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Time Scales, Viral and Human

I can tell that the current events are getting a bit overwhelming by the difficulty of writing about other topics here! I’m not specifically on a coronavirus topic today, but rather on what some of the news coverage is saying about our expectations for medical research.

One of the things people have noted about my two recent posts on potential therapies is that I have not been too optimistic about something helping us out in the near term. I don’t want that to be interpreted as “We’re All Doomed”, because we aren’t. This epidemic will pass, as they all do, but the question is of course how much damage it will cause as it peaks. And unfortunately, I don’t see much of that damage being mitigated by what I do for a living, which is early-stage drug research. That’s frustrating; in fact, I think it’s a contributing factor to my mood in general. Here I am, a person who’s made a career out of trying to develop new therapies for sick patients, and what do I have to offer?

I’ve seen a number of things in the last week or two from other folks in the drug discovery world, looking at possible new targets, new screens of chemical matter, and so on. There are several ways to look at this sort of thing. One is that efforts to find new drugs for such conditions have to start somewhere, and the things I’ve seen have been perfectly reasonable approaches to doing that. The counterpoint, though, is that a screen against a new target today might, if everything works really well, lead to a new drug in about the year 2029 (and a lot of things will have to go right for even that to happen). If you look at past respiratory viral outbreaks, a recurring feature is that drug discovery starts up, makes a bit of progress, and then the disease goes away and things go back on the shelf (H1N1, SARS, MERS, and more). Now, there’s a counterargument to that as well, and I don’t want to minimize it: the SARS work (for example) definitely informs the efforts on the current outbreak, because they’re rather similar viruses.

But if I were going to pile a lot of funding into this field right now, I would concentrate on the possibilities of repurposing existing drugs (and of getting manufacturing and distribution ramped up should something work), and on vaccine development should we have to deal with this virus again. As mentioned yesterday, we’re not going to have a vaccine in time to deal with the wave that’s hitting us now, but we can be ready if it comes back around. This seems to be just what the recently announced COVID-19 Therapeutics Accelerator effort is aiming at, and it’s good to see.

While driving this morning, I heard an NPR segment with someone warning that vaccine development was going to take longer than people thought, that the talk of taking one into trials meant that just the very first smallest steps were underway, that a year to 18 months was about the quickest imaginable timeline and that was if things went perfectly. It turned out to be Anthony Fauci being interviewed, and good for him. These don’t seem to be politically popular things to say in some parts of the administration, but we need the truth here. I worry that there’s a good-sized segment of the population that is still not realizing how bad things could get, and another good-sized one that expects biomedical research to come to the rescue shortly with a drug or vaccine that will stop things in their tracks.

Well, I am very eager to see the remdesivir trial results (we should get the first ones shortly), because I still think that’s the best shot for a repurposed drug that could have a real effect. After that, though. . .no, I don’t think there’s a lot that’s going to help out. And even remdesivir, should it have some efficacy, will be a major challenge to deploy in time. I would like to be wrong about this, believe me.

I think a lot of people have been watching a lot of TV shows that require the plot lines to be wrapped up quickly and neatly – that’s always been a particular problem with anything involving R&D, because “quickly” and “neatly” are often not very good descriptors of what we do. I shouldn’t blame TV, of course – you can go back to earlier in the 20th century and see plenty of examples from pulp science fiction and adventure stories of that peculiarly American form, the “Edisoniade”, where a competent, wisecracking team of inventors crank out one amazing new plot-resolving device after another. From the Frank Reade and Tom Swift stories through E. E. Smith, John W. Campbell, and George O. Smith (just to name a few) there’s always been a market for that genre, and the police and medical procedural shows are just another manifestation.

The good part is, we really do crank out a lot of amazing things. The bad part is that we can’t always pull that off on the tight schedules that people imagine, and this is probably going to be one of those times. It’s the low-tech stuff that’s important right now: soap and water, staying out of big crowds, etc. Keeps a person humble, it does.

56 comments on “Time Scales, Viral and Human”

  1. G. says:

    “and what do I have to offer?” a really competent and humble approach, sometimes we do not need more than that ! Great job again!

  2. Justin Gallivan says:

    The more I think about this, the more I think that Anthony Fauci (age 79!) should be speaking absolute truth to power. He’s been strong, but there’s no need to mince words. He might do some real good.

    What’s he aiming/waiting for?

    1. Will cody says:

      To Justin Gallagher, Fauci is not waiting for anything. He has been speaking frequently, as evidenced by this NPR interview. He has said that no one is holding him back from expressing his views.

      Fauci is a national treasure. For decades he has presented complex biology in clear, measured, and understandable language that most can follow. He continues to provide that service.

    2. Derek Freyberg says:

      And to echo what Will cody said, Fauci was on “60 Minutes” on Sunday and made it clear that he would say what he thought, not what someone wanted him to say.

  3. KwadGuy says:

    Derek:

    Your columns about COVID-19–and particularly this one–are islands of informed sanity in a world gone mad with hopes of unicorns.

    The key take-home being: Even in the unlikely event we get lucky with something that can pulled off the dead dogs shelf and rushed into clinic, there is not likely going to be a “cure” in time to deal with this.

    We can learn lessons, put protocols in place for the next time, etc. But as sophisticated as we think we’ve become, nature is a wily beast.

    1. MCS says:

      If onbly we could have learned lessons an put protocols in place after the last half dozen times that turned out not to be the big one that time.

      Surveillance failed because of willful concealment by the Chinese government. It’s not like the same thing isn’t likely a lot of other places.

      A test that could be quickly deployed to track community spread and to protect the most vulnerable like the nursing home patients. (Why weren’t they on guard for flu?) Instead the CDC test takes a specific instrument, each of which can process less than 200 samples in 24 hours.
      https://www.fda.gov/media/134922/download

      Who was president during SARS and MERS and 2009? It wasn’t Trump.

  4. Eleven fingerrrrrrsssss says:

    Some pessimism here on mortality rates. They usually go down a lot more…
    https://themoderatevoice.com/how-big-will-the-coronavirus-epidemic-be-an-epidemiologist-updates-his-concerns/amp/

    Good news is black plague lead to higher wages, economic renewal and the renaissance!

  5. MagickChicken says:

    “. . . that’s always been a particular problem with anything involving R&D, because ‘quickly’ and ‘neatly’ are often not very good descriptors of what we do.”

    Hell, I work in quality control, and “quickly” and “neatly” are often not very good descriptors of getting decades-old drugs out the door.

  6. philip alabi says:

    This may sound naive for a question but what becomes the standard of care or treatment options in the clinic while we wait for the small molecules snd biologics to get approvals? Is is just treatment of symptoms and what are they currently doing to patients?

    1. From the Cleveland Clinic (linked in URL):

      Q: How is COVID-19 treated?

      A: There is currently no FDA approved medication for COVID-19. People infected with this virus should receive supportive care such as rest, fluids and fever control, to help relieve symptoms. For severe cases, treatment should include care to support vital organ functions.

      Me: The latter can include using a respirator for severe cases. And also antibiotics for opportunistic bacterial pneumonia.

  7. Jim Hartley says:

    Excerpt from a post by an ICU doc in the Seattle area:
    Common scenario for our pts is, admit 1L NC. Next 12hrs -> NPPV. Next 12-24hrs -> vent/proned/Flolan. – interestingly, despite some needing Flolan, the hypoxia is not as refractory as with H1N1. Quite different, and quite unique. Odd enough that you’d notice and say hmmm. – thus far many are dying of cardiac arrest rather than inability to ventilate/oxygenate. – given the inevitable rapid progression to ETT once resp decompensation begins, we and other hosps, including Wuhan, are doing early intubation. Facemask is fine, but if needing HFNC or NPPV just tube them. They definitely will need a tube anyway, & no point risking the aerosols. – no MOSF. There’s the mild AST/ALT elevation, maybe a small Cr bump, but no florid failure. except cardiomyopathy. – multiple pts here have had nl EF on formal Echo or POCUS at time of admit (or in a couple of cases EF 40ish, chronically). Also nl Tpn from ED. Then they get the horrible resp failure, sans sepsis or shock. Then they turn the corner, off Flolan, supined, vent weaning, looking good, never any pressor requirement. Then over 12hrs, newly cold, clamped, multiple-pressor shock that looks cardiogenic, EF 10% or less, then either VT->VF-> dead or PEA-> asystole in less than a day. Needless to say this is awful for families who had started to have hope. – We have actually had more asystole than VT, other facilities report more VT/VF, but same time course, a few days or a week after admit, around the time they’re turning the corner. This occurs on med-surg pts too; one today who is elderly and chronically ill but baseline EF preserved, newly hypoTN overnight, EF<10. Already no escalation, has since passed, So presumably there is a viral CM aspect, which presents later in the course of dz. – of note, no WMAs on Echo, RV preserved, Tpns don't bump. Could be unrelated, but I've never seen anything like it before, esp in a pt who had been HD stable without sepsis

    1. ScientistSailor says:

      Can you translate this for the non-MDs here?

      1. Jim Hartley says:

        Not a doc, sorry. nl I think is normal. EF is ejection fraction of the left heart. Tpn I suppose is troponin, sign of heart damage. 1 L NC could be the oxygen supplementation via nasal cannula. Others your guess. But you get the idea these are very sick folks.

      2. SomeSoftwareGuy says:

        I thought this too, here’s my translation from Google:

        NPPV – non-invasive ventilation – facemask, no tubes into trachea
        ETT – tubes after facemask goes away and oxygenation drops (resp decompensation)
        HFNC – tubes, but just up the nose
        MOSF – multiple organ (systems) failure
        AST/ALT – liver & heart/liver hormones – signs of heart/liver stress
        VT/VF – ventricular tachycardia/fibrillation – ie. heart problems/failure
        PEA – pulseless electrical activity (of the heart) – not a proper heartbeat
        WMA – wall motion activity (of the heart)

        Append “medical abbreviation” to the acronym and Bob’s your uncle for Google-fu.

      3. steve says:

        Pretty sure he said, “It’s a bitch”.

      4. matt says:

        I am not a doctor, but I’ll ask google. Let’s see…

        Excerpt from a post by an ICU doc in the Seattle area:

        A common scenario for our patients is, on admission they are put on 1L oxygen by nasal cannula. Next 12hrs, they regress to non-invasive positive pressure ventilation, the blower. Next 12-24hrs, they regress to a ventilator in the prone position with Flolan.

        Interestingly, despite some needing Flolan, the hypoxia is not as refractory as with H1N1. Quite different, and quite unique. Odd enough that you’d notice and say hmmm.

        Thus far many are dying of cardiac arrest rather than inability to ventilate/oxygenate.

        Given the inevitable rapid progression to an endotracheal tube once respiratory decompensation begins, we and other hospitals, including Wuhan, are doing early intubation. Facemask is fine, but if needing a high-flow nasal cannula or non-invasive positive pressure ventilation, just tube them. They definitely will need a tube anyway, & no point risking the aerosols.

        Multiple-organ system failure is NOT typically seen. There’s the mild AST/ALT elevation [AST/ALT is an indicator of liver damage or hepatotoxicity], maybe a small Cr bump [Creatinine, indicator of kidney damage], but no florid failure. except cardiomyopathy.

        Multiple patients here have had normal cardio Ejection Fraction (EF) on formal Echocardiogram or point-of-care ultrasound (POCUS) at time of admit (or in a couple of cases EF 40ish, chronically [EF 40 or below may be evidence of heart failure or cardiomyopathy, 41-49 is borderline]). Also normal cardiac troponin from EmergencyDepartment[? troponin can be used to diagnose a heart attack, so probably measured on the way in].

        Then they get the horrible respiratory failure, without sepsis or shock.
        Then they turn the corner, get off Flolan, they are sitting up, weaning off the ventilator, looking good, never any pressor requirement [I think this means no blood pressure drop that would require medication to increase blood pressure].

        Then over 12hrs, newly cold, clamped, multiple-pressor shock that looks cardiogenic, EF 10% or less, then either VT [ventricular tachycardia, rapid heartbeat] progressing to VF [ventricular fibrillation, heart quivering or beating erratically] progressing to death
        OR, PEA [Pulseless Electrical Activity, got a waveform on ECG–or EKG for you German-loving chemists–but no pulse felt in the body] progressing to asystole [flatline ECG] in less than a day. Needless to say this is awful for families who had started to have hope.

        We have actually had more asystole than VT, other facilities report more VT/VF, but same time course, a few days or a week after admit, around the time they’re turning the corner. This occurs on med-surg patients too; one today who is elderly and chronically ill but baseline EF preserved, newly hypoTN overnight, EF<10. Already no escalation, has since passed, So presumably there is a viral CM aspect, which presents later in the course of days.

        Of note, no WMAs [left ventricular wall motion abnormalities, commonly seen in coronary artery disease, congestive heart failure, stress-induced cardiomyopathy, etc] on Echo, RV [right ventricular function] is preserved, Tpns [troponins] don't bump. Could be unrelated, but I've never seen anything like it before, esp in a pt who had been HD stable without sepsis.

        1. matt says:

          So, bottom line, the emergency room doc sees heart failure that comes out of the blue, after the breathing component seems to be clearing up. He is hypothesizing that COV-SARS-2 may have a direct or indirect effect (could lung compromise introduce viral or bacterial load into the bloodstream to the heart?) on the heart, delayed from the respiratory symptoms.

        2. eub says:

          Thanks, nice translation. Adding some more pieces
          “viral CM” -> “viral cardiomyopathy”, i.e. SARS-CoV-2 harm to the heart by some mechanism [eub: what does ACE2 do anyway biologically?] This seems to be the core point here.
          “EF 10% or less” -> “ejection fraction”, 10% means i.e. left ventricle is active but not pushing blood (only 10% of its contents leave at each beat)
          “HD stable” -> “hemodynamically stable”, i.e. blood pressure and heart rate aren’t thrashing up and down
          “newly cold, clamped, multiple-pressor shock” -> not sure. “multiple-pressor” I think means “shit, we tried lots of things to keep blood pressure from crashing”. “cold” is typical in shock so maybe just signifying shock? “clamped” any input?

        3. ScientistSailor says:

          Thanks!

    2. Heather Shreiner says:

      Can you provide a link to the original post? Would like to read the source. Thx.

      1. Jim Hartley says:

        This was copied from a FB women physicians group.

        We’ve been told not to share info, but we are all doing it anyway.
        Since COVID is now deemed endemic in the XXXX area, and to quote a reliable source, the rest of the country is just “lagging behind,” thought I’d share some relevant details, including from CDC teleconference today for COVID providers.
        – as we all assumed, it has been in community spread locally for weeks. We have seen idiopathic ARDS cases since early/mid-Feb. Retrospective testing is being done where possible. – the numbers presented in media do not reflect actual cases, obvs. Testing here only started 2/28. Our first CONFIRMED death was 2/23.
        =XXX State Lab can only run 26kits/day, though they are ramping up quickly. Despite strict criteria for testing, there is a 3d backlog at this time.
        – Negative Resp Path PCR is required before SARS2 test will be accepted. We have been running out of RP PCRs. This is unheard of, especially as most admitted resp pts get one during flu/cold season (mostly for approp iso, since RSV is contact). Goddess bless the local Children’s hospital for sending us 60 the other night. Your hospital should begin stocking up on RP PCRs now. Our Public Health dept does not expect SARS2 tests to be ample enough to d/c the neg RP PCR requirement.
        – on a related note, county lab no longer runs tests from pts not sick enough to be admitted, since dz is now endemic. Expect this will be the case elsewhere soon.
        – as of today, we have 21 pts and 11 deaths since 2/28. Not including the postmortem retrospective dx of pts who died with idiopathic ARDS the prior week. Of note, Harborview had an idiopath ARDS death 2/26. There will be more retrospective dx. – our mortality rate is skewed up (and in some cases, down) because many of our pts come from the LCCK SNF (Lifecare Care Center of Kirkland) & are elderly and severely chronically medically ill – the sort of pts who die of rhinovirus. Many of these patients’ families are opting for comfort care, as many are DNI. We have 3 such on the floor on comfort care now. Of note, those 3 pts have what would be considered mild infxn in a different cohort.
        – we are seeing pts who are young (20s), fit, no comorbidities, critically ill. It does happen. – media (including NYT) are mentioning “efforts to contain the outbreak” at the SNF.
        I’m sure you are all aware, but the US has been past containment since January, and the SNF cases aren’t an “outbreak” they’re a cluster. – thus far many pts have contacts there (esp visiting family members), but also at a local HD center and a car dealership. Others have zero identifiable contacts at all, tho I suspect many have Costco-horde connections, heh. – fortunately Evergreen has capability to turn all or half of any ward into a neg pressure zone
        Currently, all of ICU is for critically ill COVIDs, all of XXX floor medsurg for stable COVIDs and EOL care, half of PCU, half of ER. New resp-sx pts Pulmonary Clinic offshoot is open.
        – in XXXX, CDC is no longer imposing home quarantine on providers who were wearing only droplet iso PPE when intubating, suctioning, bronching, and in one case doing bloody neurosurgery on these pts in the week prior to testing starting. Because that resulted in our Stroke Center hospital no longer being able to admit LVOs or any kind of bleed. And decimated 10% of our Hospitalists, 3 of the 6 Night docs, and a PCCM. Plus it’s now endemic. Expect when it comes to your place you may initially have staff home-quarantined. Plan for this NOW. Consider wearing airborne iso PPE for aerosol-generating procedures in ANY pt in whom you suspect COVID, just to prevent the mass quarantines.
        – we ran out of N95s (thanks, Costco hoarders) and are bleaching and re-using PAPRs, which is not the manufacturer’s recommendation. Not surprised on N95s as we use mostly CAPRs anyway, but still. Supplies are en route, but your facility may wish to stock up now, esp if you expect each staff member and room to have its own PAPR/CAPR.
        – terminal cleans (inc UV light) for ER COVID rooms are taking forever, Enviro Services is overwhelmed. Bad as pts are stuck coughing in the waiting room. Rec planning now for Enviro upstaffing, or having a plan for sick pts to wait in their cars (that is not legal here, sadly).
        – CLINICAL INFO based on our cases and info from CDC conf call today with other COVID providers in US:
        – the Chinese data on 80% mildly ill, 14% hospital-ill, 6-8% critically ill are generally on the mark. Data very skewed by late and very limited testing, and the number of our elderly pts going to comfort care. – being young & healthy (zero medical problems) does not rule out becoming vented or dead – probably the time course to developing significant lower resp sx is about a week or longer (which also fits with timing of sick cases we started seeing here, after we all assumed it was endemic as of late Jan/early Feb). – based on our hospitalized cases (including the not formally diagnosed ones who are obviously COVID – it is quite clinically unique) about 1/3 have mild lower resp sx, need 1-5L NC. 1/3 are sicker, FM or NRB. 1/3 tubed with ARDS. Thus far, everyone is seeing: – nl WBC. Almost always lymphopenic, occasionally poly-predominant but with nl total WBC. Doesn’t change, even 10days in. – BAL lymphocytic despite blood lymphopenic (try not to bronch these pts; this data is from pre-testing time when we had several idiopathic ARDS cases) – fevers, often high, may be intermittent; persistently febrile, often for >10d. It isn’t the dexmed, it’s the SARS2. – low ProCalc; may be useful to check initially for later trending if later concern for VAP etc. – up AST/ALT, sometimes alk phos. Usually in 70-100 range. No fulminant hepatitis. Notably, in our small sample, higher transaminitis at admit (150-200) correlates with clinical deterioration and progression to ARDS. LFTs typically begin to bump in 2nd week of clinical course. – mild AKI (Cr NPPV. Next 12-24hrs -> vent/proned/Flolan. – interestingly, despite some needing Flolan, the hypoxia is not as refractory as with H1N1. Quite different, and quite unique. Odd enough that you’d notice and say hmmm. – thus far many are dying of cardiac arrest rather than inability to ventilate/oxygenate. – given the inevitable rapid progression to ETT once resp decompensation begins, we and other hosps, including Wuhan, are doing early intubation. Facemask is fine, but if needing HFNC or NPPV just tube them. They definitely will need a tube anyway, & no point risking the aerosols. – no MOSF. There’s the mild AST/ALT elevation, maybe a small Cr bump, but no florid failure. except cardiomyopathy. – multiple pts here have had nl EF on formal Echo or POCUS at time of admit (or in a couple of cases EF 40ish, chronically). Also nl Tpn from ED. Then they get the horrible resp failure, sans sepsis or shock. Then they turn the corner, off Flolan, supined, vent weaning, looking good, never any pressor requirement. Then over 12hrs, newly cold, clamped, multiple-pressor shock that looks cardiogenic, EF 10% or less, then either VT->VF-> dead or PEA-> asystole in less than a day. Needless to say this is awful for families who had started to have hope. – We have actually had more asystole than VT, other facilities report more VT/VF, but same time course, a few days or a week after admit, around the time they’re turning the corner. This occurs on med-surg pts too; one today who is elderly and chronically ill but baseline EF preserved, newly hypoTN overnight, EF5d. It might cause LFT bump, but interestingly seem to bump (200s-ish) for a day or 2 after starting then rapidly back to normal – suggests not a primary toxic hepatitis.
        – unfortunately, the Gilead compassionate use and trial programs require AST/ALT 30, which is fine. CDC is working with Gilead to get LFT reqs changed now that we know this is a mild viral hepatitis.
        -currently the Gilead trial is wrapping up, NIH trial still enrolling, some new trial soon to begin can’t remember where.
        – steroids are up in the air. In China usual clinical practice for all ARDS is high dose methylpred. Thus, ALL of their pts have had high dose methylpred. Some question whether this practice increases mortality.
        – it is likely that it increases seconday VAP/HAP. China has had a high rate of drug resistant GNR HAP/VAP and fungal pna in these pts, with resulting increases mortality. We have seen none, even in the earlier pts who were vented for >10d before being bronched (prior to test availability, again it is not a great idea to bronch these pts now).
        – unclear whether VAP-prevention strategies are also different, but wouldn’t think so?
        – Hong Kong is currently running an uncontrolled trial of HC 100IV Q8.
        – general consensus here (in US among docs who have cared for COVID pts) is that steroids will do more harm than good, unless needed for other indications.
        – many of our pts have COPD on ICS. Current consensus at Evergreen, after some observation & some clinical judgment, is to stop ICS if able, based on known data with other viral pneumonias and increased susceptibility to HAP. Thus far pts are tolerating that, no major issues with ventilating them that can’t be managed with vent changes. We also have quite a few on AE-COPD/asthma doses of methylpred, so will be interesting to see how they do.
        That’s all I got for now. Will be skipping the next 2 CDC COVID calls as working Nights, but will call in again next week and keep you all posted.
        Plz share info but preferably with no direct attribution as I need to remain employed

      2. Jim Hartley says:

        This is the full text, copied from a FB physicians group:

        We’ve been told not to share info, but we are all doing it anyway.
        Since COVID is now deemed endemic in the XXXX area, and to quote a reliable source, the rest of the country is just “lagging behind,” thought I’d share some relevant details, including from CDC teleconference today for COVID providers.
        – as we all assumed, it has been in community spread locally for weeks. We have seen idiopathic ARDS cases since early/mid-Feb. Retrospective testing is being done where possible. – the numbers presented in media do not reflect actual cases, obvs. Testing here only started 2/28. Our first CONFIRMED death was 2/23.
        =XXX State Lab can only run 26kits/day, though they are ramping up quickly. Despite strict criteria for testing, there is a 3d backlog at this time.
        – Negative Resp Path PCR is required before SARS2 test will be accepted. We have been running out of RP PCRs. This is unheard of, especially as most admitted resp pts get one during flu/cold season (mostly for approp iso, since RSV is contact). Goddess bless the local Children’s hospital for sending us 60 the other night. Your hospital should begin stocking up on RP PCRs now. Our Public Health dept does not expect SARS2 tests to be ample enough to d/c the neg RP PCR requirement.
        – on a related note, county lab no longer runs tests from pts not sick enough to be admitted, since dz is now endemic. Expect this will be the case elsewhere soon.
        – as of today, we have 21 pts and 11 deaths since 2/28. Not including the postmortem retrospective dx of pts who died with idiopathic ARDS the prior week. Of note, Harborview had an idiopath ARDS death 2/26. There will be more retrospective dx. – our mortality rate is skewed up (and in some cases, down) because many of our pts come from the LCCK SNF (Lifecare Care Center of Kirkland) & are elderly and severely chronically medically ill – the sort of pts who die of rhinovirus. Many of these patients’ families are opting for comfort care, as many are DNI. We have 3 such on the floor on comfort care now. Of note, those 3 pts have what would be considered mild infxn in a different cohort.
        – we are seeing pts who are young (20s), fit, no comorbidities, critically ill. It does happen. – media (including NYT) are mentioning “efforts to contain the outbreak” at the SNF.
        I’m sure you are all aware, but the US has been past containment since January, and the SNF cases aren’t an “outbreak” they’re a cluster. – thus far many pts have contacts there (esp visiting family members), but also at a local HD center and a car dealership. Others have zero identifiable contacts at all, tho I suspect many have Costco-horde connections, heh. – fortunately Evergreen has capability to turn all or half of any ward into a neg pressure zone
        Currently, all of ICU is for critically ill COVIDs, all of XXX floor medsurg for stable COVIDs and EOL care, half of PCU, half of ER. New resp-sx pts Pulmonary Clinic offshoot is open.
        – in XXXX, CDC is no longer imposing home quarantine on providers who were wearing only droplet iso PPE when intubating, suctioning, bronching, and in one case doing bloody neurosurgery on these pts in the week prior to testing starting. Because that resulted in our Stroke Center hospital no longer being able to admit LVOs or any kind of bleed. And decimated 10% of our Hospitalists, 3 of the 6 Night docs, and a PCCM. Plus it’s now endemic. Expect when it comes to your place you may initially have staff home-quarantined. Plan for this NOW. Consider wearing airborne iso PPE for aerosol-generating procedures in ANY pt in whom you suspect COVID, just to prevent the mass quarantines.
        – we ran out of N95s (thanks, Costco hoarders) and are bleaching and re-using PAPRs, which is not the manufacturer’s recommendation. Not surprised on N95s as we use mostly CAPRs anyway, but still. Supplies are en route, but your facility may wish to stock up now, esp if you expect each staff member and room to have its own PAPR/CAPR.
        – terminal cleans (inc UV light) for ER COVID rooms are taking forever, Enviro Services is overwhelmed. Bad as pts are stuck coughing in the waiting room. Rec planning now for Enviro upstaffing, or having a plan for sick pts to wait in their cars (that is not legal here, sadly).
        – CLINICAL INFO based on our cases and info from CDC conf call today with other COVID providers in US:
        – the Chinese data on 80% mildly ill, 14% hospital-ill, 6-8% critically ill are generally on the mark. Data very skewed by late and very limited testing, and the number of our elderly pts going to comfort care. – being young & healthy (zero medical problems) does not rule out becoming vented or dead – probably the time course to developing significant lower resp sx is about a week or longer (which also fits with timing of sick cases we started seeing here, after we all assumed it was endemic as of late Jan/early Feb). – based on our hospitalized cases (including the not formally diagnosed ones who are obviously COVID – it is quite clinically unique) about 1/3 have mild lower resp sx, need 1-5L NC. 1/3 are sicker, FM or NRB. 1/3 tubed with ARDS. Thus far, everyone is seeing: – nl WBC. Almost always lymphopenic, occasionally poly-predominant but with nl total WBC. Doesn’t change, even 10days in. – BAL lymphocytic despite blood lymphopenic (try not to bronch these pts; this data is from pre-testing time when we had several idiopathic ARDS cases) – fevers, often high, may be intermittent; persistently febrile, often for >10d. It isn’t the dexmed, it’s the SARS2. – low ProCalc; may be useful to check initially for later trending if later concern for VAP etc. – up AST/ALT, sometimes alk phos. Usually in 70-100 range. No fulminant hepatitis. Notably, in our small sample, higher transaminitis at admit (150-200) correlates with clinical deterioration and progression to ARDS. LFTs typically begin to bump in 2nd week of clinical course. – mild AKI (Cr NPPV. Next 12-24hrs -> vent/proned/Flolan. – interestingly, despite some needing Flolan, the hypoxia is not as refractory as with H1N1. Quite different, and quite unique. Odd enough that you’d notice and say hmmm. – thus far many are dying of cardiac arrest rather than inability to ventilate/oxygenate. – given the inevitable rapid progression to ETT once resp decompensation begins, we and other hosps, including Wuhan, are doing early intubation. Facemask is fine, but if needing HFNC or NPPV just tube them. They definitely will need a tube anyway, & no point risking the aerosols. – no MOSF. There’s the mild AST/ALT elevation, maybe a small Cr bump, but no florid failure. except cardiomyopathy. – multiple pts here have had nl EF on formal Echo or POCUS at time of admit (or in a couple of cases EF 40ish, chronically). Also nl Tpn from ED. Then they get the horrible resp failure, sans sepsis or shock. Then they turn the corner, off Flolan, supined, vent weaning, looking good, never any pressor requirement. Then over 12hrs, newly cold, clamped, multiple-pressor shock that looks cardiogenic, EF 10% or less, then either VT->VF-> dead or PEA-> asystole in less than a day. Needless to say this is awful for families who had started to have hope. – We have actually had more asystole than VT, other facilities report more VT/VF, but same time course, a few days or a week after admit, around the time they’re turning the corner. This occurs on med-surg pts too; one today who is elderly and chronically ill but baseline EF preserved, newly hypoTN overnight, EF5d. It might cause LFT bump, but interestingly seem to bump (200s-ish) for a day or 2 after starting then rapidly back to normal – suggests not a primary toxic hepatitis.
        – unfortunately, the Gilead compassionate use and trial programs require AST/ALT 30, which is fine. CDC is working with Gilead to get LFT reqs changed now that we know this is a mild viral hepatitis.
        -currently the Gilead trial is wrapping up, NIH trial still enrolling, some new trial soon to begin can’t remember where.
        – steroids are up in the air. In China usual clinical practice for all ARDS is high dose methylpred. Thus, ALL of their pts have had high dose methylpred. Some question whether this practice increases mortality.
        – it is likely that it increases seconday VAP/HAP. China has had a high rate of drug resistant GNR HAP/VAP and fungal pna in these pts, with resulting increases mortality. We have seen none, even in the earlier pts who were vented for >10d before being bronched (prior to test availability, again it is not a great idea to bronch these pts now).
        – unclear whether VAP-prevention strategies are also different, but wouldn’t think so?
        – Hong Kong is currently running an uncontrolled trial of HC 100IV Q8.
        – general consensus here (in US among docs who have cared for COVID pts) is that steroids will do more harm than good, unless needed for other indications.
        – many of our pts have COPD on ICS. Current consensus at Evergreen, after some observation & some clinical judgment, is to stop ICS if able, based on known data with other viral pneumonias and increased susceptibility to HAP. Thus far pts are tolerating that, no major issues with ventilating them that can’t be managed with vent changes. We also have quite a few on AE-COPD/asthma doses of methylpred, so will be interesting to see how they do.
        That’s all I got for now. Will be skipping the next 2 CDC COVID calls as working Nights, but will call in again next week and keep you all posted.
        Plz share info but preferably with no direct attribution as I need to remain employed

        1. Jim Hartley says:

          Sorry for the repetition.

  8. Giannis Zaxarioudakis says:

    Excellent work Derek.

    I would like to add that antivirals should not be the only focus. The inflammation of the lung tissue is of equal or higher importance. Unfortunately we have only anecdotal data but anti IL-6 biologics and JAK inhibitors seem to work. Also an inhaled corticosteroid (ciclesonide) seems to help in some cases.

    Also is there any person reading this with experience in pharmaceutical production? Is remedesivir a molecule that could easily be produced in China or India or does it require advanced techniques not broadly available?

  9. Anonymous says:

    Does anyone know how long SARS-CoV-2 remains infectious or contagious on surfaces in the environment(s)? I know that some viruses very rapidly “die” (viruses, on their own, aren’t living, but you know what I mean by that in this context) when exposed to “our” world and no longer being kept cozy at 37 C in cells or body fluids.

    But I don’t mean just the lab experiment of pipetting some virus solution onto a microscope slide or Petri dish.

    That is, if someone with COVID-19 sneezes on a window or elevator button, or touches their infected nose and then picks up and puts down an apple or a coffee cup or damp wash cloth, … how long will those objects remain infectious?

    When people sneeze or wipe their mouth or nose with their hand, are they spreading “free” virus particles that have been shed by dying / exploding host cells? Do any shed infected cells tag along for the ride, extending the period of cellular protection and increasing the time that those sneeze droplets and hand-touched items remain infectious? How long?

    General info (google) suggests 24 hours to 7 days. Is there any specific info re: COVID-19?

    Thank you.

    1. G. says:

      I heard/read that the virus did not survive longer than 30 min on surfaces. Not sure how the experiment was made or where the information comes from but this was an “expert” on TV trying to tell people why they could not get sick by receiving package from Amazon. But if someone has more scientific evidence, I am also curious about it.

        1. cynical1 says:

          Well if it is viable for a median half life of 8.5 hours on cardboard, that would suggest that you actually could get it from an Amazon package…….especially with Prime.

    2. buba says:

      check out this publication for a german team studying their first cases, there are some answers you have

      https://www.medrxiv.org/content/10.1101/2020.03.05.20030502v1

      or this one

      https://www.nejm.org/doi/full/10.1056/NEJMc2001468

      I understand it is not yet clear how long the new SARS virus survives on surfaces. But likely it is similar to the previous version: up to 9 days (!)

    3. eub says:

      https://www.medrxiv.org/content/10.1101/2020.03.09.20033217v1.full.pdf

      HCoV-19 was most stable on plastic and stainless steel and viable virus could be detected up to
      103 72 hours post application (Figure 1B), though by then the virus titer was greatly reduced (polypropylene
      from 103.7 to 100.6 TCID50/mL after 72 hours, stainless steel from 103.7 to 100.6 104 TCID50/mL after 48 hours,
      105 mean across three replicates)

      No viable virus could be measured after 4 hours on copper for HCoV-19 and 8
      109 hours for SARS-CoV-1, or after 24 hours on cardboard for HCoV-19 and 8 hours for SARS-CoV-1
      110 (Figure 1B).

      1. tj says:

        But how long on wood?

  10. gippgig says:

    Not the COVID-19 virus, but the similar coronavirus 229E can remain infectious for at least 5 days on Teflon, PVC, ceramic tiles, glass, silicon rubber, & stainless steel. Copper kills it in minutes.
    Human Coronavirus 229E Remains Infectious on Common Touch Surface Materials
    mBio 6 e01697-15 doi: 10.1128/mBio.01697-15

  11. loupgarous says:

    “I think a lot of people have been watching a lot of TV shows that require the plot lines to be wrapped up quickly and neatly – that’s always been a particular problem with anything involving R&D, because “quickly” and “neatly” are often not very good descriptors of what we do. I shouldn’t blame TV, of course – you can go back to earlier in the 20th century and see plenty of examples from pulp science fiction and adventure stories of that peculiarly American form, the “Edisoniade”, where a competent, wisecracking team of inventors crank out one amazing new plot-resolving device after another. From the Frank Reade and Tom Swift stories through E. E. Smith, John W. Campbell, and George O. Smith (just to name a few) there’s always been a market for that genre, and the police and medical procedural shows are just another manifestation. The good part is, we really do crank out a lot of amazing things. The bad part is that we can’t always pull that off on the tight schedules that people imagine, and this is probably going to be one of those times. It’s the low-tech stuff that’s important right now: soap and water, staying out of big crowds, etc. Keeps a person humble, it does.”

    Good point, Derek. Stargate SG-1 and Star Trek (the original series) were maybe the best TV science-fiction franchise lens through which to see our national biosecurity issues. Plenty of bad guys who weren’t going anywhere soon, regardless of who had what military toys. The viewer of ST:TOS could identify with that, because the Communist bloc was the real-life model for the Klingons and Romulans. The same goes for the Goa’uld and Ori in SG-1.

    The trick is to recruit determination to fight actual threats to our national security. The nuclear arms race won’t ever wind down. The design of fission weapons was never a defensible secret. Even without espionage, thermonuclear weapon design diffused throughout the “great powers” in less than 20 years.

    Nuclear weapons allow otherwise unemployable politicians to brandish existential threats and thereby gain undeserved importance. So we are convinced we must continue making nuclear weapons at considerable cost because other countries won’t stop aiming them at us. We don’t hate Russia or China, but their nuclear arsenals create a threat we must defend against – according to an argument widely accepted in the US.

    The fact of epidemic disease is an existential threat that doesn’t even require a villain in the plot. Humanity goes into places which, prior to the 19th century, only a tiny portion of the human population lived, because we prize minerals and other things only found in those remote places. Only those few humans whose ancestors were selected by Nature to survive infection with diseases borne by animal hosts deep in unexplored forests can deal reasonably well with “emerging diseases” such as Ebola, dengue fever, marburgvirus and (insert long list of diseases from Richard Preston’s The Hot Zone or Judith Miller’s Germs here).

    But even viruses we think we understand well, such as the influenza viruses, pop up and threaten humanity without human intervention (apart from intruding into unexplored biomes). We don’t need a bad guy to understand that the diseases themselves, not particular nations or politicians, threaten our national security. We might be able to keep our nuclear deterrent largely intact – just take the money it would take to destroy a city or military installation on, say, the second tier of nuclear targets, and spend that on expanding our existing national stockpile of medical supplies and pharmaceuticals we now wish we had to treat people sick with COVID-19 or the next dangerous mutant of influenza.

    Stephen King ruined a perfectly good parable about existential threats from dangerous viruses by inserting bad guy after bad guy, God and the Devil into his biological apocalypse novel The Stand. Without all that, he’d have made an ideal teaching tool about our current predicament. Of course, there he is with a well-deserved stellar reputation from The Stand, and here I am without anything like that. Just saying… we have the public’s attention now. It’s time to teach them the need to defend ourselves against very real threats which will always be with us as well as some possibly perceived ones.

    1. Derek Lowe says:

      Funny you should mention that last part – with all of this going on, I was remembering when I read The Stand back 30 years ago, and that I liked it better before all the mystical hoo-hah worked its way into the story. Then you have The Andromeda Strain, probably the first mass-market adult paperback novel I ever read (I must have been around 8 or 9 years old). No mysticism there, although Crichton (as he was wont to do) condenses a lot of sorta-science out of thin air as needed to keep the plot rolling.

      1. metaphysician says:

        My own opinion: The Stand should have been two separate novels. One about the collapse of civilization and people surviving it. One about the new civilizations built in the ashes. It largely feels like that anyway, and this would allow each to have a more proper beginning/middle/end. It also would allow you to tune the occult elements to the wildly separate tone and style of the two halves, in a way the actual book didn’t ( IMO, the actual apocalypse would have been more suited to a Lovecraft, cosmic horror style, instead of the later grand good-vs-evil conflict ).

      2. loupgarous says:

        Derek, you and I both read the “mass-market” version of The Stand first (1979-80). Then, his publisher didn’t want to run that huge narrative in the middle of the novel between “the Kid” and Trashcan Man, and a lot of the other mystical and just plain weird narrative that was in King’s first draft. The publisher would have gambled quite a bit of money printing a 823-page novel that might have wound up on the remainder pile at K-Mart or just pulped. King’s publisher offered to have other writers edit the original manuscript down or let him do it. King decided to trim it down himself and did a decent job.

        By 1990, Stephen King had the reputation and clout to put all of his out-takes back in, (as he says in his foreword to The Stand – the Complete and Uncut Version), to make it more “boss”. The miniseries screenplay improved on both versions of the novel, trimming back the “bossness” back quite a bit. Stephen King and Michael Crichton have that in common – usually screenplay adaptations of their novels are more enjoyable than the novels. The miniseries adaptation of Andromeda Strain was a notable exception to that role. I was looking forward to a rewrite of the novel with much new science in it… but the screenplay of the miniseries went the other direction – implausible science fantasy with no willing suspension of disbelief.

        There are more plausible movies about deadly viral outbreaks. Stephen Soderbergh made a pretty good one, Contagion which is being revisited by critics – but for the wrong reasons, its political overtones. It had some scientific hand-waving in it, but not as much as the Andromeda Strain miniseries. (Soderbergh’s dad was a professor at LSU – microbiology, I think – while I was an pre-med there). Outbreak had a slightly muddled plot and the biology of the twist at the end of the movie ruined it for me (a monkey the size of a house cat makes enough immune serum to save Rene Russo’s character and a few hundred other folks, besides). Not just handwaving, but cartwheeling.

        So, we can’t really depend on Hollywood screenwriters to give us that teaching tool about the threat to our national security that emerging infectious disease poses. That’s not their job, as their producers will remind them.

        Boston’s WGBH, which does a very decent job conveying complex biological concepts (they adapted Tom Mangold’s book Plague War to make a good documentary about biological warfare) might be the only studio capable of and inclined to educate Americans about why we need to defend ourselves from emerging highly infectious diseases in the same way we spend billions to deter nuclear attack. I’ve observed in this blog’s comment space that you and WGBH ought to talk about adapting Things I Won’t Work With to a video documentary.

        But there’s more immediate need to explain to Americans why COVID-19, unpredictably virulent influenza strains, Zika, Ebola, marburgvirus and other emerging pathogens that explode on the world scene very quickly are the BIG threat to the national security of the United States of America. We don’t need a supervillain to inflict this kind of damage on us – unprecedentedly cheap and rapid human movement across the globe is more than enough, as Richard Preston observed in The Hot Zone.

        1. NJBiologist says:

          “Outbreak had a slightly muddled plot and the biology of the twist at the end of the movie ruined it for me (a monkey the size of a house cat makes enough immune serum to save Rene Russo’s character and a few hundred other folks, besides).”

          Wait, what? Capuchins can carry Herpes simiae (typically found in old world primate pieces and fluids, lethal in humans).

          1. loupgarous says:

            I’m aware of the simian herpes problem. My point was the little monkey which Cuba Gooding’s character captures in Outbreak finally gets back to Mutabaville-By-The-Sea, and not long after that, it’s got enough antibodies to cure not just Rene Russo’s character, but the hundreds of town people not yet killed by Mutaba virus. Within hours.

            My understanding is that making therapeutic antibodies entails inoculating a challenge agent (killed Mutaba virus in this case?) in other animals, then separating the serum fraction with the useful antibody. Then you do lab work to discover the right adujvant. A lot of lab and GMP activity before and after, you’ve got your usable antibody and the movie cuts to credits. Not before.

            I’d be delighted if that process happens soon enough for the end scene not to be Dustin Hoffman’s character weeping as they bury his ex-wife.

          2. loupgarous says:

            @NJBiologist: good catch on the simian virus. Should have been a red flag.

            Those who’ve done this, could a monoclonal antibody be done in hours (theoretically, with poetic license) if you had an animal host with the natural antibody you want?

  12. gippgig says:

    “The trick is to recruit determination to fight actual threats to our national security” – no, it is to fight actual threats to the people of the world, not to nations. We need to think globally, not nationally.

    1. loupgarous says:

      To quote Tom Wolfe in The Right Stuff, “No bucks, no Buck Rogers.” I always wondered if that was based on someone’s actual words – until Richard Rhodes quoted John von Neumann in Dark Sun referring the world of ballistic missiles and nuclear weapons as “this Buck Rogers universe”.

      We in the US don’t have enough testing kits or anything else to comprehensively fight COVID-19 yet. The checks for dealing with new or re-emergent coronaviruses were never written, because not enough people were screaming at their Congressional delegations before now.

      If we’re very lucky and we get a warm, humid spring, the agitation to deal with biological threats to our national security may evaporate. Eventually, someone will travel back here carrying a “slate wiper” – something like restonvirus in its virulence, but which will kill people just as efficiently as restonvirus kills crab-eating monkeys, through the air.

    2. loupgarous says:

      ““The trick is to recruit determination to fight actual threats to our national security” – no, it is to fight actual threats to the people of the world, not to nations. We need to think globally, not nationally.”

      The last time we accomplished something truly impressive on the global scale about a troublesome pathogen, it was the eradication of smallpox in the wild. Unfortunately, recombinant work with related viruses to smallpox proceeds, and there’s evidence Russia hasn’t destroyed their stocks of smallpox.

      We can do amazing things globally but defending humanity as a whole against weapons of mass destruction doesn’t seem to be one of them, when not every nation wishes to divest itself of them.

  13. Pharmscience says:

    The best anti positive-sense and single-stranded RNA virus available now for deployment is sofosbuvir. As soon as it is tested in vitro, it can go Ph2. It can be deployed more readily than any others in trials or development.

    1. Bill O'rlys tumor says:

      When the heat is on the snowflakes melt

  14. ChairmanMao says:

    Maybe infectious disease discovery research becomes in vogue again- searching out cures instead on pinning Pharma hopes on things like orphan drugs and lifestyle drugs that get rid of double chins and obesity-

    Get your priorities straight Pharma

  15. Bob Seevers says:

    Derek, you mention George O. Smith’s as an example to rapid technological solutions to complex problems. I enjoyed his Venus Equilateral stories. Doesn’t make them a model for what the real world works like.

    1. Derek Lowe says:

      Exactly. The Venus Equilateral stories are entertaining Golden Age pieces of “planetary romance” science fiction. One great new invention per 1500 words or so is not a pace that we can aspire to!

  16. Steve says:

    While there has been a lot of talk about vaccine development and antiviral drugs there is little discussion on what is the best non-pharmacutical intervention for cities/governments to help control the spread. This paper back from 2007 PNAS was an interesting read relating to the 1918 flu.

    “Public health interventions and epidemic intensity during the 1918 influenza pandemic”
    https://doi.org/10.1073/pnas.0610941104

  17. Steve says:

    Here’s an interesting approach using the virus’ natural glycan binding to try an swamp out the virus using already approved Heparin.
    “The 2019 coronavirus (SARS-CoV-2) surface protein (Spike) S1 Receptor Binding Domain undergoes conformational change upon heparin binding”
    https://doi.org/10.1101/2020.02.29.971093

  18. Jiajia says:

    Chloroquine and hydroxychloroquine already showed some efficacy in Chinese hospitals. There were more than ten clinical trials( more than thousands of patients) took those in China right now. The high dosage does seem very important, 500mg/twice per day, for 7days. Base on the in vitro results and the super PK /distribution of chloroquine, it looks most promising so far. Two crucial advantages of chloroquine are A: it is much more accessible than anything else, including remdesivir ; B, It could be taken orally instead of going to the hospital for multiple injections. Considering the early HIV trial results with Chloroquine, I wish those could help at this point. There is not much anything left.

    https://www.unboundmedicine.com/medline/citation/32150618/In_Vitro_Antiviral_Activity_and_Projection_of_Optimized_Dosing_Design_of_Hydroxychloroquine_for_the_Treatment_of_Severe_Acute_Respiratory_Syndrome_Coronavirus_2_(SARS-CoV-2).

    1. Toni says:

      I had 125 milligrams of Resoquin yesterday.
      I don’t think I’ll tolerate higher dosages. After 10 minutes an unpleasant taste of chlorine started to build up in my nose. I got a bit dizzy and my stomach reported with a slight mumbling sound. Ok, nothing serious, but the taste of chlorine is still noticeable today. What worries me more is that I feel a slight pressure on my ears.

  19. NJBiologist says:

    Derek, FWIW, the original movie version of Andromeda Strain is a very different experience from the miniseries–I couldn’t finish the miniseries, but I liked the movie.

    1. loupgarous says:

      Robert Wise directed and produced the film Andromeda Strain. Nelson Gidding did the screen adaptation. Douglas Trumbull did the special effects). Wise knew his job. I liked the movie, too – it follows the usual rule that Crichton’s novels are better as film adaptations than as books.

      The Andromeda Strain miniseries wasn’t the “what we’ve learned since 1971” version I’d hoped for. It demolished willing suspension of disbelief. A little science fantasy can help a movie, but only Doctor Who can get away with what happened in the miniseries version of Andromeda Strain.

  20. SRP says:

    I’m surprised there has been no mention of the DARPA P3 program. Its members have been talking about having some short-term antibody-related stopgaps ready for testing by the end of the summer.

  21. Satsuma says:

    Trump fired the national security team for handling pandemics in 2018, the positions were largely left vacant until these past few weeks which unquestionably hampered the administrations response

    H1N1, SARS, MERS, etc were all scary, but none of them had infections in the US on the scale we are seeing right now (in part because all of them are less contagious, not everything is about politics)

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