Covid19 Literature 3.25

An overview of academic studies of Covid-19: transmission and incubation period, spectrum of clinical presentation, risk factors for severe disease and other topics.

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Covid19 Literature 3.25

An overview of academic studies of Covid-19: transmission and incubation period, spectrum of clinical presentation, risk factors for severe disease and other topics.

coronavirus, study, data, symptoms, patients, virology, literature

COVID-19: Describing a New Disease

Aaron Richterman, MD MPH

@AaronRichterman

Eric A Meyerowitz, MD

@EricMeyerowitz

LitCovid - https://www.ncbi.nlm.nih.gov/research/coronavirus/

As of this morning:

PubMed - 1642 papers

MedRxiv/bioRxiv - 760 pre-prints

Outline

Virology - The Basics

Transmission and Incubation Period

Spectrum of Clinical Presentation

Risk Factors for Severe Disease

Special Populations

Management

Population Risk and Mitigation

Virology - The Basics

Virology - The Basics

Viral structural proteins: most importantly S (“spike”) protein required for cellular entry

Viral nonstructural proteins: RNA-dependent RNA polymerase (RDRP) and helicase

Viral proteases that cleave non-structural proteins (PLpro and 3CLpro)

Host ACE2 membrane bound receptor is binding site for S-protein → entry by endocytosis

Host protease TMPRSS2 can cleave S into S1/S2 and entry by non-endosomal pathway at plasma membrane

Zumla Nature Review 2016 doi:10.1038/nrd.2015.37

Hoffman Cell 2020 https://doi.org/10.1016/j.cell.2020.02.052

Zumla Nature Review 2016 doi:10.1038/nrd.2015.37

Transmission and Incubation Period

Van Doremalen NEJM DOI 10.1056/NEJMc2004973C

Environmental

viability

Lauer Annals 2020 doi:10.7326/M20-0504

Incubation period: median 5.1 days

Viral shedding: site and duration

Zou NEJM 2020 382:12

Pan Lancet 2020 S1473-3099(20)30113-4

Wang JAMA doi:10.1001/jama.20203786

Liang Acta Opthalmol ttps://doi.org/10.1111/aos.14413

Chen Lancet 2020 https://doi.org/10.1016/S0140-6736(20)30360-3

SARS-CoV-2 isolated

No SARS-CoV-2 RNA isolated (to date)

Sputum (live)

Urine

Nasopharynx/oropharynx (live)

Breastmilk

Stool (RNA common, live rare to date)

Amniotic fluid

Blood (RNA, rare)

Infant cord blood

Conjunctiva (RNA, no live to date)

To Lancet ID 2020 https://doi.org/10.1016/S1473-3099(20)30196-1

Viral load may peak around time of symptom onset

“Descending infection:” VL higher in NP, then sputum

Wolfel Nature https://doi.org/10.1038/s41586-020-2196-x

IgM may be helpful for diagnosis when PCR-

Guo CID doi: 10.1093/cid/ciaa310

Severe cases may have higher viral loads, longer shedding

Liu Lancet ID doi:10.1016/S147303099(20)30232-2

Italy early data

They screened asymptomatic contacts of known COVID patients Feb 21 - 25

Compared viral loads from these “asymptomatic” individuals to VLs from symptomatic ones and found no significant difference

Caveat: these “asymptomatic people” may have actually been “pre-symptomatic”

Cereda 2020 arXiv:2003.09320

Ai Radiology 2020 doi: 10.1148/radiol.2020200642

CT abnormalities can precede +RT-PCR

Wolfel Nature https://doi.org/10.1038/s41586-020-2196-x

In mild cases, live virus isolated up to day 8, viral shedding longer

Du Emerg Inf Dis 2020 DOI: 10.3201/eid2606.200357

Evidence for pre-symptomatic transmission

Undocumented infections

In China, up to 86% of infections may have been undocumented during the early epidemic (either mild or completely asymptomatic)

Undocumented infections were estimated to be half as infectious as symptomatic infections

RT-PCR positive 1-7 days before symptoms develop

Identified family members of known COVID patients

Found they were RT-PCR positive 1-7 days before symptom onset

Younger people more likely to have more mild symptoms

CT scans on enrollment (before symptom development) normal in ONLY 29%

Wang JID doi:10.1093/infdis/jiaa119

Bai JAMA doi: 10.1001/jama.2020.2565

Qian CID doi: 10.1093/cid/ciaa316

Evidence for truly asymptomatic transmission

Series of 24 “asymptomatic” individuals in Nanjing, China -- 70% develop symptoms or have CT findings consistent with COVID

Truly “asymptomatic” individuals more likely to be younger (median age = 14 years)

RT-PCR positive 9.5 - 21 days in this cohort (potential long period of transmission)

Of Diamond Princess cohort estimates as high as 17.9% -- but not clear they were followed long enough to exclude “pre-symptomatic” individuals

Sero-surveys will be essential to determining proportion of truly asymptomatic individuals

Estimating proportion of truly asymptomatic COVID-19

Hu Sci China Life Sci 2020 https://doi.org/10.1007/s11427-020-1661-4

Mizumoto Euro Surveill 2020 https://doi.org/10.2807/1560-7917.ES.2020.25.10.2000180

McMichael MMWR 3/18/20

COVID-19 in long-term care facility, King County WA

COVID-19 in long-term care facility, King County WA

“The perfect storm”

Contributing factors

Staff members who worked while symptomatic

Staff members who worked in more than one facility

Inadequate familiarity and adherence to standard, droplet, and contact precautions and eye protection recommendations

Challenges to implementing infection control practices including inadequate supplies of PPE and other items (e.g. EtOH hand sanitizer)

Delayed recognition of cases because of low index of suspicion, limited testing availability, and difficulty identifying persons with COVID-19 based on signs and symptoms alone

McMichael MMWR 3/18/20

Close Contact Secondary Attack Rate

Bi MedRxiv doi: 10.1101/2020.03.03.20028423

391 cases and 1,286 close contacts in Shenzhen

Secondary attack rate

Household 14.9% (12.1-18.2)

All close contacts 9.6% (7.9-11.8)

Risk factors in MV analysis

Household contact (OR 6.3, 1.5-26.3)

Co-travelling (OR 7.1, 1.4-34.9)

Burke MMWR 69:9

10 cases and 445 close contacts in United States

Symptomatic secondary attack rate

Household 10.5% (2.9-31.4)

All close contacts 0.45% (0.12-1.6%)

Spectrum of Clinical Presentation

Spectrum of Clinical Presentation of SARS-CoV-2

Asymptomatic

Symptomatic, mild

Symptomatic, severe with spontaneous recovery

Symptomatic, severe with development of an ARDS-proinflammatory syndrome

Presenting symptoms

Compiled from series of hospitalized patients

The spectrum of symptoms for people with mild infection may be different

Other studies suggest GI symptoms quite common

Fever

44-99%

Cough

59-82%

Myalgias

11-44%

Fatigue

>35%

Sore throat

<20%

Nausea/vomiting/diarrhea

3-10%

Headache

<10%

Rhinorrhea

<5%

Guan NEJM DOI: 10.1056/NEJMoa2002032

Chen Lancet doi: 10.1016/S0140-6736(20)30211-7

Wang JAMA doi: 10.1001/jama.2020.1585

Huang Lancet doi: 10.1016/S0140-6736(20)30183-5

Pan AJG 10.14309/ajg.0000000000000620

Radiology / Labs on Admission

Abnormal CT findings - 86%

Lymphopenia - 83%

Platelets <150,000 - 36%

CRP > 10 - 61%

Procalcitonin > 0.5 - 5.5%

LDH > 250 - 41%

AST/ALT elevated - 22/21%

Bili elevated - 11%

D-dimer > 0.5 mg/L 46%

Guan NEJM DOI: 10.1056/NEJMoa2002032

Shi Lancet 2020 doi: 10.1016/s1473-3099(20)30086-4

Wang JID doi:10.1093/infdis/jiaa119

CT abnormalities common for all hospitalized patients with COVID and may precede symptom onset

Siddiqi JHLT 2020 doi:10.1016/j.healun.2020.03.012

Zhou Lancet doi: 10.1016/50140-6736(20)30566-4

Typical course for critically ill patients

Risk Factors for Severe Disease

Risk Factors for Severe COVID-19 Disease

Epidemiological

Vital Signs

Labs

Older Age

Respiratory rate > 24 breaths/min

D-dimer > 1000 ng/mL

Pre-existing pulmonary disease

Heart rate > 125 beats/min

Elevated CPK

Chronic kidney disease

SpO2 < 90% on ambient air

Elevated CRP

Diabetes

SOFA score

Admission absolute lymphocyte count < 0.8

History of hypertension

Elevated LDH

History of cardiovascular disease

Elevated troponin

Use of biologics (presumed)

Elevated ferritin

History of transplant or other immunosuppression (presumed)

Elevated IL-6

HIV, CD4 cell count <200 or unknown CD4 count (presumed)

Evidence of “hyperinflammatory state”

Zhou Lancet 2020 https://doi.org/10.1016/S0140-6736(20)30566-3

Wang JAMA 2020 doi:10.1001/jama.2020.1585

Wu Nature doi: 10.1038/s41591-020-0822-7

Estimating Symptomatic Case Fatality Risk

Wu Nature doi: 10.1038/s41591-020-0822-7

Estimating Symptomatic Case Fatality Risk

Special Populations

Pregnancy

Li Emerg Inf Dis 26:6 2020

Case report - woman with mild COVID-19

LPV/r, methylpred

C-section at week 35

Infant OP, blood, urine negative up to day 2

Schwartz APLM doi: 10.5858/arpa.2020-0901-SA

38 pregnant women, no maternal or fetal deaths

All neonatal specimens (including placentas) negative for SARS-CoV-2

Chen Front. Pediatr 8:104 2020

4 infants born at term to mothers with COVID-19

3 out of 4 c-sections

3 out of 4 tested, all negative for SARS-CoV-2

Chen Lancet 2020; 395:809-15

9 infants born c-section to mothers with COVID-19

No evidence of vertical transmission

Korean Society of Infectious Diseases. J Korean Med Sci. 2020 Mar 16:35(10):e112

SARS-CoV-2 in children - South Korea

SARS-CoV-2 in children - China

1% of 72,314 cases

Of 1,391 children tested at Wuhan Children’s Hospital, 171 (12.3%) positive

Median age 6.7

Symptoms

Cough 49%

Pharyngeal edema 46%

Fever 42%

Diarrhea 9%

Rhinorrhea 8%

Vomiting 6%

3 children required ICU and mechanical ventilation, all with co-morbidities

One death

Lu NEJM DOI 10.1056/NEJMc2005073

Management

Summary of Treatment Trials/Cohorts to Date

Antivirals: Immunomodulators:

Lopinavir/ritonavir (LPV/r) Tocilizumab

Hydroxychloroquine (HCQ) IVIG (tiny series of 3 patients)

Hydroxychloroquine + azithromycin

Favipiravir (FPV)

Remdesivir (RDV) - currently under investigation

Interferon (no clinical data for COVID to date)

Lots of bad information (fake news?) out there

LPV/r vs control: open label RCT

Participants enrolled median of 13 days after symptom onset

No difference for clinical improvement (primary outcome)

Trend towards faster improvement in sub-group when started earlier (before 12 days of symptoms)

Fewer days in ICU (median 6 vs 11)

This implies that is not useful late in therapy, but needs to be studied earlier on in disease course

Hydroxychloroquine (HCQ)

Blocks viral entry and intracellular transport

Interim report (unclear how studied) from China reported efficacy and safety leading to expert consensus in China to recommend chloroquine for all patients with COVID-19

Tiny RCT in China, relatively mild patients, no difference HCQ versus not

Small non-randomized French clinical trial suggests faster viral clearance for HCQ

Wang Cell Research 2020

Covid19 Literature 3.25
Info
Tags Coronavirus, Study, Data, Symptoms, Patients, Virology, Literature
Type Google Slide
Published 27/03/2021, 12:23:03

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