COVID: new NIH guidelines; T-cells having viral receptors

The NIH just released their Covid-19 treatment guidelines (see https://covid19treatmentguidelines.nih.gov/introduction/). This blog will not go into details on the inpatient management. I have embedded my comments in the text in brackets

Overall rating system:

A=strong recommendation

B=moderate recommendation

C= optional

Modifiers:

I: 1 or more RCTs with clinical outcomes and/or validated lab endpoints

II: 1 or more well-designed, nonrandomized trials or observational cohort studies

III: expert opinion

Details (overall):

-- the treatment panel does not recommend the use of any agents for preexposure prophylaxis or postexposure prophylaxis against SARS-CoV-2, outside of a clinical trial (level AIII recommendations for both)

-- there is no additional lab testing or specific treatment for those with asymptomatic or presymptomatic SARS-CoV-2 infection (AIII)

-- at present no drug is proven to be safe and effective for treating Covid-19. There are insufficient data to recommend either for or against the use of any antiviral or immunomodulatory therapy in those with Covid-19 who have mild, moderate, and severe or critical illness (AIII)

-- testing:

    --best to get lower respiratory tract samples (BII recommendation), but they acknowledge that this may not be appropriate because of likely increased aerosolization of virus by doing so [lower tract sampling is mostly for ICU patients]

    --nasal swabs or oropharyngeal swabs “may be acceptable alternatives” to nasopharyngeal samples

--the panel does recommend prone ventilation for 12-16 hrs/d in mechanically-ventilated adults with refractory hypoxemia (BII)

--treatment:

-- as noted above: all of the treatment recommendations are based on expert opinion, not based on good studies, mostly saying there are insufficient clinical data to recommend for or against using them, including :

    --chloroquine or hydroxychloroqine (AIII)

    --remdesivir (AIII)

    --convalescent plasma or hyperimmune immunoglobulin (AIII)

    --IL-6 or IL-1 inhibitors (AIII)

    --interferons or Janus kinase inhibitors (AIII)

  --they do, however, recommend against:

    --hydroxychloroquine plus azithromycin (based on potential toxicities)

    --lopinavir/ritonavir (AI) or other HIV protease inhibitors (AIII) [though, the trial of lopinavir was really not a great trial, had significant methodologic problems, and was still very close to statistically significant for their primary clinical outcomes; and length of ICU stays/time to clinical improvement/and % with clinical improvement in 14 days were overall better with the lopinavir/ritonavir: see http://gmodestmedblogs.blogspot.com/2020/03/covid-19-lopinavir-does-not-work-but-is.html ). though, that being said, it would not reach the top of my list for meds….  Just that they are condemning it based on a single not-so-great study]

--concommitant meds:

    --ACE/ARBs:

        --okay to use if cardiovasc indication (AIII)

        --Not okay to use for Covid-19 treatment (AIII) [these meds do increase ACE-2 levels, the major SARS-CoV-2 binding receptors, but unclear what their effect would be on Covid-19. By the way, there are other likely binding sites of SARS-CoV-2, including T-cells. more below on this in the commentary]

    --corticosteroids:

        --not use for treatment of mechanically ventilated patients without ARDS (AIII)

        --not use in non-ICU patients (AIII)

        --insufficient evidence in those with ARDS (C1)

        --use low dose in those with refractory shock (BII)

        --if on chronic steroid for other condition, may need stress doses (AIII)

        --if on inhaled steroids, do not discontinue (AIII)

     --pregnancy considerations:

        --betamethasone and dexamethasone cross the placenta and should only be used for fetal benefit (CIII)

        --other steroids can be used during pregnancy (CIII)

            --though modifications to care may be individualized (CIII)

    --Statins

        --okay to continue for cardiovasc indications (AIII)

        --don’t start for treatment of Covid-19 (AIII) [this presumably has to do with the possible benefit of their anti-inflammatory effects]

    --NSAIDS

        --okay to continue if needed (AIII)

        --no difference between them or acetaminophen for antipyretic strategies (AIII) [though, overall I think NSAIDs are overused and have myriad potential adverse effects; there is some evidence they increase ACE-2 levels (see http://gmodestmedblogs.blogspot.com/2020/03/covid-ace2-ibuprofen-and-grasping-for.html ); so I personally recommend trying acetaminophen first, or, better, trying local remedies, either topicals (eg capsaicin, liodociaien, diclofenac) or injections]

Commentary (a few  more general comments):

--as noted, the above recommendations are not evidence-based, largely because there is no good evidence.  All of the studies I have seen on therapy, for example, are either observational and with mostly bad/inconsistent methodology, or in the case of lopinavir/ritonavir (as above) was really trashed in the study abstract, the local newspapers, and in organizations briefly summarizing the results (eg Physicians’ First Watch), though reviewing the trial actually did show some promise. 

    --Hopefully, my assessments of these medications were balanced: showing the striking flaws in the studies but suggesting that these might be useful agents, pending good RCTs)

--and, unfortunately, our state of affairs currently, as reflected in the above guidelines by their almost 100% being “expert opinion”, is pretty evidence-free, despite there being 2.6 million cases worldwide and 850K in the US!!!

    --and, no doubt these numbers are gross underestimates:

        --there has been essentially no systematic community data that includes large samples of asymptomatic patients (which might be a really significant number, with 25% quoted based on not much data)

        --there are many patients with symptomatic Covid-19 who are not tested (eg, I have several families where one patient has documented Covid-19, but several others soon develop consistent symptoms and are not tested, and probably do not need to be: sort of like with influenza, when in a clear local outbreak, people with typical symptoms do not need to be tested, and a negative test is mostly likely a false negative…). though not testing these high probability patients will certainly deflate the overall numbers counted

        --there are many patients with very mild URI-type symptoms that resolve pretty rapidly and don’t get tested (anecdotally, last week one of my 95 yo patients had a mild cough with slight fever, tested positive, and when i called her the next and subsequent days, she was totally fine)

        --and, as per recent studies, there is evidence that the SARS-CoV-2 virus was around for awhile prior to being identified and quantified: eg see the NY times article on genetic fingerprinting: https://www.nytimes.com/2020/04/22/us/coronavirus-sequencing.html?campaign_id=9&emc=edit_NN_p_20200422&instance_id=17849&nl=morning-briefing&regi_id=67866768&section=topNews&segment_id=25713&te=1&user_id=44a0ffdebe23c4195e1f7dab1c01b52e

--I should put these guidelines, however, in some perspective: guidelines overall are not very evidence-based  (there are lots of things we do that do not have studies to back them up). One analysis of cardiac guidelines (which are probably about the best of them), found that both the ACC/AHA and European guidelines had a very small minority of the recommendations being level A (having RCT back-up): see http://gmodestmedblogs.blogspot.com/2019/04/guidelines-lacking-evidence-based.html )

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--in terms of cellular binding of SARS-CoV-2, here is an interesting article and comments from Anita Ung (sent with her permission):

Nature had a  preprint  article of in-vitro studies showing  that SARS-CoV-2 can infect specific T cells lines (see https://www.nature.com/articles/s41423-020-0424-9.pdf):
- The capacity to infect T cells does correlates with reported initial lymphopenia among many COVID-19 patients
- This is a new tropism different from SARS-CoV; that coronavirus could NOT infect T cell lines
- Even with low expression of ACE2 in T cells, SARS-CoV-2 can get in
- T cell receptor CD147 is a likely novel SARS-CoV-2 entry route

so, the good and the bad:

--good: nice to have a summary of where we are, with an appropriate bias to not just use medications that do not have adequate studies to support them. and only do so in the setting of clinical studies

--bad: there are just so many lacunae (or, in some international parlance: holes, huecos, furos, des trous etc etc) in our approach to the hordes of Covid-19 patients.

 so, we all are just waiting for some answers (which is getting increasingly hard to do) .....

geoff

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