Friends,
As COVID-19 has exploded, so has the amount of information about COVID-19. There are currently over 700 publications regarding coronavirus listed in PubMed within the past few months. More are being released daily. Many haven’t been catalogued on PubMed yet.
This chapter will attempt to synthesize the latest and most important information on COVID-19. I will need your help to provide post-publication peer review and point me towards new developments.
I will be revising this on a daily basis until things settle down. It's currently a bit rough, but I wanted to get it out without further delay. Regular programming on PulmCrit and the IBCC will be suspended for now (but rest assured, they will eventually resume).
COVID-19 is outstripping the ability of most traditional information sources to keep up. In this context, FOAMed may be an ideal medium to discuss and share late-breaking information. The hashtag #COVID19foam can be used to tag and track useful information on twitter.
An IBCC podcast on this will be coming out in several days, following an initial period of peer review and shaped by ongoing online discussions.
Thank you for all your help.
Sincerely,
Josh
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The IBCC chapter is located here.
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Hello. Thank you for doing this.
A. I was wondering if COVID 19 had Neuraminidase activity, i.e would it make sense to try Oseltamivir?
B. Since it binds through the ACE2 receptor, I wonder if ACE inhibitors would have a protective efffect?
C. How about Baloxavir? Any possibility it might work from what we know about COVID19’s Virology?
Thanks,
Sherif Yacoub, MD
Endocrinologist
Employed Physician with a community hospital
My comments and questions do not represent their views
I have no conflict of interest
a) Oseltamavir doesn’t seem to have any activity.
b) Theoretically maybe, but I think to have any sort of effect you’d probably need to tank the blood pressure and give everyone renal failure from the ACEi – so probably wouldn’t work?
c) Baloxivir is super interesting, I think they’re running some trials with it in China, so stay tuned on that. Currently I don’t think there’s enough evidence to support its use (pubmed search comes up dry).
Hi doctor. Are you not familiar with the fact that they are successfully using Tamiflu in combination with Kaletra in Thailand? 20 patients went from seropositive seronegative in two days on this combination. They’ve also tried Tamiflu alone and it has reduced viral load counts. Can you please provide the source of your information establishing that it has had no effect with “19“? Thanks.
I couldn’t find anything supporting its use in PubMed. If you have any evidence supporting its use please post it here.
In light of the link below, would it be prudent to decrease the dose of linosinopril from 20 mg to 10 mg when the blood pressure is not a problem (123/82). Some argue that ACE inhibitors could help fight COVID-19, but cf. below others argue it could be fatal.
https://emcrit.org/pulmcrit/covid19/#comment-278845
IMHO the correct dose of lisinopril in a critically ill patient is generally zero milligrams .
Thank you for your answer. Since high blood pressure seems to be a clear risk factor, it would be nice to have blood pressure under control also if infected. What about diuretics?
Although ACEI/ARB may not be helpful when renal failure/shock are already an issue, I wonder if it can be effective for keeping people out of hospitals/critical care units before they reach that stage, or if it may have a role in prevention. No evidence yet beyond theoretical mechanisms, though, as far as I know.
ACE inhibitors don’t seem to make any sense but ARBs May block bindi g of the virus and reduce severity of disease. Re: tanking BP, most at Risk pts are older probably have HTN and regimen could be adjusted to include ARB. Essentially no risk to patient but potential benefit.. also even low doses could be beneficial. I suggest a multifaceted approach with ARB, boosted protease inhibitor eg Kaletra or Prezcobix plus Remdesivir if available and chloroquine . HIV requires three drug cocktail this may be similar. Any studies on this approach?
Hey Josh,
Any thoughts on using IVIG to mitigate the cytokine storm seen in late-stage COVID? Was trying to think through other possible interventions that could be started early in the ED or for the younger patients.
Thanks for everything you are doing!
Hi! I’m working at University Hospital in Japan. It seems in my place, the onsets are strictly limited in the population with certain activities (drinking in hall, exercise in gym, family of the patients etc.). I found your comments interesting. I also saw the brief report in the internet about the oseltamavir use for CoVID-19 patients in Rajavithi Hospital, Thailand which was successful, but I haven’t found the report in Pubmed. I think the rationale for suing oselatmavir in CoVid-19 came from the few successful experiences in MERS. However, there is no proven rationale for using oselatmavir in MERS. There… Read more »
Regarding the thought about Ace inhibitors. Apparently ACE I may actually constitute a risk factor. https://doi.org/10.1136/bmj.m810
yeah I usually stop ACEi in critically ill patients due to risk of renal failure. I would do the same for a COVID patient.
Hi. I didn’t see the reference to ACEI in the editorial you linked. Please clarify. Regarding my question about ACEI, it was regarding the role in decreasing the likelihood of acquiring the infection or progression from mild to severe, in view of the fact that binding of viral particles to lung tissue requires ACE. It goes without saying that ACEI and other anti-hypertensives should be discontinued in the critically ill, not to mention the fact that if they are at the point of critical illness, the infection has already progressed to lung tissue so that binding or non-binding of new… Read more »
https://www.bmj.com/content/368/bmj.m406/rr-11
Good day to all,
As a clinical pharmacologist i also find the potential benifits of the AcE inhibitors inhibitors intersting. Competitive binding to prevent viral access.
Theoretically, what kind of dose would we be looking at to be effective in this regard?
I think its a diff enzyme? ACEIs inhibit angiotensin convering enzyme (ACE) which catalyzes the conversion of AngI to AngII. COVID19 binds to and enters the cell via pulmonary ACE2 (also expressed in heart/kidneys). This membrane bound enzyme,I believe, is downstream of ACE and i do no think current RAAS drugs would inhibit it. ACE2 catalyzes the conversion of both AngI and AngII further to nanopeptides angiotensin(1-9) and angiotensin(1-7). From what I can tell these molecules are less well studied but may have some role +/- in heart failure, fibrosis, pulm htn. I also saw an article theorizing that treatment… Read more »
ACEIs inhibit angiotensin convering enzyme (ACE) which catalyzes the conversion of AngI to AngII. COVID19 binds to and enters the cell via pulmonary ACE2. This membrane bound enzyme, I believe, is downstream of ACE and i do no think current RAAS drugs would inhibit it. ACE2 catalyzes the conversion of both AngI and AngII further to nanopeptides angiotensin(1-9) and angiotensin(1-7). From what I can tell these molecules are less well studied but may have some role +/- in heart failure, fibrosis, pulm htn. I also saw an article theorizing that treatment with ACEI/ARB may actually UPregulate ACE2 potentially increasing the… Read more »
On PPE, if you don’t have long enough gloves, we’ve taken to taping the arm of the gloves after you’ve put them on,
Great tip, we will need to get creative especially as supplies start running low
Or cut a thumb hole with a pair of shears. Does the trick too.
Steroid –
This Chest 2006 paper present a retrospective study showing benefit of steroid in SARS-COV1.
Chen RC Tang XP Tan SY et al.Treatment of severe acute respiratory syndrome with glucosteroids: the Guangzhou experience.Chest. 2006; 129: 1441-1452
This Lancet paper (DOI:https://doi.org/10.1016/S2213-2600(20)30071-0) recommends (In emergency cases, such as SpO2 <90%), dexamethasone 5–10 mg or methylprednisolone 40–80 mg intravenously before transfer.
These are really interesting papers, thanks for bringing them to my attention. The Lancet paper refers back to the Chest paper. In Chen et al, steroid wasn’t associated with mortality (either use or timing; see Table 2). There was a very weak relationship with mortality (p close to 0.05) using a multivariable regression analysis. So this is interesting, but it’s far from definitive. The discussion section is instructive in exploring risks and benefits. It seems like even in 2006, many years after the SARS outbreak, this remained quite unclear. I think there’s agreement that pulse-dose steroid (e.g. 1000 mg methylprednisolone… Read more »
Given the DEXA-ARDS trial, why are steroids not recommended? Is it the increased viral shedding?
No COI
Steroid could:
(1) increase viral levels & virus-induced lung damage (and yes, along these lines steroid could increase virus shedding)
(2) reduce a pathological hyper-immune response to the virus
The balance of these factors would determine whether steroid is beneficial or harmful. I don’t think anyone knows for sure (certainly not me). This is probably pretty complex and could depend on the level of hyper-immune response (e.g. levels of CRP & ferritin) and time-course in the disease process. My guess is that there may be some role for steroid, but we haven’t quite figured it out yet.
I think Adrenal response is very important when taking steroids into consideration. If the patient is in shock, an ACTH stim test should be done, and you should see a response above 20. At the very least, random cortisol should be obtained. In an intubated patient on pressors you should see a random cortisol above 25 (that was the cutoff used by a CHEST article in 2002 I believe, but ACTH stim is better. In this case, the dose of steroids should be Hydrocortisone 100 mg IV q8h or q6h
With regards to the potential timing of steroid use, this over-compensating adaptive immune response in some patients would seem like a window to start steroids. Have you heard any anecdotal experience with COVID-19 patients who have responded to steroids when initiated once entering the adaptive immune response?
Thank you for this very comprehensive and easy to follow analysis.
My distant knowledge of biochemistry is being taxed a bit — But after reading the Wang article in JAMA my interest was piqued in the “cytokine storm” mechanism suggestion.
Could activation of the cholinergic anti-inflammatory pathway through vagal nerve stimulation or mimcs of Nicotinic Acethylcholine such as galantine possibly offer some relief or slow the inflammatory process. I’m also curious about the potential of Cox-2 production inhibition in aveolar cells with Celebrex???
COX-2 inhibition is an interesting thought process, but are NSAIDs. Further, I could see this present a chance of renal issues, and gastrointestinal side effects that would be exacerbated by other concurrent treatments. Blood pressure effects might also be in consideration here. The monotherapy treatments to manage cytokine storm after CAR-T therapies like ones mentioned above or even Dasatinib I would assume offer the quickest and most broad control of the storm from my knowledge. GI symptoms would likely occur, but better than the alternative. Here is an article going over the review with Dasatinib. Note: The therapies mentioned above… Read more »
In Germany our CDC-aquivalent (RKI) recommends hygiene precautions and screening when viral respiratory infection is highly suspected , even in cases without contact to other COVID-19 patients and without having traveled to problematic countries. Only difference is that they do not need to be reported.
(Group 4 in this flowchart: https://www.rki.de/DE/Content/InfAZ/N/Neuartiges_Coronavirus/Massnahmen_Verdachtsfall_Infografik_DINA3.pdf?__blob=publicationFile)
Yes, as the virus starts spreading in community standards will change for who needs screening. I will work on updating this – probably will vary depending on location so yes would absolutely follow your local health guidance.
Hello, community EM physician here. I know that the realization of 2 haplotypes is new, but do you think that exposure to the less virulent S Haplotype and recovery would lead to immunity for both the S and L haplotypes? Or is this similar to Influenza in that one could get Influenza A and B at separate times in the same flu season? I have no COI and thank you immensely for your comprehensive review.
I don’t know. For now my guess would be that the haplotypes are similar enough that immunity to one would confer immunity to the other.
But on a larger time frame, one big question is whether coronavirus will continue to circulate indefinitely (similar to influenza) – with ongoing mutations and new strains arising each season or from time to time. That seems possible.
Hello,
I was just wondering if there is any information on cytokine profiling of these patients with poor outcomes? I would be interested to know also if anyone is looking at the timing of steroid administration? Might be interesting to see how the cytokine response is changing in mild vs acute cases..
Thanks!
Jill Granger
There are several studies which have shown higher cytokine levels in more severe illness, but this is very difficult to parse out with regards to causality. For example, more severe illness also correlates with higher levels of some anti-inflammatory cytokines (e.g. IL-10). That could be interpreted in a half of a dozen different ways (e.g. is IL-10 causing things to be worse, or is this just a response to a higher viral load, or is this a reaction to higher levels of pro-inflammatory cytokines, etc). The timing issue with steroids is super interesting, but at the same time would be… Read more »
Josh:
thanks for putting all this together!
You mention that “The virus persists on fomites in the environment. Human coronaviruses can survive on surfaces for up to about a week. It’s unknown how long COVID-19 can survive in the environment, but it might be even longer (some animal coronaviruses can survive for weeks!).
From what I have read, the COVID-19 can survive only up to 4 hours on fomites (watch the ESICM video you included – about at 18:00). Do you any other source of info?
Best,
Petros
The best article I came across on this is : https://www.ncbi.nlm.nih.gov/pubmed/32035997
Coronaviruses can often survive much longer than 4 hours. The four hours statement may be incorrect. I don’t think anyone has yet figured out exactly how long COVID-19 can survive in the environment.
Hi and thanks for setting up this great resource. My question is in relation to Chloroquine Phosphate. I have seen a lot online about the Chinese saying it was appearing to be very useful and helping to mitigate a large number of cases, with reduction in symptoms and severity of illness noteable. However, although there are numerous studies quoted, I have been unable to find any interim results. I am keen to find out more as I am cosidering using Chloroquine Phosphate on myself if I become confirmed infected. To that end, I would also be very interested if anyone… Read more »
Yes there are articles coming out of China that allude to good results with chloroquine, but I’ve been unable to find any actual data on it. To date there is no high quality evidence on using chloroquine in humans at all for coronaviruses. And the chiungunya experience with chloroquine proves that cell lines can be misleading (https://www.ncbi.nlm.nih.gov/pubmed/29772762). So I would be very careful about using chloroquine until we have actual evidence on humans.
Thanks for the reply. Yes, it would be extremely useful if some actual trial results or interim results were released. Time is very much of the essence with the virus spreading quickly in so many places. From what I can see so far here in the UK, if you are normally fit and healthy and under age 50 it is likely you will be asked to stay at home and take paracetamol and rest up. My concern over this, is that it seems that the virus can appear reletively mild and benign for up to about a week, before then… Read more »
Have you seen this trial on Vitamin C ongoing in China? Recruitement should have been started in february. 24 g daily for one week. A dosage definitely higher then the HAT protocol of Marik and the Citris trial. But I wonder if there are any ongoing studies in which the administration of C vitamin starts immediatly in the ED, like for antiobitics in septic shock, instead after ICU, when the patients has already developed an ARDS.
https://clinicaltrials.gov/ct2/show/NCT04264533
We will have to wait and see. My concern is that it sounds like hundreds of trials are ongoing in China and many of them may end up being underpowered (because patients may need to be split between numerous trials).
Unfortunately I don’t have time to wait the results of trials. My hospital borders the heavily affected areas of Italy and within two weeks I expect the “tsunami” of interstitial pneumonias to arrive. Colleagues who currently work in the most affected cities told of dozens of people with viral pneumonia who come to the ER every day. Fortunately, very few actually need intensive care. In some ICU in my region, vitamin C is used, but most intensivist are skeptical. I work in an ER connected to a ward with semi-intensive monitoring, where hypoxaemic patients, who do not yet need intensive… Read more »
Marik supports the use of IV vitamin C in COVID, but everyone should come to their own conclusions.
Thanks a lot for your great work of communication of science and for your great intellectual honesty
Thanks for compiling this! It is the best clinical overview I’ve seen and have shared it with our residency. I have been searching all over for good sensitivity/specificity numbers and could only find the same study you did (70% comparing to CT). Do we think doing PCR x 2 improves sensitivity? And if not, care to comment on how the tests are being implemented (both in US and abroad) and the risks of continued transmission with false negative tests? interesting also that now so many different sites are developing their own test, and Im’ not sure what they are using… Read more »
1) repeating PCR does increase sensitivity, but studies have often repeated after a few days. So for maximal effect you might want to repeat after 48-72hr rather than 24 hr.
2) yeah there are going to be lots of different tests developed by different places, which may not all have the same performance.
3) once we can get a COVID test with fast turn-around time and some more data on lung sonography I think we could start creating better algorithms… but for now this is a real mess.
LPV/r – tabs have a film coat, crushing to administer via NG/OG/etc in a pt on a mech vent may result in a ~50% decrease in AUC (www.ncbi.nlm.nih.gov/pmc/articles/PMC3205189/). It might be reasonable to double the dose for these patients if being used for salvage therapy, but unclear exactly what additive toxicities this might come with (LFTs, QTc, etc). It’s hard to find consistent info on what formulation is being used in the small CoVID and previous SARS studies.. Commercially available suspension is (sigh) on nationwide back-order. If you are a part of a large system and anticipate treating sick patients… Read more »
Great point !!! I’ve updated the chapter and added this reference.
Josh what is the definition of “prolonged period of time”? Asking this question in the context of exposure and transmission of COVID-19 . Thanks.
It looks like after recovery, pharyngeal PCR may remain positive for a long time but shedding of live virus decreases after ~8 days. I just updated the chapter about this – take another look.
Nadia Mascolini Italia regione Campania Medicina d’urgenza
https://www.ottopagine.it/na/attualita/211403/covid-19-al-cotugno-sperimentato-farmaco-per-casi-gravi.shtml
The theoretical risk associated with Ace inhibitors is pretty compelling. The theory being that ACE inhibitors cause an increase in ACE2 surface receptors which are instrumental in the virus obtaining access to alveolar cells. This is a possible explanation for why people with stroke, cardiovascular disease, and diabetes have substantial increased risk of death as the majority of these patients are on these medications.
I’m not recommending ACEi. This is potentially very dangerous with regards to causing shock, hypotention, and renal failure.
For clarification, what I’m referring to is the theoretical possibility of ace inhibitors increasing risk of severe infection via increasing ace2 activity given that this is the entry point for the virus. I’m not discussing the value (or lack thereof) of ace inhibitors in critical care medicine. The relevant timeframe for the issue I am discussing would rather be the early phase of infection. No need to respond to this.
This is an extremely interesting topic. A few points – In the literature it is difficult to determine if ACEi result in increased ACE2 or not. From what I can gather ACE2 remains net neutral, ACE may increase/upregulate (2 different branches of the RAS system) The question of increased ACE2 acting as an entry receptor for COVID19 is an interesting one. We need to go back to SARS. SARS was known to have an unusual predilection for the younger adult (20s, 30s) compared to other viruses like flu (though I believe half of mortality was still in over 65 age… Read more »
ACE1 Catalyses Ang1–>AngII–Vasoconstrictor via AT1 Receptor ACE2 Catalyses AngII–> Ang (1-7)–vasodilator The density of ACE2 receptor after 28 days of therapy with ARB = X5 times normal ACE2 serves as the receptor for SARS-COV2 (that causes COVID-19) After binding to the receptor, ACE2 receptor is downregulated, consequences of this include 1. Hypertension, because of unopposed AngII action on AT1 receptor with downstream inflammatory consequences 2. More people with COVID-19 with elevated BP during their disease were more likely to progress to ARDS and die 3. AT1 receptor blockers e.g. Losartan has been shown to increase ACE-2 receptor density and promote… Read more »
Thank you for the contribution.
Do you think it would be possible to decrease the density of ACE2 receptor in only 28 days? Is the increase in ACE2 receptor density during 28 days based on evidence from an animal or human study?
As suggested in the Lancet correspondence, I have decided to switch from ACE inhibitor to a calcium channel blocker. Do you consider switching from losartan to a calcium channel blocker?
I believe this is becoming more clear for COVID19 as well. http://www.nephjc.com/news/covidace2 – as I mentioned above There are a number of studies that show ACE2 declines with age. Please see this recent paper – https://www.preprints.org/manuscript/202003.0191/v1 It seems unlikely that ACE2 as a receptor is a risk factor in those with increased levels. If elevated ACE2 were a significant risk factor than Type 2 diabetics and the elderly should be affected less severely than the young population. The protection ACE2 provides in the lungs appears to be more important. Also avoiding hypokalemia. Does anyone have access to data from a… Read more »
Would you stop diuretic with potassium chloride if the patient has Covid-19?
Do you know if blood pressure increases in patients with Covid-19?
This is very concerning to me because I have pots syndrome (so does my teen son) and it has been shown some pots patients have high angiotensin 2 in plasma, but low ace 2 activity. ..
I m not a scientist but could this possibly put us at higher risk?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3050076/
Any research with measurements of bradykinin levels in patients infected with Covid-19?
Thanks!
This is a post about Losartan. Comments are encouraged. ACE2 is a major player in COVID-19. When membrane bound, it serves as the mode of viral cellular entry. On the other hand ACE2 degrades Ang II, counterbalancing the RAAS. The question devolves to ACE2: good or bad? Highlights of very recent articles (based on studies on mice and human embryonic kidney cells). 1) The ACE2 receptor is not separate but forms a complex with AT1R on the cellular membrane. 2) ACE2 with or without the attached SARS CoV2 can only enter the cell when Ang II attaches to AT1R 3)… Read more »
As it binds to ACE receptors and ACE i seen to be leading to increased expression of ACE2 receptors on pneumocytes does it follow that stopping ACE i and ARBs would be beneficial?
My opinion: It would be a tough recommendation to defend with the caliber of evidence currently, being that all we have is a potential mechanism. But I think stopping an ACE I or an ARB is worth considering on a case-by-case basis. For instance my father-in-law takes a low-dose Lisinopril for borderline stage 1 hypertension, but has no other cardiovascular risk factors. It seems reasonable in a situation like this to temporarily stop or change to an alternative. Similarly for the tens of thousands of diabetics who are on low dose lisinopril for renal protection, temporary cessation would seem reasonable… Read more »
If that mechanism causes more vulnerability, then theoretically ACEI would be bad but ARB good?
If you know case reports about correlation with specific anti-hypertensive therapy, please share. I think the idea is intriguing.
Can you elaborate on why ACEi potentially bad but ARB good in that case? I’m having trouble wrapping my head around this.
Can you elaborate on this idea that ACE-I bad but ARB good? Not sure I understand the mechanism and would love to know more. Thank you!
Your article slightly confuses me.
“Patients with COVID-19 are often relatively young and suffering from single-organ failure due to a reversible etiology, so many would be excellent candidates for ECMO (probably mostly VV ECMO).”
“Risk factors
Older age
Male sex
Medical comorbidities
Chronic pulmonary disease
Cardiovascular disease (including hypertension and coronary artery disease)
Cerebrovascular disease
Diabetes”
So which is it? Are the sicker patients with COVID-19 old or young? Thank you.
Jim
Are there any online resources on how to manage an overload of patients at hospital level? (The current reports from Italy are scary and I think everyone should prepare for it)
E.g. triage strategies, creating beds for invasive ventilation out of nothing; balancing 1. patient care, 2. protection for your healthcare workers, and 3. scarce resources (masks etc)
Maybe some Korean colleagues have published their strategies?
I am working as an intensivist in a medium sized community hospital, and can foresee that our healthcare system will be overwhelmed once COVID-19 starts in our community. Currently every hospital is working on its own to fight against the virus infection. If we can work together and cohort all the patients in a few hospitals, it may reduce the infection to medical staff so the system won’t be overwhelmed. All of us can rotate to take care of these COVID-19 patients. I t will also save our limited resources of PPE.
Thanks for the summary – I agree with your comments regarding HFNO and unknown risk – Many of my colleagues are concerned regarding possible spread to Health Workers with HFNO.
If we were to provide it in an isolated patient bay with health care workers in PPE and only COVID +ve patients in the bay, Would you say on current evidence, benefit outweighs risk ( of spread to Health Care workers)
This is something that needs to be addressed throughout tertiary centers in the USA. I know of at least a handful of centers that have taken recommendations to avoid HFNC and BiPAP in Covid-19 patients or PUI by the CDC. One center on the west coast has a COVID-19 response team and these patients will be intubated once they fail a non-rebreather mask. As you stated this is likely just robbing Peter to pay Paul with putting healthcare teams at risk, but we cannot forget about this also creating a likely measurable degree of iatrogenic injury to these younger patients.… Read more »
I totally agree with avoiding intubation at all costs. When we intubate we are reversing the natural was of achieving adequate V/Q matching. When we take a breath air rushes into the chest and venous return increases. When we intubate the opposite occurs, brute force pushes air into the chest and venous return slows bringing about V/Q mismatch. Needless to say that if the patient has a bad Right Ventricle(RV) brute force and elevated levels of PEEP compromise the capacity of the RV even more. If we try to diverse the patients to keep them in a more negative balance… Read more »
Hello,
Any advice to stop ACE-inhibitor or ARB in patients treated with these since there is data that they up-regulate ACE2 level?
Sorry just saw previous coomments on this topic after Writing my question so please disregard
Thanks.
Its a really important question. I posted an answer below but want to re-iterate…if increased ACE2 levels in pulmonary tissue were a risk factor then it seems that children should be most affected by this coronavirus. They have ACE2 levels that are significantly higher than the over 65 group. (and these higher ACE2 levels may be what protects the young from lung damage). From my fairly brief literature search the only information I can find is that ACE2 levels in pulmonary tissue seem to stay stable with ACEi, but ACE rises…this changes the ratio and tips the balance toward increased… Read more »
Do you have source that elaborates on ace2 activity/expression in children?
I have a few here. The data tends to be in mice of course. The data is limited. I don’t know that many folks have looked at this. There are a few articles about ACE2 RESPONSE in ARDS in juveniles compared to adults but this would not apply…we are looking at baseline ACE2 levels not response during illness. In illness in general ACE2 seems to upregulate and seems to upregulate consistently across ages…again data is limited. https://www.bmj.com/content/368/bmj.m810/rr-24 https://download.lww.com/wolterskluwer_vitalstream_com/PermaLink/CCM/C/CCM_44_12_2016_08_04_HELMERHORST_CCMED-D-15-01556_SDC1.pdf https://www.ahajournals.org/doi/10.1161/STROKEAHA.112.667063 Now this article is interesting – https://www.ncbi.nlm.nih.gov/pubmed/16303146/ The conclusion is that ACE2 being significantly higher in the young might be the… Read more »
A few errors in my logic above…please note new copy with appropriate edits. —– I have a few sources here. The data tends to be in mice of course. The data is limited. I don’t know that many folks have looked at this. There are a few articles about ACE2 RESPONSE in ARDS in juveniles compared to adults but this would not apply…we are looking at baseline ACE2 levels not response during illness. In illness in general ACE2 seems to upregulate and seems to upregulate consistently across ages…again data is limited. https://www.bmj.com/content/368/bmj.m810/rr-24 https://download.lww.com/wolterskluwer_vitalstream_com/PermaLink/CCM/C/CCM_44_12_2016_08_04_HELMERHORST_CCMED-D-15-01556_SDC1.pdf https://www.ahajournals.org/doi/10.1161/STROKEAHA.112.667063 Now this article is interesting –… Read more »
I posted a fairly long reply and I worry it may not have posted. I will re post more briefly – a few sources – hard to find as data seems to be collected in the setting of ARDS, not baseline – https://www.ahajournals.org/doi/10.1161/STROKEAHA.112.667063 https://download.lww.com/wolterskluwer_vitalstream_com/PermaLink/CCM/C/CCM_44_12_2016_08_04_HELMERHORST_CCMED-D-15-01556_SDC1.pdf https://www.bmj.com/content/368/bmj.m810/rr-24 Here is an interesting one – https://www.ncbi.nlm.nih.gov/pubmed/16303146/ This article actually proposed that younger folks were target of SARS because of their increased ACE2…but that doesn’t really pan out. When we look at ACE2 and age and SARS and COVID19 that argument isn’t consistent. and very young children were not at risk in SARS…they should have… Read more »
I posted a fairly long reply and I worry it may not have posted. I will re post more briefly – a few sources – hard to find as data seems to be collected in the setting of ARDS, not baseline – https://www.ahajournals.org/doi/10.1161/STROKEAHA.112.667063 https://download.lww.com/wolterskluwer_vitalstream_com/PermaLink/CCM/C/CCM_44_12_2016_08_04_HELMERHORST_CCMED-D-15-01556_SDC1.pdf https://www.bmj.com/content/368/bmj.m810/rr-24 Here is an interesting one – https://www.ncbi.nlm.nih.gov/pubmed/16303146/ This article actually proposed that younger folks were target of SARS because of their increased ACE2…but that doesn’t really pan out. When we look at ACE2 and age and SARS and COVID19 that argument isn’t consistent. and very young children were not at risk in SARS…they should have… Read more »
All my academic cardiologist colleagues have stopped their ACEI. The theoretical evidence is pretty compelling. It also might explain why DM, heart ds and HTN are all risk factors (likely to be on ACEI) and why Italy has been hit so hard – elderly population more likely to have the comorbidities- national health care and generally considered to be one of the best systems in the world – potentially more people taking ACEI.
But there’s also compelling ideas that ARBs/ACE-Is could be beneficial. The issues as far as I can tell are: 1) Viral entry – this virus gains entry by binding to ACE2 – ace2 is up-regulated in people taking ARBs – therefore, ARBs theoretically bad because they increase the chance for virus to invade… BUT, 2) ACE2 is potentially protective in lung diseases – It works by decreasing the amount of angiotensin II, which is a pro-inflammatory peptide, thereby decreasing pro-inflammatory factors – therefore, theoretically having more ACE2 around could be beneficial because the way people are dying is from the… Read more »
Excellent synopsis here of ACE2, ACEi , COVID19 conundrum. (Also reviews the new study revealing hypokalemia as an important factor in COVD19)
http://www.nephjc.com/news/covidace2
Camostat Mesilate seems to be on everyone’s radar a TMPRSS2 protease inhibitor. Any thoughts as a use for treatment or prevention?
I am a geriatrician and very concerned and confused about the relationship between chronic ace-inhibitor/ARB use and covid19. The fact that fatalities are preferentially occurring in pts with htn, DM, and cardiovascular disease- all conditions for which ace-is and arbs are indicated and frequently prescribed – is especially concerning in light of our knowledge of the ace2 as virus binding site. This article (https://onlinelibrary.wiley.com/doi/full/10.1002/ddr.21656 ) seems to suggest protection, but I understand the literature is mixed. Are any providers changing prescribing practice in light of this?
Hey there, EM Resident in a city hospital in NYC here.. Haven’t personally seen any COVID-19 patients just yet, but they’re definitely coming.. Any recommendations on ways to mitigate potential aerosolization when using HFNC with COVID-19 patients? Any thoughts about utility of putting a surgical mask on the patient with the HFNC under it? Also, I’ve read a few prelim articles about ACEi use as a possible risk factor for COVID-19 infection (in patients and possibly Healthcare workers).. Any ideas about whether this is potentially modifiable risk factor? For example, should ACEi/ARB use Be discontinued while in the pandemic phase… Read more »
RE: ACEi/ARB.. I have seen similar statements from individuals popping up around the web, nothing concrete or evidence based. I would caution anything that would scare people off their antihypertensives as HTN/Cardiovascular disease is definitely been shown to be a risk factor in patients with severe disease. I did find this position statement from the European Society of Cardiology on this very issue.
Sorry Link: https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang
Is there an asymptomatic transmission of COVID-19? Adult virus carriers without symptoms at all (ever), like a super-contagious HIV-type, where a carrier will never develop any symptoms, but can and will infect others?
probably yes. or patients may have such minimal symptoms that they don’t really think they’re seriously ill
Re: counter-intuitive to increase ACE2 binding sites via sartans but may reduce inflammation and lung damage see:
“Angiotensin receptor blockers as tentative SARS‐CoV‐2 therapeutics”, https://onlinelibrary.wiley.com/doi/full/10.1002/ddr.21656#ddr21656-bib-0014
(4 March 2020)
For a concise description of proposed mechanism see:
The BMJ
Rapid Response
Response to the emerging novel coronavirus outbreak
,,,
“COVID-19 induced Renin–Angiotensin System (RAS) imbalance may drive acute lung injury: the evidence and therapeutic options”
https://www.bmj.com/content/368/bmj.m406/rr-19
(12 March 2020)
and:
…
“Re: Possible use of ARBs to mitigate lung damage caused by coronavirus”
https://www.bmj.com/content/368/bmj.m406/rr-15
(29 Feb 2020)
No conflicts
Thank you for posting this page on COVID-19. Many years ago, butylated hydroxytoluene (BHT) was touted as being able to weaken the lipid coat on certain viruses, most specifically HSV.-1 and -2. This is purely anecdotal, but I found it worked to prevent cold sore breakouts when I took it for approximately one year at a fairly low dose (due to liver toxicity concerns, I took nowhere near the 2-6 gram range some people suggested). Is there any evidence BHT could be useful in COVID-19 cases?
There is a guy named Tyler over at the ” Earth Clinic ” who says he cured his covid 19 infection using BHT.
This is a very practical question that most of my ED colleagues have. Should we be wearing PPE including mask, gown, gloves for all patients with respiratory symptoms. We’ve not had guidance from our hospital system. Thank you for the GREAT article.
Our institution is defining ‘low risk of exposure’ in the outpatient setting as both provider and patient wearing at least a surgical mask (N95 if available). If only one wears a mask, it elevates the risk to ‘moderate’, and provider would likely qualify for quarantine if the patient ended up testing positive. We are trying to use our full PPE judidciously, as we are in short supply as an outpatient FM office.
I believe the magnitude of this situation is going to require an all hands on deck approach, and some outside the box thinking. Any idea if hospital based sleep labs could be repurposed, and sleep techs be used to assist with things like BIPAP and O2 administration? I foresee many labs being closed soon regardless, as patients begin to avoid going to the hospital for anything other than emergencies. I would like to find a way to keep other techs working, and to make myself useful, however possible. All thoughts are appreciated.
Great stuff as always- might be useful to stress likely non-utility of nebs. Many of my colleagues in the community tend to just throw on scheduled neb treatments as part of supportive treatment for flu, sending in our RT friends unnecessarily. Also re: competing infections- Flu/RVP pathway might be useful while we still have testing scarcity. This weeks’ stanford grand rounds their ID doc suggests their viral coinfection rate is higher than commonly quoted <2%, so they test in parallel rather than waiting for Flu-/RVP-. Anecdotally others aren't finding it to hold as well (https://twitter.com/ercowboy/status/1238437612853100546) – Downside of a missed… Read more »
yep super important point – added that to the chapter! thanks.
Take a look at this test, Josh.
It is an antibody test kit and the device is meant to work like a home pregnancy test kit
https://thecoronavirustestkit.com/products/diagnostic-kit-for-detection-of-igm-gg-antibody-to-sars-cov-2colloidal-gold-single-unit
I have no COI
https://twitter.com/JMRothberg/status/1236289160253767681?s=20
Not ready for prime time. But a potential gamechanger.
Hey Petros, looks like there’s 2 published trials on this sort of device, one from China (with one of the authors working for the company that designed it) which showed promising results (https://www.ncbi.nlm.nih.gov/pubmed/32104917), and a second trial from Italy that looked pretty dismal https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.25800
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30566-3/fulltext
This article hints at a disturbing issue regarding possible futility of intubation/ventilation. Of the 191 in this series treated at that institution 32 required intubation and ventilation, and of these 32 only 1 survived. Those requiring noninvasive ventilation didn’t fair much better.
Does anyone have any more encouraging experience?
Does anyone have any data about the relationship between COVID-19 and Ibuprofen?
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30116-8/fulltext
” The expression of ACE2 is substantially increased in patients with type 1 or type 2 diabetes, who are treated with ACE inhibitors and angiotensin II type-I receptor blockers (ARBs).4 Hypertension is also treated with ACE inhibitors and ARBs, which results in an upregulation of ACE2.5 ACE2 can also be increased by thiazolidinediones and ibuprofen. “
Why not try TUDCA? There also is a probiotic that releases Ang (1-7)
I have Cpn triggered asthma + was exposed to brevetoxin in FL.
What about Aciclovir? Does it work? And another question regarding bipap machines, I’m using a bipap (because of my severe sleep apnea) and I once saw all of these in-Stock unused thousands machines in the health service companies which refurbish disinfect and rent them to new patients… could be better used for corona patients instead of waiting there for new sleep apnea patients?
What about BHT and it’s effect on lipid viruses?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC429695/
Love the site. This has been really helpful. I am fascinated by this virus and how it works. I was talking with colleagues at lunch who had mentioned the rumor that “ACE inhibitors or ARBS could be used to help treat or prevent infection from the coronavirus” It seems like these medications could cause the exact opposite effect as the ACE 2 is converted into the ACE enzyme and that by inhibiting ACE or AR this could result in less conversion of ACE2 to ACE, hence put patients with DM and HTN at increased risk of acquiring infection. My thoughts… Read more »
Disregard my post. It is very possible I misunderstood my colleagues. It seems almost all of this has been discussed ad nauseum in the other comments. Thanks. Very informative.
Chinese have issued their latest (7th edition) guidelines on treating COVID19. In them, they specifically mention the use of Chloroquine Phosphate 500mg BD for 7 days as a useful treatment (for patients 18-65 and over 50KG). Has anyone an opinion on this, I realise the full results of controlled trials are still as yet unobtainanable.
Where can you find these guidelines? Thanks
I’ve updated the stuff on hydroxychloroquine and chloroquine yesterday. It looks promising – take another look.
Hi,
First of all, thanks for your great work.
This isn’t an antiviral treatment, but according to the “cytokine storm” mechanism I’ve read recently about the potential benefit of Tocilizumab (since IL-6 seems to play a key role in the cytokine storm).
The title is: Effective Treatment of Severe COVID-19 Patients with Tocilizumab
(Xiaoling, Xu)
In this context, some of my colleagues have proposed the utility of plasmapheresis or high flow renal replacement therapy in the most severely ill patients as a way to “remove” the cytokines.
Do you have more information?
What do you think about?
thanks, yes that’s an important paper, I added it, thanks for the heads up !!
take a look at the new section on tociluzimab
Hi _ we are thinking about requistioning our unused home CPAP machines for oxygenation use. Putting aside arguments re infectivity risks; Does anywone have an estimate of FI02 produced with say 15L/min of wall mounted Oxygen and CPAP with a pessure of say 5- 8 cm H20 ? – A quick google serch has come out as approx 70 % – Does this sound correct ?
Greetings, I’m posting here because I have come across rumors that the novel coronavirus could potentially damage male fertility. This is thought of because it can attach to ACE2 receptors, which are also present in the cells of testicles. I haven’t been able to find much actual info about this, other than this non-peer reviewed study; https://www.medrxiv.org/content/10.1101/2020.02.12.20022418v1.full.pdf I know there is barely any research into this, but what do you think? Is this something researchers are looking into? Does the theory hold any water? And if so, how worried should we be? Should only certain groups of men be concerned,… Read more »
Edit: I found a couple more studies; https://www.ncbi.nlm.nih.gov/gene/59272
https://www.preprints.org/manuscript/202002.0299/v1
Hello and thanks for your great work! family dr,here. i wonder if use of The Macrophage Inhibitor CNI-1493 Semapimod (INN), formerly known as CNI-1493, which has anti-inflammatory,[1] anti-cytokine,[2] immunomodulatory,[3] antiviral[4] and antimalarial[5] properties.can help I ask that after reading that paper of which I quote:: Severe lung and systemic inflammation is believed to result from cytokine dysregulation; in patients with SARS elevated levels of cytokines such as TNF-α, IP10, IL-6 and IL-8 likely contributed to the poor outcome (17). Such an exuberant innate cytokine response was attributed to hyper-activation of macrophage/monocyte lineage cells. Additionally, elevated levels of type I interferon… Read more »
This is the best overview that I have read. Thank you for compiling it.
hi Josh
just wished to thank you both for this extraordinary, detailed, and easy to assimilate pod. pleasant to listen to; intense in the breadth of coverage. critical at this time, of course. thank you.
tom
Thanks Tom!
There is a lot of Vitamine D hype, any insights? It seems Vitamine D is influencing ACE2 which currently is not known if it’s good or bad. So what would be the recommendation? Take it or not?
Does anyone have any experience with Vapotherm Hi-VNI treatment? Would indications/risk of aerosolization be any different here than standard high-flow?
In that vein, are people planning on using HFNC as a front-line NIV? Or skipping the NIV step altogether to go straight to mechanical ventilation? HFNC w/ a mask?
Would use vapotherm the same as any other form of high flow nasal cannulae (e.g. Fisher-Paykel). Aerosolization is debatable, ANZICS says OK to use as long as you’re using an N95 with aerosol precautions. We are using this for patients who don’t require intubation but need a bit more support than low-flow nasal cannulae – see the section on HFNC.
Thank you for a great resource. I’ve been following your updates since your original posting. One question regarding markers of severe illness. Since the severe effects of the infection seem somewhat delayed after initial symptom onset possibly signaling the progression to the “adaptive stage” of illness, is there literature to suggest a progressive rise in the crp, ferritin levels or other markers that may indicate a shift toward the inflammatory stage of the illness and the optimal timing of initiation of some antiinflammatory therapy (i.e. steroids, etc) to counter the hyperimmune response?
See the graphs in the prognosis section – over time, patients with poor prognosis definitely accrue increasing amounts of inflammation. Optimal timing of anti-inflammatory therapy is unknown at this point in time.
Is lisinopril a bad medication for covid-19 patients?
Debatable. I would certainly stop it in any patient acutely admitted to the hospital with COVID. Whether to continue in healthy outpatients is controversial and beyond my scope of practice.
I know the sensitivity of testing is going to be variable and we have no gold standard, but the 60-70% (maybe up to 80%) you mentioned, is that still accurate and how does that compare to the testing that came out of S. Korea, and/or China, if we know. Thanks.
really hard to know, we are dealing with lots of assays being unrolled rapidly.
may relate to numerous factors including quality of the lab & how well sample is obtained (need to really obtain a deep swab)
Any current recommendations for IM or IV epi as an adjunct to MDIs for a possible reactive airway component? Using the 0.3mg-0.5mg IM dose? Any IV infusion recs?
I would suggest to evaluate the effect of PDE4 inhibitors on COVID-19. These are potent anti-inflammatory drugs used in COPD patients, which are not in contrast to corticosteroids not associated with increased risk of infectious complications in COPD patients. Currently, roflumilast is the only PDE4 inhibitor that has received regulatory approval for use in patients with COPD. Roflumilast is an oral agent and does have mainly gastrointestinal adverse side effects but usually no serious adverse side effects. PDE4 inhibitors inhibit neutrophils, macrophages, CD4 cells, CD8 cells, B cells and dendritic cells (https://bmcpulmmed.biomedcentral.com/articles/10.1186/1471-2466-8-17). CHIESI is trialing a inhalation PDE4 inhibitor CHF6001… Read more »