the next pandemic … and from ourselves.

Advertisement

An Engineering Perspective on Accelerating Vaccine Distribution

by Daniel Lenski

Key Points:

• We can continuously prioritize vaccination of the most at-risk populations, and at the same time immediately offer remaining vaccine doses to lower-priority recipients.
• We can plan for optimal inter-dose timing for 2-dose vaccines without holding back half the supply of those vaccines.
• We can build a system to maintain consistent levels of availability and prioritization in all regions of the country for the months and years it will take to produce enough vaccines for near-universal immunization.
• The field of industrial engineering offers well-studied and proven techniques to accomplish this.

---

The rapid design, development, and validation of multiple safe and highly effective vaccines for COVID-19, by scientists in the US and around the world, has been a stunning achievement. Our challenge has now pivoted to the task of inoculation against this pandemic disease.  How quickly can we produce and deliver sufficient vaccines to maximize protection of life and health, offering the hope of returning to more normal lives and economies? 

Vaccine manufacturers AztraZeneca, Pfizer, and Moderna expect to produce enough vaccine to inoculate only one-third of the world’s population in 2021,^[1] and the US expects to receive enough to inoculate only 50 million Americans by the end of March.^[2]  Production will certainly limit the rate at which we can achieve a high level of immunity in our populations, but the slow roll-out of vaccination in the USA underscores how much we must also optimize delivery.

As of January 11, 25.5 million doses have been provided by the US government, but only 9 million doses (35%) have been injected into the arms of willing and available recipients.^[3] Vaccine stockpiles continue to grow, indicating clearly that delivery, not manufacture, is currently the bottleneck. Delays have been ascribed to insufficient guidance and funding for states and cities, limited and confusing schedules for vaccination appointments, and confusion about current prioritization schemes.  In an example of the floundering, one week ago New York governor Andrew Cuomo instituted harsh penalties both for providers who vaccinated ineligible recipients and for providers who allowed doses to expire or otherwise go to waste. These requirements of maximally efficient utilization and strict prioritization are both logical and important, but they are inevitably in tension with each other. In the absence of clear and simple guidance for how to resolve this conflict, it is unsurprising that these dual mandates have led to a very low pace of vaccination in New York.

How should a program of mass vaccination operate amid a deadly pandemic? What should its goal be, day in and day out, from individual vaccine providers to cities and states to the country as a whole? The goal, as I see it, is to get vaccine doses into every willing recipient^[4] while consistently ensuring that the most vulnerable, at-risk groups have prioritized access, and at the same time dispensing vaccines as fast as they can be produced.  A vial of vaccine sitting in a freezer for days or weeks, awaiting the arrival of a high-priority recipient, does no good for anyone. In contrast, vaccinating any human right away will eliminate a vector for the spread of the disease, and move all of us one step closer to ending the pandemic.

The field of industrial engineering can provide us with crucial techniques and tools to sustain a balance between rapid delivery and prioritization for the months and years ahead.  From 2015-2020, I worked with semiconductor factories in the US and around the world providing advice and software.  Our services addressed problems such as: maximizing throughput by identifying and removing bottlenecks in multi-step processes; making efficient use of scarce resources, including time, labor, and raw materials; prioritizing completion of urgently-needed output; and adhering to constraints in the relative timing of critical steps to ensure quality and reliability.

The problems of vaccine delivery are strikingly similar: for maximum efficacy, the Pfizer vaccine’s two doses should be delivered 21-28 days apart^[5]; it’s critical to vaccinate at-risk groups early on^[6]; all currently approved vaccines require storage and transportation in expensive deep freezers, must be thawed in multi-dose batches, and expire wastefully if not dispensed quickly.

The tradeoff between prioritization and maximally efficient use of time and materials, illustrated by Governor Cuomo’s orders, is a glaringly obvious one to industrial engineers. If a strict sequential order is followed, the next recipient may not be available in time to use the next vaccine dose (leading to expiration and waste), while giving the vaccine on a purely first-come-first-served basis will maximize utilization but hinder rapid access for the highest-priority recipients. It is clear, however, that some members of high-priority vulnerable groups are either unable or hesitant to receive COVID-19 vaccination right now, while some members of low-priority populations are willing and eager to receive it immediately, but cannot due to lack of both eligibility and information about availability. Industrial engineering offers simple mechanisms to achieve an efficient and dynamic balance between these competing demands, such as by creating multiple priority queues at each vaccination provider and switching from higher- to lower-priority recipients immediately when the former are not present.

Experience from manufacturing can also clarify the problem of delivering second doses with optimal timing. Available quantities of Pfizer and Moderna vaccines in the USA were effectively halved by the initial plan to reserve a second dose of vaccine for each patient as soon as their first dose is administered. Some experts have recently suggested distributing all available 2-dose vaccines as first doses,^[7] reasoning that rapidly dispensing single doses will save more lives than a predictable but slow pace of second doses, while virologists warn that the reduced efficacy of single doses could have grave consequences in the longer term, by allowing vaccine-resistant variants of the SARS-CoV-2 virus to evolve and spread. In fact, neither reserving second doses nor abandoning their correct timing is necessary. Because future delivery of vaccine supplies to the USA is relatively predictable (at least in terms of the lower bound), an optimal steady-state solution is for providers to limit the rate at which they dispense first doses to half the rate at which they expect to receive future doses, which will leave them with sufficient supplies to consistently vaccinate patients returning for their second doses during the optimal time window.^[8]

Beyond the failure to balance between rapidly dispensing available vaccines and prioritizing them, along with a sub-optimal approach to reserving second doses, vaccine distribution in the USA appears gummed up by a pernicious combination of insufficient information about when and where COVID-19 vaccines are available, and complex paperwork and administrative requirements.^[9]

If the incoming Biden administration were to ask me to design a plan for rapid distribution of COVID-19 vaccine, my proposal would include the following elements:

• A national database to track vaccine inventory and rates of dispensation at the level of each provider, in near real-time. This will be crucial for determining the appropriate rates at which to resupply providers with more vaccine doses, so as to sustain and maintain inventory of vaccines across the country without developing geographical and temporal imbalances in inventory.
• First-come-first-served vaccine dispensation at the level of individual providers, with the crucial addition of multiple queues for patient intake, so that the most vulnerable can always receive the vaccine before others, no matter when they decide to get it.
• Training for all vaccination providers to implement the queuing system uniformly and consistently, along with minimal and consistent administrative requirements.
• A website to track wait times for each queue, at each provider, in near real-time. The availability of wait times at nearby locations will likely be crucial to motivate a continuous high rate of vaccine delivery, by allowing many Americans to seek out the vaccine on short notice when wait times are short for their eligibility cohorts.

Ending the COVID-19 pandemic through mass vaccination will present an extraordinary range of challenges for physicians, public health officials, scientists, politicians, and society at large. The tools of industrial engineering certainly cannot help with many of these challenges; however, they can help us achieve and sustain one crucial goal at all scales: getting vaccine doses into every available, willing human being as fast as they can be produced, while continuously ensuring that the most vulnerable people have the most rapid and streamlined access to the vaccine. I know that President-Elect Joe Biden’s COVID-19 task force will include epidemiologists, physicians, and virologists.^[10] I would encourage him also to appoint experts in industrial engineering and operations research, who can provide strategic guidance and tactical advice to speed up and smooth out nationwide vaccine distribution.

---

Appendix: A Specific Proposal

If the incoming Biden administration were to ask me to design a national vaccination program with the above goal of dispensing vaccines as rapidly as they are manufactured, while also continuously guaranteeing preferential access to prioritized populations, here’s what I’d propose. To simplify, I’ll assume that our present vaccine distribution bottlenecks are indeed overwhelmingly a “last mile” problem,^[11] and that there are no major logistical impediments to reliably delivering vaccine supplies to providers anywhere in the country within timescales of 1-2 weeks.

First, establish a national database of vaccine-dispensing providers, and a mechanism to log daily inventory for each provider. Apportion newly-manufactured vaccine among the states and territories, and from there down to the level of individual providers. The first round of apportionment will take some guesswork; in the interests of speed and simplicity, my strong inclination would be to apportion the first round simply by population. Subsequent rounds should be adjusted up and down based on past demand and current inventory, in order to prevent geographical and temporal imbalances in inventory.

Second, each provider should dispense vaccines on a first-come-first-served basis, but with multiple priority queues with extremely simple selection criteria. Age is the simplest and most easily documented criterion, and so I have used only that below. Other criteria, such as health-risk factors, occupation, and race or ethnicity have been proposed. However, more complex prioritization runs the risk of slowing down the process for everyone^[12], by turning “eligibility determination” into the rate-limiting step. Something like the following:

• Monday-Wednesday: 6 queues. One for recipients over 80 years age, one for 70+, one for 60+, one for 50+, one for 40+, and one for everyone else.
• Thursday: 5 queues. 80+, 70+, 60+, 50+, everyone else.
• Friday: 4 queues. 80+, 70+, 60+, everyone else.
• Saturday: 3 queues. 80+, 70+, everyone else
• Sunday: 2 queues. 80+, everyone else.

These queues should literally be lines that people who want the vaccine wait in, clearly marked according to the age criteria. During operating hours, patients should be free to join the appropriate queue at any time. Providers should accept and vaccinate all available patients from higher-priority queues before accepting any from lower-priority queues, but should immediately switch over to lower-priority queues if a higher-priority queue is empty. Example: it’s Tuesday, and there are 10 people in the 80+ queue, 30 in the 70+ queue, and 100 in the everyone-else queue. Providers should vaccinate all of the 80+ patients, then immediately start vaccinating all of the 70+ patients, then immediately start vaccinating “everyone else.” If two more 80+ patients arrive after that initial queue has emptied, they would be accepted and vaccinated immediately. Available vaccine doses should be logged daily to the national database. Acceptance of patients from each queue should be logged in real-time so that it’s possible to publish intake rates in real-time for each and every provider.^[13]

This scheme is intended to achieve the following results:

1. No matter when a higher-priority person decides to get vaccinated, they’ll be able to get it with less waiting than all lower-priority individuals.
2. Lower-priority individuals will not have to wait to receive the vaccine unless higher-priority recipients are waiting for it right now.
3. Wait times will be relatively measurable and predictable, encouraging people to drop in and get vaccinated when lines are short, and stay home when lines are long for their priority groups.
4. Vaccine will be dispensed continuously during the operating hours of each provider, ensuring minimal wasted or expiring doses. (Round-the-clock operation should be able to eliminate this entirely.)
5. This weekly cycle is intended to prevent overcrowding of lower-priority patients if there’s sustained high demand from higher-priority groups. For example, given the above prioritization scheme, few 35 year-olds will want to line up on Tuesdays. However, those who do will probably have very good reasons to endure a long wait for the possibility of vaccination, e.g. an immune-compromised family member. By later in the weekly cycle, the wait times and intake rates for the younger age groups should be more predictable based on previous days.

---

^[1]    https://www.nature.com/articles/d41586-020-03370-6

^[2]    https://www.nytimes.com/live/2020/12/15/world/covid-19-coronavirus

^[3]    https://www.nytimes.com/interactive/2020/us/covid-19-vaccine-doses.html

^[4]    Appropriately spaced when 2 doses are required, and excepting those with contraindications.

^[5]    https://www.biopharma-reporter.com/Article/2021/01/07/WHO-weighs-in-on-COVID-19-vaccine-second-dose-delay

^[6]    Modeling from Israel indicates that vaccinating the most vulnerable 7.5% of the population would reduce overall death rates by 75%. https://twitter.com/dwallacewells/status/1340397154683269123

^[7]    https://www.washingtonpost.com/opinions/2021/01/03/its-time-consider-delaying-second-dose-coronavirus-vaccine/

^[8]    This problem gets more complex when the rate of future availability is unpredictable, or when there’s a large build-up of current inventory.

^[9]    https://www.newsweek.com/senior-citizens-wanting-covid-vaccine-face-51-step-online-registration-process-1560622

^[10] https://www.forbes.com/sites/judystone/2020/11/09/president-elect-biden-names-new-covid-19-task-force–whats-the-enthusiasm-about/?sh=723ade8a458f

^[11]   https://www.reuters.com/article/health-coronavirus-vaccine-challenges-tr/analysis-covid-19-vaccines-raise-hope-but-the-last-mile-challenge-looms-idUSKBN28P124

^[12] https://www.wsj.com/articles/vaccination-by-age-is-the-way-to-go-11610476439?mod=hp_opin_pos_3

^[13]  Let’s say it’s Monday at 10 am. I should be able to pull up a page for the pharmacy at the corner of 10th & Elm street, and see that in the last hour:
80+ queue: 12 patients accepted, est. 2 currently in line (→ ~10 minute wait time)
everyone-else queue: 24 patients accepted, est. 20 currently in line (→ ~50 minute wait time)

---

They’re back!

They’re back! After a six-month interruption, Devin Lake restarted the long-term evolution experiment and the 12 LTEE lines from the 73,000-generation freezer samples. Now the bacteria are back in their home-sweet-homes: Erlenmeyer flasks with DM25 medium and the shaking incubator set to 37C.

We’re keeping the lab at very low occupancy, and using masks and physical distancing when more than one person is present in a room) until this damn SARS-CoV-2 pandemic is under control.

MSU also has a spit-based surveillence program in place for those entering campus buildings. Each sample is split, and then put into two pools for PCR testing. With each individual’s sample split into two pools, the testing can identify which individual in any reaction that proves to be positive is the source of the virus. That person is then notified and told to isolate and get a definitive diagnostic test.

[Both photos below courtesy of Devin Lake]

We Interrupt This Experiment

Today I made the decision to close the lab and temporarily suspend our experiments, including the LTEE, in light of the expanding SARS-CoV-2 outbreak.

I started to say it was a difficult decision, but really it was not all that difficult.  Several considerations led me to this decision.

1/ The SARS-CoV-2 outbreak appears to be taking off in many countries, including the USA, despite the substantial containment that has been orchestrated in Wuhan and elsewhere in China.

2/ The absence of evidence of any local cases is not as comforting as it might be, given the near-absence of testing here and in most of the USA.

3/ MSU students just returned from spring break today.  Some of the superb undergrads who work in my lab went to places that have confirmed cases. None of the places they went are among the locations with intense outbreaks, but the confirmed cases in at least one location have grown noticeably in the past week. They also flew on planes to and from their vacations.

4/ As a team, we’re connected not only to one another, but also to people who are health-care workers and others with increased vulnerabilities to infections. (Not to mention that I’m over 60 …) When you think about it, pretty much everyone has those connections.

5/ We’re very lucky because our work is easy to stop and re-start. Our study organisms can be frozen away and revived whenever we see fit.  In the meantime, everyone has classes to take, papers to read and write, data to analyze, etc.  And a little extra time, hopefully, to reflect on and maintain the health and well-being of our friends, families, and selves.  So, we will all be busy, but doing things a bit differently than we had planned.

6/ As we freeze away the long-term lines, the lab notebook will record:  “On this day, the LTEE was temporarily halted and frozen down for the coronavirus pandemic of 2020.”

Hopefully, some future historian of science will look back on today’s entry and say: “What the hell was that all about?”

[Devin Lake putting the LTEE populations into the ultra-low freezer, where they will stay until they are called back into action … evolution in action.]

The Lenski Lab Health Plan for the New Coronavirus Outbreak

The future is unknown, as it always is.  We do know that the SARS-CoV-2 virus is spreading around the globe, but we don’t know how many people will be infected.  Some experts are predicting that something like half of the adult population will be infected, although not all at the same time.  We also know that many cases are relatively mild (like a cold or the usual flu), and some infections may be asymptomatic. However, we also know that some other cases—perhaps 20% or so—are very serious, and some of those are life-threatening.

See MSU’s coronavirus page for University policy, information, and advice.

What can we do, as individuals and a lab group, to protect ourselves, our families, each other, our communities, and our research?  Here are my current thoughts, with an emphasis on activities related to our laboratory and our academic setting.

1/ If you haven’t done so already, get your flu shot. It won’t protect against the coronavirus, and it doesn’t provide perfect protection against the influenza virus, but it will reduce the chance of getting the flu (and save health-care resources for others in need).

2/ Make sure you and your household are prepared for a period of self-isolation or quarantine lasting 2 weeks, or perhaps longer.  This means stocking up on food staples and, importantly, any medicines that you and your household need.  For medicines, I suggest having at least a full month’s supply, maybe longer, in case there are disruptions to availability.  Talk to your doctor about extending prescriptions or any other special needs you might have.

3/ If you develop symptoms of a cold or flu—even mild symptoms—please stay at home and don’t come into the office or the lab.  We don’t want you to spread the infection.  Just email the group list to let us know what’s up, and work from home on your writing and reading if you feel up to it. You won’t impress me, or anyone, by trying to work while you’re sick.

4/ If a member of your household becomes ill, see and follow point 3 above.

5/ Let’s all start practicing more restrained physical interactions, and thus set good examples not only among ourselves but also for our colleagues and friends. That means skipping hugs and handshakes, for the time being.  Instead, you might put your own hands together and bow your head slightly to greet or congratulate someone. Or maybe an elbow bump, if you really must make contact.  Foot bumps are apparently another new thing, too.

6/ Be prepared to stop your lab work on short notice.  In the meantime, I guess March might be a good time to get a week-long or two-week experiment done, before the epidemic grows too large (if it does).  However, I suggest holding off, for the time being, on any plan to start a large and/or long experiment.

7/ Speaking of long experiments, you will recall that we have a certain long-term experiment in our lab.  The LTEE will soon hit 73,500 generations, at which time the samples will be frozen as usual.  After that date, I’d like population samples to be frozen more often, say, every 2 or 3 weeks.  Just freeze away a copy of each population (no need to plate cells)—basically, so we have samples to restart in the event that people get sick, or if the university should at some point curtail certain activities for a while.

8/ Be prepared to cancel your attendance at scientific conferences and other academic or social events as new information arises. Even if an event organizer decides to push ahead, you don’t have to go if you feel it is risky for you personally. As an aside, I recommend delaying purchases of airfares until an event is closer in time, given the current uncertainty.  (Refundable tickets on most airlines are very expensive, and other tickets have restrictions.)  Hotel reservations can usually be cancelled on shorter notice (a day or week, check to be sure), but not if they were booked through a discounter.

9/ And maybe the hardest advice of all is to practice good personal hygiene. Cover your mouth with your forearm or the inside of your elbow when you cough or sneeze unexpectedly.  (If you know you’re sick, then you should have disposable tissues handy. Use those to cover your nose and mouth completely, and dispose of a tissue after one use.) If you find yourself coughing or sneezing repeatedly, see point 3 above. Wash your hands thoroughly [Click that link, with the sound on, and stay for the end!] after you’ve touched shared surfaces, especially before eating. And most difficult of all, avoid touching your own face.  This coronavirus can survive for hours as tiny droplets on surfaces, which we may inadvertently touch (“fomite transmission”). Then, when we touch our mouth, nose, or eyes, we can infect ourselves.

10/ ADDED: Follow the news, and get your news from trustworthy, reliable sources. If it becomes clear that infections are spreading locally, or even if you are just concerned about that possibility, then avoid crowded public venues. (But this does not mean that you should follow the news obsessively, as that can be exhausting. h/t Carl Bergstrom.)

11/ ADDED: If you do isolate yourself, whether because of illness or concern, make sure to maintain frequent social contact with your family, friends, and the lab via phone, email, or whatever works best for you. Don’t let physical isolation and loneliness make you feel miserable. We are all stronger together, even if we might have to be physically apart.

12/ ADDED: Please read these Words of Wisdom, regarding preparedness for infectious disease outbreaks, from Michael Leavitt, a former Secretary of Health and Human Services.

13/ ADDED:  This one is for those of you in science or other relevant scholarly fields.  Do you have data in your lab notebooks and/or on computers accessible only in the lab?  Are the datasets ones that you might need for your analyses and writing if, say, you end up confined at home for a few weeks?  If so, I recommend that you copy it (but only if it’s allowed in the case of certain types of sensitive data!) by scanning it and/or copying it to your personal computer. That way, you can use it while working from home if you decide, or are required, to do so.

Take care everyone.  Please let me know of any errors, omissions, and practical suggestions.

 

 

 

Updates on the SARS-CoV-2 Outbreak

SHUTTING DOWN THESE UPDATES: The SARS-CoV-2 outbreak has continued to grow and expand its reach. I’m not able to keep up with any semblance of an update at this point, so I will shut this thread down. If things change, and I can contribute, as I’ve done with my lab health plan, I’ll do so in separate posts.

For those wanting summaries of events on a more-or-less daily basis, I recommend the writeups from the University of Minnesota’s Center for Infectious Disease Research and Policy (CIDRAP). For those wanting up-to-the-minute reports of developments, I’ve found  @BNODesk and COVID19 (@V2019N) on Twitter to be reliable.  Others I follow closely on Twitter for synthesis, analysis, and perspective include Helen Branswell (@HelenBranswell), Marc Lipsitch (@mlipsitch), and Carl Zimmer (@carlzimmer). Neil Ferguson (@neil_ferguson) rarely tweets, but provides another expert voice.  Trevor Bedford (@trvrb) provides authoritative analysis of the genomic changes in the virus, which are useful for understanding the dynamics of the global spread. As he’s located in Seattle, he’s also a good person to follow for developments concerning the outbreak in that region.

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

To make new information on this viral story easier to find, I’m adding updates with the most recent at the top.

As a reminder, I’m neither an epidemiologist nor a public-health expert, but I study microbial populations from a basic-science perspective. So I have a pretty good sense of what the experts are saying, what is reliable within the stated limits of uncertainty and assumptions, and so on. However, keep in mind that this is a rapidly developing situation, so the “facts” (data and interpretations) may change quickly.

UPDATE 7:55 pm (Feb 29): So much news today that I feel unable to provide even a short summary, including an apparent cluster of cases involving patients and staff at a nursing home in the state of Washington. Fortunately, others have provided summaries of today’s coronavirus news, including this clear and authorative writeup from CIDRAP. I would encourage individuals, families, businesses, local governments, and other groups to begin thoughtfully preparing for the possibility of infections in your own communities, if you haven’t already done so. I’ve posted the planning document for my own lab group.

UPDATE 11:00 & 11:30 pm (Feb 28): Second, third, and now fourth cases of infections in the US without travel history or known conacts with infected people–the second such case in California, and the first each in Oregon and Washington. The Washington case is a teenager, and the infected person in Oregon works at a school, adding yet additional worrisome elements. New cases and fatalities continue to rise dramatically in South Korea, Italy, and Iran. Several dozen other countries now also have cases. Markets in turmoil, leadership unfocused and/or in denial here in the US and some other places as well.  Here’s a 25-minute podcast interview with Harvard infectious-disease epidemiologist Marc Lipsitch about why he thinks it’s likely now that perhaps half of all adults will be infected at some point (but not all at the same time), and how to think about your own preparations. It’s well worth listening to the whole interview, whether you’re a scientist or not. (There are a few slightly technical bits, but none that go on for long–the interview stays focused on the big picture.) Lipsitch is very clear and soft spoken, despite the troubling implications of this new disease.

UPDATE 10:00 pm (Feb 27):  The big news reported here in the US is an infection in northern California with no international travel nor, apprently, known contacts with anyone infected, suggesting a case of community transmission. Of interest, and possible concern, that viral isolate’s genome differs by only a single mutation from another California isolate. Could that have come from a repatriated and quarantined individual?  If that proves to be the case–and I repeat, if-– then it suggests there was some “leak” in the quarantine.  Meanwhile, individuals involved in those repatriations may not have received appropriate gear and/or instructions to protect themselves.  California health officials are monitoring thousands of individuals, but lack necessary kits to test for infections. Elsewhere in the world, Japanese schools are told to close for the next month. French and German authorities announce that epidemics are underway in those countries, while new cases continue to mount in South Korea, Italy, and Iran.

UPDATE 9:30 pm (Feb 26):  South Korea reported another 334 cases just today, bringing the total there to almost 1600 from just 31 a week ago.  And Italy reported 52 new cases, bringing its total to 128.  Here’s an image of an empty scientific meeting in Trieste, Italy — the meeting was cancelled, but the lectures were made available online. How many more cancellations of social, scientific, and business gatherings might we see in the weeks and months ahead?  Meanwhile, several countries reported their first SARS-CoV-2 cases today, including Brazil, following an individual’s travel from Italy … and with Carnival getting underway, that’s a potentially worrisome development there. Germany’s Ministry of Health has now found 18 cases, and officials warn of an epidemic potentially starting there.  A new case in California, someone with no relevant travel history, is a concern in the US because it suggests community spread.

UPDATE 9:00 pm (Feb 25):  South Korea cases up to 1,146 cases, up from just 31 less than a week ago. In Iran, who knows many cases of COVID-19, but the deputy health minister has it.

UPDATE 8:00 pm (Feb 24):  Five countries in Middle East report first cases, while Iran’s cases are up to 61, with 12 fatalities.  Italy’s cases up to 227, including 6 deaths.

UPDATE 7:10 am (Feb 24): Over 60 new cases reported today in Italy, with total now over 200 and 5 deaths to date. Official report from Iran states 12 deaths, but a lawmaker there says the actual number is much higher. South Korea total cases now reported as 833, with 7 deaths.

UPDATE 9:00 pm (Feb 23): Cases in South Korea continue to grow, now at 763 from just 31 several days ago.  Given the delay between infections and deaths (a few weeks, for those unfortunate minority of cases), the deaths in Italy indicate a larger outbreak that has grew undetected. Same for Iran, but we’re less likely to get reliable data from there.

EXPERT PERSPECTIVE 11:55 pm (Feb 22):  What countermeasures can we take to reduce the harm and disruption caused by this outbreak-turned-pandemic?  Read this excellent thread from epidemiologist Marc Lipsitch about short-term and long-term strategies for dealing with the expanding SARS-CoV-2 outbreak and the COVID-19 disease that it causes. Full of ideas, advice, evidence, and concern for our individual and collective well-being.

UPDATES 9:30 pm (Feb 22): Where to start? How about South Korea, from 31 cases a few days ago to more than 500 (with 4 deaths) today. Or maybe Japan, where a quarantine officer at an airport has contracted the infection.  Then there’s Italy, with dozens of new cases today and many of those seriously ill, 11 towns in “lockdown” mode, and no clear understanding of how the outbreak began in that country.  And what’s up with Iran, which has an outbreak of unknown scope, and which has apparently exported cases to other countries including Canada and Iraq, which suggests the outbreak in Iran is large.  And the US? It’s hard to tell.  Have we been diligent and successful in limiting, identifying, and isolating potential infected persons?  Or have we been slow and too limited in testing?

PERSPECTIVE 9:10 pm (Feb 22): It pains me to write this, but I think there can be no doubt now that we are in the midst of pandemic caused by the SARS-CoV-2 coronavirus. No, it does not mean the end of the world, nor pervasive death, nor anything like that. But it does mean this infection has spread to, and continues to spread in, multiple countries on multiple continents. And with its spread will come substantial illness in some or many communities, some deaths, pressure on health-care systems, personal inconvenience, economic disruption, and discomforting uncertainty.  Stay strong, everyone. Respect and help your neighbors, while also practicing basic hygiene like handwashing, tracking the news in your own country and community, and so on.

STATUS 9:00 pm (Feb 22): I’ve been preoccupied today with an analysis of mutations in the SARS-CoV-2 genome. It’s undoubtedly a small side story, at best, but it interests me scientifically.  Also, I am “splitting” this web page into two parts with this page providing occasional updates to scope of this–yes, I will now call it what it has become–pandemic. I’ve added a separate post that provides occasional links to, and discussion of, Expert Analyses of the SARS-CoV-2 Coronavirus Outbreak.

UPDATE 10:10 am (Feb 22):  A large jump in SARS-CoV-2 infections reported in Italy, up to 54 from just 21 yesterday. Also, a second death was reported there.

UPDATE 10:15 pm (Feb 21): Another big jump in cases in South Korea.  The 142 new cases bring the total to 346 — it was just 31 three days ago.

UPDATE 11:30 am (Feb 21):  A new cluster of six youngish (~40 years old) cases, this one in Italy, and most of them are in serious condition. This cluster is possibly linked to another cluster elsewhere in Italy. About 250 contacts have been placed in isolation and will be tested for the SARS-CoV-2 coronavirus.

UPDATE 9:40 am (Feb 21):  Two prisons in China now reporting hundreds of cases.

UPDATE 9:30 am (Feb 21): Iran is reporting multiple cases in several cities: “The spread of the coronavirus started in Qom and with attention to people’s travels has now reached several cities in the country, including Tehran, Babol, Arak, Isfahan, Rasht, and other cities. And it is possible that it exists in all cities in Iran,” according to an official of Iran’s Health Ministry. Meanwhile, Lebanon has reported its first case–a traveler from Iran.

UPDATE 8:50 am (Feb 21): Now more than 200 cases in South Korea. Helen Branswell has posted a graph of the sudden rise of COVID-19 in that country.

UPDATE 10:50 pm (Feb 20):  Yet more cases reported from South Korea. The total is now 156. Many, but not all of them, are part of a large cluster associated with a church group.

UPDATE 9:45 am (Feb 20): Yikes again, Helen Branswell of statnews just reported that South Korea has had another jump to 104 in confirmed cases, up from just 31 two days ago. Not clear to me whether these are symtomatic cases of the disease COVID-19, or confirmed infections with the SARS-CoV-2 coronavirus.  And if I read this report correctly, there are another 1,860 suspected cases awaiting test results, although many previous suspected cases have returned negative results.

UPDATE 9:35 pm (Feb 19):  Yikes, this new report has South Korea’s cases up to 82, from just 51 yesterday and 31 before that.

UPDATE 6:20 pm (Feb 19): The latest concersn are jumps in the number of reported cases in some countries, including ones that hadn’t previously reported SARS-CoV-2 infections. South Korea reported a big jump from 31 to 51 cases, including a cluster of 16 cases in one city. This demonstrated the potential, at least for outbreaks to take hold outside of China. Meanwhile, Iran has few travelers from China, and was not known to have any cases. But two cases were reported today in Iran, and both patients have died. The Iranian health ministry is trying understand how those individuals became infected. And in Japan, the number of cases has more than doubled in a week, with 74 documented cases. And that doesn’t include the 600+ cases on the cruiseship Diamond Princess, now docked near Tokyo. Many of the other passengers are now being released from quarantine. But given the ever-increasing number of positive tests that were discovered, have new asymptomatic and/or presymptomatic infections been released into Japan and beyond? All of these reports are concerning not because they represent a large number of cases–the number of cases in all other countries combined remains far smaller than the number in Wuhan alone. Rather, the concern is that these represent and/or may seed new outbreaks that will be increasingly hard to trace and contain, as in the possible scenerios discussed by Trevor Bedford (see Expert Perspective posted at 4:30 pm on Feb 8), Richard Neher (see Model of Global Spread posted at 8:45 pm on Feb 9), Marc Lipsitch (see Expert Perspective posted at 1:15 pm on Feb 14), Neil Ferguson (see Expert Perspective posted at 8:00 pm on Feb 16), and other experts.

UPDATE 11:45 am (Feb 18):  Today’s report from Japan brings another 88 cases of SARS-CoV-2 infections on the quarantined Diamond Princess cruise ship. That brings the total number of infections detected so far to 542.

EXPERT ANALYSIS 9:50 am (Feb 18):  Adam Kucharski explains why estimating the case fataility rate for COVID-19 is complicated, and why the rate can appear to increase when the outbreak is slowing down.

EXCELLENT RESOURCE 7:30 pm (Feb 17):  The Center for Infectious Disease Research And Policy (CIDRAP) at the University of Minnesota has a superb (almost) daily summary of news about COV-19 and the SARS-CoV-2 virus.  Here’s the summary for today, and here’s the webpage linking to all the summaries — bookmark it!  (h/t @mlipsitch)

UPDATE 4:30 pm (Feb 17): Some readers may recall debate (and confusion) about whether the most closely related viral sequences to the SARS-CoV-2 outbreak had come from pangolins (scaly anteaters) instead of from a bat. [See the update titled “Waiting for more info but …” posted on Feb 7.]  The genome sequences of several SARS-like viruses sampled from pangolins have been shared by scientists from Beijing and Hong Kong. Trevor Bedford has included these sequences in his latest phylogenetic analysis to assess relatedness. As Bedford explains, “these pangolin viruses are closely related to the COVID19 epidemic, but [they are an] outgroup relative to bat/Yunnan/RaTG13/2013.” In other words, the isolate sampled from a bat in Yunnan in 2013 remains the closest relative seen thus far to the SARS-CoV-2 that caused the outbreak in Wuhan. Bedford points out, though, that “additional sampling may reveal a direct intermediate” from bats, pangolins, or some other animal. (Bedford posted another thread that elaborates on the difference between this latest work and some of the confusing earlier reports, for which no data has been made public to date.)

UPDATE 12:10 pm (Feb 17):  CDC has updated their test results for SARS-CoV-2 in the US. The latest report shows 15 postive and 392 negative tests, with 60 other cases pending. These data mean that the most recent 45 tests (since the update on Feb 14) have all been negative. There are a number of people with confirmed infections who have been evacuated from the Diamond Princess cruise ship, who are returning to quarantine in the US. It’s unclear whether they will be counted in futue CDC reports.

UPDATE 11:00 am (Feb 17): As much as it’s been a disaster for the affected individuals, the continuing outbreak aboard the Diamond Princess is providing valuable information on the distribution of the severity of outcomes for infected individuals. About a quarter of those tested so far have been infected.  Of those whose tests indicate they are infected, about 40% are asymptomatic (or, perhaps, presymptomatic). Of the 60% with symptoms, about 7.5% (= 19/254) are in critical condition. Of course, we need to keep in mind the demographics of the passengers, most of whom are older than the overall population. The large crew population, which is generally younger, should provide a valuable contrast for epidemiologists. (h/t @drkuehnert)

MODEL WITH SEASONAL VARIATION IN TRANSMISSION 10:30 am (Feb 17):  Richard Neher, Emma Hodcroft, and co-authors have posted a paper (not yet reviewed by other experts) where they analyze the possible effects of seasonality on the extent of the SARS-CoV-2 outbreak. Their model assumes that the virus, owing to its transmissibility and the global mobility of people, will eventually become established globally. (That’s not certain at this time, but many experts think it is likely.) They begin by noting that four other coronaviruses that circulate in the human population (typically causing symptoms similar to the common cold) are more prevalent in the winter and early spring. The good news from their model is that this seasonal variation in transmission should slow the spread of the new coronavirus in the coming months. The bad news, though, is that SARS-CoV-2 infections are likely to reach a peak next winter (2020/2021). At least that provides more time for health-care systems to prepare. They also emphasize that health officials and others should not assume the virus is under control based on diminishing case counts, because seasonality (along with quarantines and other social-distancing efforts) may give a false impression that the virus has been brought under control. Hodcroft has a nicely illustrated and explained Twiiter thread that summarizes this work. A few hours later, Neher posted another excellent thread on this work.

UPDATE 10:00 am (Feb 17):  Japan officials reported that another 99 cases of SARS-CoV-2 infections on the Diamond Princess cruise ship, docked near Toyko. That brings the total number of infections to 454, out of about 3700 passengers and crew in total.  Yesterday, more than 300 Americans who had been on the ship were flown from Japan and will be further quarantined in the US.  For those left onboard the ship, their quarantine was supposed to end this Wednesday … but given the ever-growing number of infections, that seems unlikely.

EXPERT PERSPECTIVE 8:00 pm (Feb 16): Neil Ferguson is an epidemiologist who models the dynamics of infectious diseases. In a technical, yet sobering, interview he works through estimates of various quantities relevant to the SARS-CoV-2 outbreak. He takes great care to acknowledge the uncertainties around his estimates. Here’s my effort to summarize what I understand him to say.

1. The large number of cases on the Diamond Princess cruise ship shows how easily the virus spreads.
2. The number of cases in Wuhan (city) and Hubei (province) appears to be plateauing, as predicted given the stringent quarantine imposed weeks ago.
3. It’s hard to know what’s happening elsewhere in China because they only test people with travel history to Wuhan and Hubei, which would miss community transmissions and thus under-estimate the extent of the outbreak elsewhere.
4. There are anecdotal reports of surges in pneumonia cases in other cities in China, consistent with under-testing and under-reporting of the new coronavirus.
5. Regarding the severity of this disease, it’s difficult to say in part because different surveillance methods pick up different categories of severity.
6. In China, only the most severe cases are routinely tested for the virus. Ferguson’s team estimates that about 18% of the severe cases in the Wuhan epicenter may die.
7. That does not mean, however, that 18% of the people infected die because many have mild or even no symptoms, and they are not tested. Ferguson’s team estimates that only about 5% of infected people are actually tested in Wuhan. So combining this fraction with the severe cases, one would estimate an overall mortality rate across all infections (mild and severe) of roughly 1%.
8. Another comparison group includes the ~300 cases of international travelers, where there have been 2 deaths (as of the time of this inetrview). However, there is a delay of ~3 weeks between diagnosis and death in the severe cases, and so that fraction needs to be adjusted to account for this delay. When accounting for this delay, Ferguson estimates that the mortality rate will eventually prove to be between 2% and 5% in this group. Once again, however, these cases are focused on travelers who already showed observable signs of illness when they entered a country, so this rate will also be higher than for other infections.
9. To adjust for this bias in detection as a function of severity, one needs to estimate the fraction of all travelers from the affected areas who are infected. To estimate this infection prevalence, Ferguson uses data obtained from the evacuation flights, where travelers who returned to their home countries were systematically quarantined and tested for the coronavirus, whether or not they showed symptoms. From these data, Ferguson estimates there were 3 to 4 times more infections than discovered when screening travelers. This means two things. First, the mortality rate estimated from travelers who show symptoms is once again too high by several fold,  If all infections were taken into account, the overall death rate is something on the order of 1%. Second, it means that many countries probably have SARS-Cov-2 transmissions occurring undetected in some communities.
10. Given all of the statistical noise in the data, Ferguson says that the uncertainty around these estimates of 1% mortality is about 4-fold in each direction. So bottom line, he thinks the true mortality rate lies between about 0.25% (1 in 400) and 4% (1 in 25).
11. The lower value would be similar to the pandemic influenza years of 1957 and 1968, while the high end would be more comparable to the 1918 pandemic.
12. The potential scope of the pandemic in terms of how many people will be infected is also difficult to predict. Going from past experience with influenza pandemics, Ferguson suggests that roughly half of the population might be infected in the first year, when one includes both those people who become ill and those with mild or no symptoms.
13. Despite these uncertainties, Ferguson explains that such numbers are valuable for countries and their health-care systems to formulate appropriate plans to deal with this “serious threat.” 

NEW INFO 7:00 pm, updated at 10:05 pm based on corrected info from Dr. Gottlieb (Feb 16):  Scott Gottlieb, an MD and former commissioner of the FDA, makes an interesting comparison between the number of cases of COVID-19 in the US versus Japan and Singapore. Japan has 4 times as many known cases as the US, despite having only twice as many travelers from China. (Note: Gottlieb is not including those on the cruiseship quarantined near Tokyo.) Singapore has 5 times as many cases as the US, with about the same number of Chinese visitors. Both Japan and Singpaore have some community transmission involving unknown contacts. Taken at face value, these comparisons “might suggest there are undiagnosed cases in U.S.“

UPDATE 3:45 pm (Feb 15):  The Diamond Princess is not the only cruiseship with a troubling story. The Westerdam was turned away from several Asian ports over concerns of the new SARS-CoV-2 coronavirus. However, it was allowed to dock in a Cambodian port yesterday, and 2257 passengers and crew were allowed to disembark after some health screening. A group of 145 of the ship’s passengers then flew to Malaysia — and one, an elderly American woman, had symptoms when she landed. She has reportedly tested positive for the virus, while her husband did not.

NEW INFO 3:15 pm (Feb 15):  Epidemiologist Michael Mina summarizes an important study from a team of medical scientists in Wuhan. (The linked paper is a preprint, and it has not been fully vetted by other scientists. However, it passed muster with an expert in the field, which suggests to me that it provides valuable information.)  Over 8000 people identified as contacts of people with COVID-19 were tested for the SARS-CoV-2 virus that causes that disease. More than one-third of the contacts tested positive for the viral infection, reinforcing the contagiousness of this disease. Fortunately, however, most of the infected contacts had only mild symptoms and were not sick enough to require medical care — at least not when they were tested. Presumably, the contacts have been quarantined and their health will be tracked.

INTERESTING READ 2:05 pm (Feb 15):  An interesting news story from UC-Berkeley about why bats seem to carry many viruses that cause problems when humans acquire those infections.

NEW INFO 1:00 pm (Feb 15):  The US readies coronavirus quarantine facilities at 15 military bases around the country. 

MONEY LAUNDERING 12:40 pm (Feb 15): “Money from key virus-hit areas [in China] will be sanitized with ultraviolet rays or heated and locked up for at least 14 days, before it is distributed again,” according to Fan Yifei, deputy governor of the People’s Bank of China.

UPDATE 11:00 am (Feb 15):  First COVID-19 death reported in Europe, as an 80-year-old Chinese tourist dies in France of the new coronavirus after 3 weeks in hospital.

UPDATE 9:35 am (Feb 15):  A second suspected case of COVID-19 reported in Africa, this one in eSwatini (Swaziland), near South Africa. Yesterday a case was confirmed in Egypt. Both cases followed international travel.

UPDATE 9:20 am (Feb 15):  From Helen Branswell, Singpore now has 72 confirmed cases of COVID-19. Despite diligent epidemiological tracking, however, it remains unclear how 8 cases became infected with the SARS-CoV-2 that causes the disease COVID-19.

UPDATE 8:30 am (Feb 15): Another 67 cases of SARS-CoV-2 infections have tested positive onboard the Diamond Princess cruiseship quarantined near Tokyo. That brings the total to 285. Also, the CDC announced that it will evacuate all US healthy citizens from the ship and bring them to military bases in the US, where they will undergo further quarantine. Those who have already tested postive and/or who have symptoms may have to remain quarantined in Japan for a while longer.

MODEL WITH VARIABLE TRANSMISSION 10:45 pm (Feb 14): Kyra Grantz, Jessica Metcalf, and Justin Lessler tackle an apparent dilemma in the epidemiological data on the spread of the coronavirus SARS-CoV-2. On the one hand, the value of R0 appears to be greater than 2 based on data from China, meaning that each infected person, on average, infects 2 or more people. On the other hand, most infected travelers do not seem to have set off significant transmission chains outside of China (although there certainly have been some secondary infections). How can these patterns be reconciled? In short, the resolution may lie in the variability between infected persons–or the settings when they are most infectious–in their propensity to infect others. So, for example, if most infected people start to feel a bit sick and stay home, but a few still feel well enough to go to a conference, then the average number of transmissions over all cases might be 2, but the variation in the number of transmissions could be quite high. In that case, most introductions of an infected traveler into a new community may lead nowhere (and appear inconsistent with a high rate of spread), but the occasional introduction could lead to a much larger (and potentially hard to contain) outbreak. In this scenario, it becomes harder to control the spread of an epidemic unless one can systematically identify the situations where such “super-spreading” events tend to occur; if one can identify and prevent those situations, however, then control of the outbreak may be more feasible. Lessler clearly explains and illustrates the ideas in a Twitter thread. 

NEW INFO 8:30 pm (Feb 14):  First confirmed case of COVID-19 (name of the syndrome caused by the new coronavirus) in Africa. The case was a traveler diagnosed in Egypt.

NEW INFO 8:20 pm (Feb 14):  The CDC will begin testing people with flu-like symptoms for the SARS-CoV-2 in five cities (Chicago, Los Angeles, New York, San Francisco, and Seattle), according to Scott Gottlieb, former FDA commissioner. This information won’t halt any outbreak that gets underway, but it will indicate when and where the virus gains a footfold in the US, and at what prevalence among people with flu-like illness. 

UPDATE 3:15 pm (Feb 14):  The latest update from CDC on testing for the coronavirus SARS-CoV-2 in the US is now showing 15 postive tests and 347 negative tests, with 81 cases pending. That’s 3 new positive cases and 29 negative results since the last update that I reported on Feb 10. 

UPDATE 3:00 pm (Feb 14): Epidemiologist Marc Lipsitch and colleagues estimate that fewer than half of COVID-19 cases are being detected in travelers, based on data from Singapore. This implies that there are more cases than known. It also implies that the average case severity is lower, because the less severe cases are more likely to escape detection. That said, however, those less severe cases may transmit the coronavirus, leading to more infections–including severe cases–in the long run. 

IN-DEPTH ANALYSES 1:30 pm (Feb 14): Computational biologist Joshua Weitz shared with me the link to a special event featuring 3 short talks on the SARS-CoV-2 outbreak that was organized this past Monday by the Center for Microbial Dynamics and Infection at Georgia Tech. The first speaker was Trevor Bedford, who leads the Nextstrain project that uses changes over time in microbial genome sequences, including the SARS-CoV-2 coronavirus, to understand the origin, transmission, and evolution of various pathogens. The second speaker was Weitz, who spoke about how experts use data to estimate the strength, speed, and final size of disease outbreaks in general, and the ongoing coronavirus outbreak in particular. He provided a separate link to his very clear slides. Importantly, Weitz explains some some of the uncertainties associated with these estimates, and some implications of these uncertainties for understanding the future of this outbreak. The third speaker was Phil Santangelo, who spoke on potential strategies used in antiviral drug design.

EXPERT PERSPECTIVE 1:15 pm (Feb 14): Infectious-disease epidemiologist Marc Lipsitch is quoted in the Wall Street Journal as saying “It is likely we’ll see a global pandemic … If a pandemic happens, 40% to 70% of people world-wide are likely to be infected in the coming year.” In an informative Twitter thread, Lipsitch elaborates on why he thinks this pandemic scenario is likely, and what factors might prevent a pandemic from unfolding (including control measures, especially in countries with strong healthcare systems). He closes by saying that “Predictions can be wrong and I very much hope this is, but better to be prepared.”

NEW INFO 12:45 pm (Feb 14): In another worrisome development, Japan is experiencing a “stealth outbreak” with several cases of the coronavirus infection in people without any travel history to China, and some without any known links to others who have had this infection. These findings led infectious-disease modeler Richard Neher to tweet that “Reports like this make me doubt that containment of SARSCoV2 is likely.” You can read more about Neher’s concerns in the “Model of Global Spread” post below (8:45 pm on Feb 9). 

NOT SHIPSHAPE 11:40 pm (Feb 13): The situation on the cruiseship Diamond Princess continues to worsen. The passengers and crew are quarantined onboard the ship, which is docked near Tokyo. A passenger who was onboard the ship from January 20-25 was subsequently found to be infected in Hong Kong. Now a total of 218 passengers and crew have been found to be infected, with the totals increasing by over 40 since the previous report just two days ago. Given a difficult situation that seems to have been handled poorly, one can only hope that at least some valuable epidemiological evidence will come from the cases. It would be nice, for example, to have multiple viral genomes sequenced from each of the infected individuals, along with information about the people’s onboard contacts, dining, proximity of cabins, ventilation, etc. Similarly, given the relatively large (but still manageable) number of cases, this outbreak might provide better information on the distribution of severity in a country, Japan, with a strong (and not overwhelmed) medical system.

AN UNKNOWN 11:30 pm (Feb 13): Despite speculation that the SARS-CoV-2 outbreak will be limited by seasonality, that remains unknown. One of many important unknowns at present.  (h/t @mlipsitch)

STATUS 11:00 pm (Feb 13): Sorry for the lack of any updates over the previous two days. My work-related travel made it impossible. I did manage to retweet a few stories when I had breaks, but I wasn’t really able to synthesize things in my own mind.  This was mostly a reflection of my travel, but perhaps it’s also an indication that we have entered a period of considerable uncertainty when it comes to this viral epidemic. Before the quarantines in Wuhan and other Chinese cities, we had frequent numbers that allowed estimates of R0 and other quantities. Undoubtedly the quarantines helped reduce the rate of spread, but they also made it harder to interpret the more recent data.  Also, there are uncertainities associated with testing capacity, false negatives (failure to detect the virus in some infected people), and even changing criteria for diagnosing COVID-19. Some combination of these factors presumably explains the huge jump in cases reported yesterday–almost 15,000 newly confirmed cases in Hubei province, or about 10 times as many as the previous day. There also remains a lot of uncertainty about the distribution of the severity of the infection. That’s in part a reflection of the fact that the distribution of the severeity is very broad, with many infections producing mild symptoms (or none at all) and others requiring prolonged hospitalization, often under intensive care.

NEW NAME 2 pm (Feb 11): The coronavirus formerly known as nCoV2019 has been renamed COVID-19.  Correction: COVID-19 is the new name of the disease, not the virus itself. AND the virus is now named SARS-CoV-2 (for severe acute respiratory syndrome coronavirus 2).

UPDATE 11:10 pm (Feb 10): Several nCoV2019 genomes have been sequenced from Japan and Vietnam, and the data added to the @nextstrain phylogenetic tree. This tree shows the ancestry of the virus, based on the mutations that accumulate in different lineages. The new viral sequences from Japan and Vietnam fall in the large, growing cluster that includes most of the international travel-related cases.

UPDATE 10:35 pm (Feb 10):  Latest update from the CDC on testing for nCoV2019 in “people under investigation” (PUI) in the United States. They are currently reporting only 12 postive tests (same as last report), and now with 318 negative tests. So all 93 tests since the last update have been negative. However, there is a report tonight of another positive test, this one in San Diego for a person on one of the quarantined evacuation flights out of China, This person first tested negative, but was retested and found to have the nCoV2019 infection.

NEW INFO 8:30 am (Feb 10):  Two nCoV2019 viral genomes were isolated by the Chinese CDC from environmental samples at the Huanan Seafood Market in Wuhan, and they have been sequenced. The @nextstrain team analyzed the sequences, and they cluster with other early sequences isolated from infected people. This result strongly bolsters the supposition that this market was the source of the initial outbreak. Despite “seafood” in the market’s name, many other animals were sold there. Trevor Bedford suggests that the high level of viral contamination detected there might have been associated with butchering an infected animal, which seems quite plausible. In any case, the virus has subsequently been spreading from person to person.

MODEL OF GLOBAL SPREAD 8:45 pm (Feb 9): Biophysicist Richard Neher updates his graphical presentation of the increase in nCoV2019 cases in Hubei and elsewhere in China. The good news is that the rate of increase is declining. That’s expected given the extreme quarantine measures taken in Wuhan and other cities. However, it’s also clear that many smaller outbreaks have been seeded elsewhere in China and other countries. Some of these outbreaks will be contained with expertise and diligence, but others will likely escape notice until they become too large to contain. With travel, these outbreaks can seed new outbreaks, and so on, as discussed and illustrated by Trevor Bedford. (See the Expert Perspective posted below at 4:30 pm on Feb 8.) Neher has run simulations to get a handle on this scenario, using his educated guesses for the relevant parameters. In brief, he assumes there are many such outbreaks already underway, but running 2 or 3 months behind the Wuhan outbreak. With increased awareness among the public and health-care workers, many of these outbreaks will grow more slowly than Wuhan did and be contained. And even those that grow large will, like Wuhan, slow down once they become very large due to quarantines and other social distancing.  Nevertheless, Neher finds it’s quite possible to envision total global cases in several months that dwarf those seen in Hubei by 100-fold, even while it looks as though (as it does now) that the rate of increase is declining. I’ve posted a screen shot of this scenario below.

CONCERN NOTED 4:00 pm (Feb 9): Responding to news of several unlinked cases of nCoV2019 in Singapore, infectious-disease epidemiologist Mark Lipsitch notes that they “are expert at contact tracing [but this situation] increases level of concern that similar transmission may be occurring under the radar elsewhere. And deflates the notion that tropics not vulnerable.”

THINKING OUT LOUD 10:30 am (Feb 9): Following my comment on Twitter that draws attention to the large, globally emerging clade in the nCoV2019 sequence data (as I also explained in the Update just below), Dr. Emma Hodcroft commented that “it might be worth exploring a different root for the tree, given this cluster. Certainly notable!” That led me to recall that epidemiological data now indicates that, despite most of the early cases being associated with the Wuhan Seafood Market, there were a few even earlier cases that did not have any connections to that market. Therefore, the earliest sequenced viruses (which include several identical Wuhan islates and offshoots from those) likely derive from the market-associated outbreak. This large, emerging, globally spreading cluster of nCoV2019 sequences may well derive from the incipient outbreak that pre-dated the market-associated outbreak. Updated (see the New Info at 8:30 am Feb 10): With the new finding that environmentally isolated viral genome sequences from the market in Wuhan closely match many of the early cases, it now seems likely that the market was indeed the source of the oubreak. That said, I think the large, globally emerging clade discussed here bears watching and in-depth epidemiological investigation.

UPDATE 9:45 am (Feb 9): The @nextstrain team has just added several more genome sequences from nCoV2019 isolates to their analysis pipeline. There had been a period without new sequence data from China, so the only new data were coming from overseas cases. This update adds several more recent (but still January) sequences from China and Taiwan. What strikes me is the large cluster that emerges down at the bottom of the image (copied below), with cases now in mainland China, Taiwan, Korea, the US, Australia, England, and Belgium. And those in China include 1 sequence from Wuhan (WH04/20202) at base of this clade to two of the sequences just added (from Yunnan and Sichaun).

EXPERT PERSPECTIVE 4:30 pm (Feb 8): A short, and excellent, thread from infectious disease epidemiologist Trevor Bedford explaining why the next several months are so critical for the potential for global spread of nCoV2019. In essence, the Wuhan outbreak seeded new outbreaks in China and elsewhere. We now know that the Wuhan outbreak was not contained until it became huge. (See, for example, my simple estimate from 27 January that there were already on the order of 100,000 infected people in Wuhan). Not all of these infections led to “cases” in the sense of hospitalized patients or even those that saw a doctor. That’s because most infected people have only mild symptoms, but it appears that these mild infections can still contribute to the virus’s spread. (See updates below from Feb 4, regarding such cases in Germany and Hong Kong. There are probably many more such cases.) Importantly, all of the newly seeded outbreaks have to be much better contained to keep things in control. Bedford nicely shows this basic idea in his hand-drawn picture, which I’ve reproduced here.

UPDATE 10:20 pm (Feb 7):  Latest update from the CDC on testing for nCoV2019 in “people under investigation” (PUI) in the United States. Currently reporting 12 postive tests, with 225 negative tests, and 100 cases pending. So ~5% of cumulative tests have proven positive to date, similar to CDC’s recent reports. As noted two days ago, CDC will also now allow states to perform these tests. No states have reported test results to date, to my knowledge. Will states report test results directly, or via these CDC summaries?

CONCERN NOTED 12:45 pm (Feb 7):  Epidemiologist Maia Majumder expresses concern about nCoV2019 cases onboard cruise ships, including one quarantined off Japan, which now has 41 new cases (making a total of 61).  She points out that “cruise ships are notorious for infectious disease activity. A confined space with shared water, sanitation, and hygiene infrastructure; predominant activity in community spaces; and a plethora of buffets … will do that.”

NEW INFO 12:30 pnm (Feb 7): JAMA Network report on “Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan.”   Summary of findings reads as follows:  “In this single-center case series involving 138 patients with NCIP, 26% of patients required admission to the intensive care unit and 4.3% died. Presumed human-to-human hospital-associated transmission of 2019-nCoV was suspected in 41% of patients.”

NEW INFO 11:10 am (Feb 7): Helen Branswell reports that Maria Van Kerkhove, an epidemiologist with the World Health Organization, has analyzed data from 17,000 cases of nCoV2019 infections and found that “82% of cases are mild, 15% are severe and 3% are critical.” (Link to the verbal report here.) Numbers are presumably still based only on the cases that make it into the Chinese medical reporting system–without any serological testing of the population at large. So hopefully the percentages of severe and critical infections (versus cases) will turn out to be much lower. On the other hand, more undiagnosed cases mean more opportunities for long transmission chains in the community. The quarantines in hard-hit Chinese cities, and social distancing elsewhere, should reduce the number of such chains. But are they enough to halt the spread?

NEW INFO 11:00 am (Feb 7):  STAT news reporting that US hospitals are preparing for a possible spike in coronavirus cases. “Much of that work revolves around hospitals planning for what [Dr. Paul] Biddinger [medical director of emergency preparedness at Massachusetts General Hospital] called the ‘four S’s’ of a surge in patients amid an outbreak: supplies, staff, space, and the system that governs all of them.”

WAITING FOR MORE INFO BUT … 10:45 to 11:45 am (Feb 7): Reports circulating on Twitter that a  coronavirus isolated from a pangolin is an even closer genomic match to the Wuhan virus nCoV2019 than the closely related isolate from a bat. I await expert analysis and confirmation (or refutation) from Trevor Bedford and others. Pangolins are also called scaly anteaters. They are sometimes used in traditional Chinese medicine and their meat is considered a delicacy by some.  Expert Richard Neher weighs in. He says if the claim is based on the same pangolin-derived virus isolate that was discussed previously, then its genome sequence is certainly more distant to the outbreak isolates than one from a bat. However, infectious disease epidemiologist Tara Smith counters that the previously discussed virus isolate from a pangolin came  from another country, and there should be forthcoming new genome sequences from coronaviral isolates from pangolins recently obtained in China. In other words, this issue of the animal source still appears unsettled. Nature also has a news story about this, but nothing yet published in terms of data.

NEW INFO 11:00 pm (Feb 6):  Using expectations based on travel patterns from Wuhan to other countries, Marc Lipsitch and colleagues from Harvard’s School of Public Health suggest that Indonesia, Thailand, and perhaps Cambodia are “missing” nCoV2019 cases. This pattern means that the virus might be escaping notice, allowing more opportunities for it to gain a foothold in those countries.

EXPERT PERSPECTIVE 8:35 pm (Feb 6): Tom Inglesby is the Director of the Johns Hopkins University Center for Health Security. He has a must-read twitter thread calling on the US and international political, medical, and public-health communities to undertake coordinated action to prepare for a possible pandemic. Some of the points Dr. Inglesby makes (with my emphasis in bold):

• “Continued efforts are being made toward containing and ending the nCoV outbreak before it leads to widespread community transmission in countries around the world. However what we know about this virus /epidemic suggests this goal is likely not attainable”
• “… extent of nCoV in China w/daily rise in numbers; high connectedness of China to rest of world; high r(0) of virus; spread of cases before containment started; cases in other countries that seem only explainable by community transmission – all suggest nCoV not containable.”
• “Domestically — Is there community transmission in US? Given the thousands of passengers arriving daily from China in last 2 months prior to the recent travel restrictions, and given how transmissible nCov is seems possible, if not likely, there is already US transmission.”
• “Need plan of action for ramping up preparedness of US hospitals to care for high numbers of ARDS [acute respiratory distress syndrome] patients. Training & protecting HCWs [health care workers]. Assessment and management of PPE [personal protective equipment] supply. Understand vent supply in private sector and SNS [social netork services]. Screening and triage practices.”

NEW INFO 8:00 pm (Feb 6):  Extremely concerning news that 3 of 5 confirmed nCoV2019 cases in France are in intensive care, including a couple in their early 30s. While it appears that many cases (around the world) are not much worse than a cold, some others become extremely serious, even for healthy young adults. Why? No one knows.

NEW INFO 1:00 pm (Feb 6):  Kaiyuan Sun and colleagues estimate relative risk of nCoV2019 as a function of age. Strikingly lower risk for kids and youngest adults. h/t Richard Neher.

NEWS 11:00 am (Feb 6):  One of the first doctors to recognize the nCoV2019 outbreak, and reprimanded by police in Wuhan for trying to inform the medical community about this new danger, has himself died from the virus.  RIP, Doctor Li Wenliang.

NEWS 3:00 pm (Feb 5): Wisconsin has reported its first confirmed case of nCoV2019. Interestingly, it involves someone who was infected in Beijing, but not Wuhan or the Hubei province.

NEWS 12:30 pm (Feb 5): The US FDA has granted permission to the various state public-health laboratories to test for the new coronavirus, nCoV2019. Previously, only the CDC could perform the tests. State labs will also send samples to the CDC for confirmation tests.

UPDATE 11:05 am (Feb 4): It’s now reported by expert Helen Branswell that the traveler from Wuhan who infected co-workers in Germany was not entirely asymptomatic, contrary to the Lancet paper. [See New Info from 5:00 pm on Jan 29 below for discussion of that paper.] Still, her symptoms were not obvious to others, and with the potential for hidden transmission chains, that seems pretty important. Moreover, that same paper reported that first German who was infected had a very high viral load in his sputum even after he seemed to have recovered, again suggesting the potential for hidden transmissions.

NEWS 10:30 am (Feb 4): Several new cases in Hong Kong do not have recent travel history to mainland China, nor other obvious connections to travelers. According to Chuang Shuk-kwan, head of the Centre for Health Protection’s communicable disease branch: “It is highly probably the four cases were infected locally, so there could be invisible chains of infection happening within communities … We do not rule out a large spread [of the virus] in the future.”

NEWS 10:20 am (Feb 4): There are some reports of travel-related nCoV2019 cases that do not involve travel to or from China. According to this tweet, a Korean may have been infected in Thailand, and a Malaysian in Singapore.

UPDATE 9:45 am (Feb 4): Richard Neher updates his informative graphs showing growth in cumulative numbers of nCoV2019 cases reported in Hubei (province where Wuhan is located) and elsewhere in China, as well as reported death rates and international travel cases. As Neher notes, there’s much we still don’t know well at all, such as the mortality rate. [See the Update from 6:20 pm on Feb 1 below for some of the complicated issues surrounding even a seemingly simple concept like the death rate.] While it is now clear that many cases are mild, there are also many cases that have not caused death (at least yet), but where the patients are critically ill. To my mind, a huge unknown is whether we will see other hotspots of this coronavirus in China (see News just below) and elsewhere, especially in areas with less developed medical systems and public-health infrastructure, in the weeks and months ahead.

NEWS 11:00 pm (Feb 3):  China closes off another large city, Wenzhou, according to The Straits Times. An east coast city with 9 million residents, Wenzhou is some distance from Wuhan. Only one resident per household can leave home every second day to shop for necessities. Schools are closed until March, and most businesses are shut for two weeks.

UPDATE 10:30 pm (Feb 3):  CDC updated its test results for “people under invesigation” (PUI) — that is, possible cases of nCoV2019 infection. The cumulative totals include 11 positives and 167 negatives, for an overall proportion of 6.2% positive tests. That’s up a bit from the previous report at 5%, although I think the new data includes two secondary infections of spouses.  So not much change. The backlog of pending cases is currently 82, down from 121 in the previous report. With the travel restrictions in place, I would guess that the number of new PUI cases would continue to decline … at least for a while. But we now enter a period of great uncertainty, as the outbreak spreads in China and into other countries.  From the NY Times:

• “It’s very, very transmissible, and it almost certainly is going to be a pandemic,” said Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Disease. “But will it be catastrophic? I don’t know.”
• It is “increasingly unlikely that the virus can be contained,” said Dr. Thomas R. Frieden, a former director of the Centers for Disease Control and Prevention who now runs Resolve to Save Lives, a nonprofit devoted to fighting epidemics. “It is therefore likely that it will spread, as flu and other organisms do, but we still don’t know how far, wide or deadly it will be.”

UPDATE 6:20 pm (Feb 1):  Epidemiologist Maia Majumder (@maiamajumder) provides a clear and concise explanation of the different ways of measuring and describing the “deadliness” of infectious diseases. As importantly, she explains why the different estimates change over time. In the case of the population mortality rate, that will tend to increase as an outbreak grows in size, before eventually reversing course once an outbreak has been brought under control. By contrast, the case fatality rate (CFR) reflects the fraction of diagnosed infections that cause death. This latter rate is subject to an early spike because the earliest cases are often the most severe. Also, increased awareness and testing of less severe cases tends to increase over time. Both of these factors mean the CFR typically declines as an outbreak progresses. On the other hand, many serious cases (as reported for nCoV2019 by Chinese health authorities) have not yet resolved. In short, the CFR remains poorly understood at this time. Then, too, there are some people who get an infection, including the nCoV2019 virus, but with no or minimal symptoms, and so they are not diagnosed, These subclinical cases can be discovered later on when populations are surveyed serologically, allowing a further, lower estimate of the fraction of total infections (those discovered later as well as those discovered clinically) that cause death. Dr. Majumder also reminds us that different subpopulations (such as those with chronic diseases) may face different risks.

COMMENT 1:15 pm (Feb 1): There’s plenty of reasons to be worried about this nCoV2019 outbreak, especially if you’re in the most affected areas of China. Hopefully, journalists, scientists, clinicians, and everyone else on social media can communicate and amplify the relevant facts and uncertainties, and avoid sloppy thinking and conspiracy theories.

UPDATE 1:10 pm (Feb 1):  Boom. Trevor Bedford demolishes the claim that the nCoV2019 genome contains bits of HIV sequence, and thereby destroys the conspiracy theory that this corona virus was a bioengineered strain.

UPDATE 12:20 pm (Feb 1): Using his knowledge as an infectious disease specialist combined with common sense, Adam Lauring dismantles the assertion that people might become reinfected with nCoV2019. That’s not to say it’s impossible, but it’s extremely unlikely given such closely related strains (just a few mutations different), and there’s no way of testing that yet. Perhaps something was lost in translation, and the original work only meant to say that nCoV2019 infections increased one’s risk of other secondary infections?

NEW INFO 11:20 am (Feb 1): Simple graphs can reveal a lot. Biophysicist Richard Neher plotted the number of nCoV2019 cases in Hubei and the rest of China over time. Note the log-transformed scale, so a linear trend corresponds to exponential growth. Neher notes some slight decline in the rate of increase, which could mean either that the number of new cases is decelerating (which would be good news) or that the testing capacity is limited and becoming saturated (not good news). Daniel Falush weighed in, suggesting that the number of deaths—alas, not subject to testing limits—would be a better indicator, and he thought that would show signs of slowing. So Neher produced a plot of those data. And yikes: There’s no hint of any slowing, with the number of fatalities doubling about every 3 days. Here’s a screen shot of Neher’s plot:

UPDATE 6:30 pm (Jan 31):  CDC has updated data on the numbers of positive, negative, and pending cases for “patients under investigation.” The proportion of positive tests continues to drop, which is good news:  It’s now 6/120 = 5.0% of the tests of potential nCoV2019 cases in the US that have proven to be positive to date, down from 6.8% a few days ago and 13.5% before that. However, the number of pending (unresolved) cases has continued to increase and now stands at 121.

AN IDEA 11:45 am (Jan 31): For biology teachers at multiple levels (including high school, undergrad, and graduate), this on-going corona virus outbreak could provide valuable information and timely data for teaching core concepts like R0, transmission chains, genomes, phylogenies & more. Students could even analyze and/or interpret new incoming data themselves to draw their own inferences. To see what I mean, check out the superb multi-slide presentation of important concepts, data, and inferences based on the first 42 sequenced genomes of the virus produced and made freely available by the @nextstrain team.

NEW ANALYSIS 10:15 am (Jan 31): The ever-clever Trevor Bedford (say that 10 times fast!) has a twitter thread explaining his new analysis for estimating the probability distribution of the number of new mutations in the viral genome per transmission from one person to another. It relies on knowing the time course of infections and transmissions, as well as the mutation rate, but these parameters are reasonably bounded and becoming better estimated over time. One can also do the inverse analysis to estimate the number of intermediate infections in a transmission chain, which could be useful for epidemiological tracking and investigation.

NEW INFO 10:00 am (Jan 31): New clinical and epidemiologically relevant information on secondary infections in Germany reported in New England Journal of Medicine. h/t @HelenBranswell, who highlights that Patient 1 had “recovered” enough to go to work, but when tested had “a high viral load of 10^8 [100,000,000] copies per milliliter in his sputum.” If this situation is common, it would seem to present a new set of serious challenges.

UPDATE 7:00 pm (Jan 30):The number of international-travel cases continues to increase exponentially, as shown in graph produced by Trevor Bedford. Note the logarithmic y-axis, so a straight line corresponds to exponential growth. With more travel restrictions in place, we would expect that to slow down, even if the epidemic within Wuhan, or China more broadly, continues. So Trevor says he will try to track these data as a function of airplane passengers.

NEW INFO 1:20 pm (Jan 30): First case of transmission within US reported by CDC. Involves a husband and wife, so no evidence of any community-wide spread here in the US to date.

UPDATE 1:00 pm (Jan 30): The @nextstrain team has updated their excellent multi-slide presentation of important inferences based on the first 42 sequenced genomes of the virus. These data continue to point to a single recent origin of the outbreak, with rapid expansion from there. As I noted yesterday, there appear to be clusters of travelers that share one or two mutations, presumably derived from the same intermediate source in the chains of transmissions. These cases, if investigated epidemiologically, might provide valuable clues about the transmission dynamics.

NEW INFO 5:00 pm (Jan 29): I’ve mentioned that we know little about the distribution of outcomes with respect to disease severity. The Lancet (a leading medical journal) has just published a paper analyzing 99 of the early cases in Wuhan, China, that were confiirmed as involving the new nCoV2019 corona virus. These cases involved hospitalization, during a period of considerable stress on the health-care system.  Half of these cases involved patients with other underlying chronic diseases. Nonetheless, about 75% of the patients now have a good prognosis, and about a third have been discharged from the hospital. However, many of the others developed “acute respitory distress syndrome” and 11 of the 99 died. Again, these are atypically severe cases. It’s also very interesting that almost half of all the cases involved individuals who worked at the Wuhan seafood market.  However, the earliest cases appear to not involve that market, which makes this association rather curious.  Also, we still don’t know much about the infections that are less severe for individuals, but which are nonetheless very important for understanding the viral transmission dynamics.

NEW INFO 6:10 pm (Jan 29): From Richard Neher via twitter, a report that 4 Germans who tested postitive after contact with a work-place visitor from Wuhan are apparently asymptomatic. It’s unclear from the short tweet whether the Germans never exhbited any symptoms at all, or only very mild ones, but they are now recovered. This finding supports the conclusion that there are many mild infections (good news), but it also implies that the number of infected people–some of whom might transmit the virus–is quite large (bad news), in line with some of the calculations of the number infected.

NEW INFO 5:20 pm (Jan 29): More nCoV2019 viral genomes have been sequenced from around the world and placed in their phylogenetic context by the @nextstrain team.  I’ve copied a screenshot below that shows the latest version, plotted in terms of mutational distance from the earliest Wuhan samples. It’s very interesting that there are clusters of some of the international-travel cases including (about 2/3 of the way down) the French (2 identical isolates), one from the USA, and a Taiwan case. They all share one mutation that none of the other isolates have. That might not seem like much, but with so few mutations in total (over the whole tree), it strongly suggests that these cases all have some secondary (or later) source in common along the viral transmission chain.  And just above that cluster is another cluster of isolates that all share 2 mutations with an interesting mix of international and non-Wuhan Chinese samples. So there might be some useful epidemiological clues in there, if this information can be coupled with careful studies of patient travel and contacts. 

NEW INFO 12:45 pm (Jan 29): Physicist Dirk Brockmann presents an analysis that uses actual worldwide travel data to estimate the relative probabilities (“import risks”) that travelers from Wuhan enter other countries via specific airports. The results align quite well with where new international cases have been turning up.  [h/t to Richard Neher @richardneher via twitter]

NEW INFO 12:15 pm (Jan 29):  I had read some discussions on the web that the nCoV2019 outbreak might be caused by a “recombinant” virus. This, in turn, led to some conspiracy-type speculation about a virus that escaped from a lab. Recombinants can occur naturally, as well as be made in the lab. So I wondered whether there was good evidence for recombination in these viruses and, if so, whether the recombination pre-dated or post-dated the split between the most closely related bat strain and the Wuhan strain nCoV2019. I turned, once again, to expert Trevor Bedford (@trvrb), since this is a phylogenetically based question. He pointed me to in-depth analyses and discussion of these issues among experts.  First, some genetic recombination has occasionally occurred in these viruses in nature. Second, he sees no evidence of “recombination in the ~50 years since the ancestor of nCoV outbreak viruses split from RaTG13” (i.e., the most closely related corona virus in the data base, which derives from a bat in the year 2013).

NEW INFO 11:00 am (Jan 29):  A bit of good news from CDC. Now 5/73 = 6.8% tests of potential nCoV2019 cases in US have been positive to date. It had been 5/37 = 13.5% at last update. That means no new confirmed positive cases in US. As expected given the spreading infection and expanding concern, the number of pending (unresolved) cases has increased.

NEW INFO 2:00 pm (Jan 27):  On Twitter @afferent_input found monthly data on visitors to US from China. Seasonal data suggest number of travelers in this period might be ~2X higher than my crude estimate, which would reduce the inferred infection proportion and numbers relative to my initial estimates. This factor and the other new info posted [just below] might roughly cancel. Again, all of this information is rough and crudely extrapolated. And none of it bears on critical issues of distribution of severity of infections, etc. 

NEW INFO 1:20 pm (Jan 27):   Here’s another interesting (and concerning) bit of data from the CDC. So far, 37 cases have been investigated.  Of these, 5 have been positive, and 32 negative. However, there are 73 more cases with pending test results in just this first week of CDC data. If the % positive holds in these pending cases, that would triple my estimate of proportion & number infected.  That is, the product (5/37) x 73 suggests that an additional 10 or so infected individuals will be identified as having entered the US in this first week. Again, this is a crude estimate with assumptions, and these potential cases are also presumably in isolation, etc.

Links to my first two posts

Jan 29:  Developing News on the Wuhan Corona Virus, nCoV2019

Jan 27:  Quick-and-Dirty Estimate of Number of nCoV2019 Infections in Wuhan

 

Developing News on the Wuhan Corona Virus, nCoV2019

This post links to some important new findings about the corona virus, nCoV2019, from Wuhan, China.  I’m neither an epidemiologist nor a public-health expert, but I study microbial population dynamics and evolution from a basic-science perspective. So I have a pretty good sense of what the experts are saying, what is reliable within the stated limits of uncertainty and assumptions, and so on. However, keep in mind that this is a very rapidly developing situation, so the “facts” (data and interpretations) may change quickly.

Genomic analysis points to a single recent origin of this outbreak [from Trevor Bedford (@trvrb) and @nextstrain]

Excellent multi-slide presentation of important inferences based on the first 27 sequenced genomes of the virus. These data clearly point to a single recent origin of the outbreak, with rapid expansion from there.

Genomic analysis also points to bats as likely source of infection [also from Trevor Bedford (@trvrb) and @nextstrain]  

Phylogenetic analysis of genomes of the Wuhan outbreak virus and other corona viruses indicates close relationship with isolates from bats.

The closest bat isolate and the current outbreak strain probably diverged several decades ago, given genomic differences and rates of sequence evolution in related viruses. That might seem a long time ago for such a recent outbreak, but it’s not as though this individual bat gave rise to the infection that started the outbreak. (That individual bat has probably been dead for some time.) It’s cousin, so to say, or maybe even a different species of bat, was probably the source.

In any case, the very few genetic differences among the human isolates imply a single, recent origin of the current outbreak. Various estimates point to the initial infection in Wuhan having likely occurred sometime in November or thereabout.

Detailed report estimating epidemiological parameters [from Jonathan Read (@JonRead15) and colleagues]

A detailed report of epidemiological parameter estimates taking into account many factors.

Just how many people are infected in Wuhan?

Nobody knows for sure, but it’s certainly well above the number of confirmed cases.  Several estimates from different groups suggest tens of thousands, and perhaps even hundreds of thousands.

Article quoting Neil Ferguson, an expert at Imperial College: “My best guess now is perhaps 100,000 cases right now” [as of Sunday, Jan 26]. “Almost certainly many tens of thousands of people are infected.”

Above referenced report from Read and colleagues, page 4: “We estimate that on 22 January, in Wuhan there were currently 14,464 infected individuals (prediction interval 6,510-25,095), and a total 21,022 infections (prediction interval 11,090-33,490) since the start of the year.” [The difference in these estimates would reflect individuals who recovered or died.]

My own quick-and-dirty estimate of ~100,000, which shows one very rough way of making an approximation quickly and easily from public data. I emphasize that the other groups are doing far more thorough, competent, and expert analyses than my own. My approach is meant to illustrate one way of making a complicated problem more tractable.

How fast is the virus now spreading outside China? 

Again from Trevor Bedford: The number of international travel cases is still increasing exponentially. (Note the logarithmic scale on the y-axis, such that a straight line indicates exponential growth. The image below is from Bedford’s linked tweet.)

That’s unfortunate, but not too surprising at this stage, because there’s a delay between becoming infected, traveling, and entering another country.  The extent and seriousness of the situation has only been recognized in the last couple of weeks.  With the quarantine and isolation procedures in Wuhan and elsewhere, and with new travel restrictions and monitoring, we can expect this rate of increase to decline and, hopefully, reverse. However, when and by how much things improve will depend on unknowns including whether any additional hotspots take hold, whether some people can transmit the virus while they are asymptomatic (see below), etc.

R0 and what it means

R0 is an important quantity when trying to control an infectious disease.  In words, it refers to the average number of secondary infections that result from each new infection.  So if R0 for some disease is 2, it means that each infected person infects 2 other people before the first one is no longer infectious (say, because they’ve recovered). Any number greater than 1 implies a sort of chain reaction, unless control measures are taken.  (If the number is less than 1, then a disease will likely die out on its own—this can happen, for example, if the disease comes from another species but is rarely transmissible between humans.) The goal of public-health strategies—including vaccination (when available) and isolation/quarantine procedures—is to reduce the likelihood of secondary infections. So if R0 = 2 without public-health measures, the spread of the disease through a population can be halted by preventing ~50% of the transmissions that would otherwise occur without that measure.  If R0 = 4, then stopping the disease’s spread would require blocking 75% of the potential transmissions.  For the new corona virus, the latest estimates suggest a value of R0 of ~2.5 (with a plausible range from 2.0 to 3.1 in one recent estimation based on data through Jan-26).

Science writer Ed Yong has a very nice article about R0 and what it means and doesn’t mean.

Some Important Unknowns

There remain some extremely important unknowns.  One unknown concerns the distribution of the severity for those infected.  The reported numbers are extremely scary, with the number of reported deaths in Wuhan exceeding the number of recovered from this infection. (See 5:00 pm Jan 29 update below. Though still scary, the recoveries now exceed deaths, as was expected as more data came in.) However, those statistics deal with cases that are diagnosed in hospital settings, and so they are heavily biased toward the most severe cases. It also appears that individuals with other health issues are more susceptible, or at least are more prone to severe infections. But much remains unknown about the overall distribution of severity of infections at this stage, and how it depends on age and other factors.

A second important unknown concerns the timing of transmission. There are some reports that some individuals might be infectious before they show symptoms such as fever and the like.  If this proves to be true, and especially if it proves to be fairly common, then it makes it more difficult to control the spread of a disease because an infected person may have infected other individuals before being isolated and carefully monitored. Some experts are skeptical about these reports of contagiousness before symptoms appear—let’s hope they’re right, as that would help with timely interventions to break transmission chains.

I welcome any comments, corrections, additions from reliable sources, and updates.

NEW INFO 11:00 am (Jan 29):  A bit of good news from CDC. Now 5/73 = 6.8% tests of potential nCoV2019 cases in US have been positive to date. It had been 5/37 = 13.5% at last update. That means no new confirmed positive cases in US. As expected given the spreading infection and expanding concern, the number of pending (unresolved) cases has increased.

NEW INFO 12:15 pm (Jan 29):  I had read some discussions on the web that the nCoV2019 outbreak might be caused by a “recombinant” virus. This, in turn, led to some conspiracy-type speculation about a virus that escaped from a lab. Recombinants can occur naturally, as well as be made in the lab. So I wondered whether there was good evidence for recombination in these viruses and, if so, whether the recombination pre-dated or post-dated the split between the most closely related bat strain and the Wuhan strain nCoV2019. I turned, once again, to expert Trevor Bedford (@trvrb), since this is a phylogenetically based question (see first two entries in this post). He pointed me to in-depth analyses and discussion of these issues by experts.  First, some genetic recombination has occasionally occurred in these viruses in nature. Second, he sees no evidence of “recombination in the ~50 years since the ancestor of nCoV outbreak viruses split from RaTG13” (i.e., the most closely related corona virus in the data base, which derives from a bat in the year 2013).

NEW INFO 12:45 pm (Jan 29): Physicist Dirk Brockmann presents an analysis that uses actual worldwide travel data to estimate the relative probabilities (“import risks”) that travelers from Wuhan enter other countries via specific airports. The results align quite well with where new international cases have been turning up.  [h/t to Richard Neher @richardneher via twitter]

NEW INFO 5:00 pm (Jan 29): I’ve mentioned that we know little about distribution of outcomes with respect to disease severity and outcomes. The Lancet (a leading medical journal) has just published a paper analyzing 99 of the early cases in Wuhan, China, that were confiirmed as involving the new nCoV2019 corona virus. These cases involved hospitalization, during a period of considerable stress on the health-care system.  Half of these cases involved patients with other underlying chronic diseases. Nonetheless, about 75% of the patients now have a good prognosis, and about a third have been discharged from the hospital. However, many of the others developed “acute respitory distress syndrome” and 11 of the 99 died. Again, these are atypically severe cases. It’s also very interesting that almost half of all the cases involved individuals who worked at the Wuhan seafood market.  However, the earliest cases appear to not involve that market, which makes this association rather curious.  Also, we still don’t know much about the infections that are less severe for individuals, but which are nonetheless very important for understanding the viral transmission dynamics.

NEW INFO 5:20 pm (Jan 29): More nCoV2019 viral genomes have been sequenced from around the world and placed in their phylogenetic context by the @nextstrain team.  I’ve copied a screenshot below that shows the latest version, plotted in terms of mutational distance from the earliest Wuhan samples. It’s very interesting that there are clusters of some of the international-travel cases including (about 2/3 of the way down) the French (2 identical isolates), one from the USA, and a Taiwan case. They all share one mutation that none of the other isolates have. That might not seem like much, but with so few mutations in total (over the whole tree), it strongly suggests that these cases all have some secondary (or later) source in common along the viral transmission chain.  And just above that cluster is another cluster of isolates that all share 2 mutations with an interesting mix of international and non-Wuhan Chinese samples. So there might be some useful epidemiological clues in there, if this information can be coupled with careful studies of patient travel and contacts.

NEW INFO 6:10 pm (Jan 29): From Richard Neher via twitter, a report that 4 Germans who tested postitive after contact with a work-place visitor from Wuhan are apparently asymptomatic. It’s unclear from the short tweet whether the Germans never exhbited any symptoms at all, or only very mild ones, but they are now recovered. This finding supports the conclusion that there are many mild infections (good news), but it also implies that the number of infected people–some of whom might transmit the virus–is quite large (bad news), in line with some of the calculations of the number infected.