Thread by @AaronRichterman

.@EricMeyerowitz and my talk about #COVID-19 literature update today -

Slides: docs.google.com/presentation/d…

Recording:
dropbox.com/s/bj0bbvggh1jr…

Key points with slides, links to papers below 👇

Virology: most important structural protein S ("spike") protein required for cell entry; nonstructural protein RNA polymerase, helicase; viral proteases that cleave non-structural proteins (PLpro, 3CLpro). Cell entry via ACE2/non-endosomal path

Below=SARS
nature.com/articles/nrd.2…

Environmental viability in EXPERIMENTAL conditions - 3+ hrs aerosol (does not imply routine aerosolization by patients), up to 72 hours steel and plastic.

nejm.org/doi/full/10.10…

Median incubation period (time from exposure to symptom onset) 5.1 days. 1/100 cases will develop symptoms after 14 day monitoring period

annals.org/aim/fullarticl…

Number of studies looking at viral identification, either RNA or live virus, at various sites and during various time points.

Viral load seems to peak around time of symptom onset

thelancet.com/journals/lanin…

Mild cases: Viral RNA in nasopharynx may fall earlier than sputum. Seroconversion occurred 6-12 days after symptom onset and followed by rapid decline in viral loads.
medrxiv.org/content/10.110…

IgM may be helpful for diagnosis, particularly later in disease (after ~5.5 days)(although anecdotally seeing negative PCR become positive on second check)
academic.oup.com/cid/advance-ar…

Severe cases may have higher viral loads with longer viral shedding.
thelancet.com/journals/lanin…

Early Italy data suggests viral loads similar in asymptomatic vs symptomatic cases, although unclear whether asymptomatic = presymptomatic.
arxiv.org/abs/2003.09320

CT abnormalities seem to occur early in disease and may precede positive PCR. Interpret with caution before more/larger studies.
pubs.rsna.org/doi/10.1148/ra…

In mild cases, live virus isolated up to 8 days after symptom onset, correlates with PCR positivity although PCR positivity can last much longer (weeks). Length of time for live virus shedding in severe cases not yet described.
medrxiv.org/content/10.110…

Serial interval (length of time between symptom onset in transmitter and transmittee) ~4 days. Importantly, ~12.6% transmissions are presymptomatic.

Estimated 86% of infections during early epidemic in Wuhan were undocumented, i.e. most likely mild or asymptomatic. Modelling suggests asymptomatic infections half as infectious as symptomatic, but interpret with caution.
science.sciencemag.org/content/early/…

PCR positivity in presymptomatic cases occurred 1-7 days prior to symptom onset. Highlights possible infectiousness prior to symptom onset. Again, CT abnormalities seem to occur very early, even before symptoms.

academic.oup.com/jid/advance-ar…

Clusters suggesting asymptomatic / presymptomatic transmission.
jamanetwork.com/journals/jama/…
academic.oup.com/cid/advance-ar…

Proportion of truly asymptomatic cases unknown. Viral reservoir in asymptomatic children?

Awful example of how badly transmission and outcomes can go when necessary precautions aren't taken. 81 out of 130 residents infected, 27% died.
cdc.gov/mmwr/volumes/6…

Contributing factors to the severe outbreak, all of which will be familiar to some extent to clinicians working during this pandemic

cdc.gov/mmwr/volumes/6…

Household contact rate ~10-15% in two studies in China / US, despite isolation of cases. Rate presumed to be much higher in circumstance of case not being identified / isolated.
medrxiv.org/content/10.110…
cdc.gov/mmwr/volumes/6…

Variety of presenting symptoms, most commonly fever, cough, myalgias. Caveat: hospitalized patients. Refs on slide

GI symptoms common as chief complaint, although not often in isolation.
journals.lww.com/ajg/Documents/…

At time of hospital admission, majority with CT abnormalities, lymphopenia. Vast majority with procalcitonin <0.5.
nejm.org/doi/full/10.10…

CT abnormalities are common in hospitalized patients and may precede symptom onset.
thelancet.com/journals/lanin…
academic.oup.com/jid/advance-ar…

Disease course marked by acute mild phase and possible progression into ARDS/pro-inflammatory phase. Graphic by @EricMeyerowitz

Illness theorized to be bi-phasic with viral response phase early and possible progression into host inflammatory response phase / cytokine storm.
jhltonline.org/article/S1053-…

Typical courses for critically ill patients. Looong hospitalizations, late intubations.
thelancet.com/journals/lance…

Risk factors for severe disease from published literature put together by @EricMeyerowitz

Laboratory evidence for hyper-inflammatory state in later disease with severe outcomes.
thelancet.com/journals/lance…
jamanetwork.com/journals/jama/…

Reported CFRs can be biased 1) upwards if underidentifaction of cases 2) downwards if deaths have not yet occurred in setting of ongoing illness. Study below attempts to account for these and estimates 1.4% symptomatic CFR.
nature.com/articles/s4159…

In a number of relatively small case series of pregnant women in 3rd trimester, no evidence of vertical transmission or poor maternal/fetal outcomes. Many delivered via c-section for unclear reasons. Interpret with caution given low numbers!!

Children - 1% of overall infections in China, and at one children's hospitals 12% of those tested were positive with median age ~7. Varied presenting symptoms, 3 children required ICU and one died, all with co-morbidities.
nejm.org/doi/full/10.10…

Summary of some treatments under investigation

Importantly - no proven therapies!! Lots of bad information being propagated.

Lopinavir-ritonavir RCT showed no difference for clinical improvement. However, participants enrolled late in disease course. Need to study earlier before shutting the door on LPV/r.
nejm.org/doi/full/10.10…

Hydroxychloroquine / chloroquine - a couple weak studies referenced below. No evidence for routine use. RCTs coming.

Hydroxychloroquine + azithromycin - very poor quality / uninterpretable data. Wait for more before considering potentially toxic therapies.
mediterranee-infection.com/wp-content/upl…

Favipiravir - one non-randomized study with faster viral clearance compared to LPV/r. Waiting for RCTs.
sciencedirect.com/science/articl…

Tocilizumab - one case series of 21 patients showed good safety, improvements in lab markers. Waiting for RCTs (broken record)
chinaxiv.org/abs/202003.000…

Health systems overload - take some time to look in detail at the two graphs in the paper below. Too much to describe in tweet, but scary prospects for any place that does/can not take population control measures.
medrxiv.org/content/10.110…

Change in reproductive number over 4 time periods in wuhan - 1) no restrictions 2) massive human movement 3) enforced social distancing 4) centralized quarantine.

3) is not enough, suggests importance of centralized quarantine measures.

medrxiv.org/content/10.110…

OK that's everything, again a team effort with @EricMeyerowitz. I'm sure we missed some, please share. Some pointed to studies in Chinese as well which we were unable to review. Updates to come at some point.

Youtube recording here:

Another good paper in JAMA analyzing reasons for differences in CFR by setting h/t Dr Jason Sanders.

jamanetwork.com/journals/jama/…

In reference to another study in children that we didn't cover for reasons I outline here:

https://twitter.com/AaronRichterman/status/1243187882405310465