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