Comprehensive COVID-19 Slideset:

Symptoms and Clinical Manifestations

Version 5 – August 8, 2022

This program is supported by an educational grant from Gilead Sciences, Inc.

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Faculty
Arthur Kim, MD
Associate Professor
Department of Medicine
Harvard Medical School
Director, Viral Hepatitis Clinic
Division of Infectious Diseases
Massachusetts General Hospital
Boston, Massachusetts
Sharon R. Lewin, AO, FRACP, PhD,
FAHMS
Director, The Peter Doherty Institute
for Infection and Immunity
Professor of Infectious Diseases
University of Melbourne
Consultant Infectious Disease
Physician, Alfred Hospital and Royal
Melbourne Hospital
Melbourne, Australia
Faculty
Kristen Marks, MD
Associate Professor of Medicine
Division of Infectious Diseases
Weill Cornell Medicine
New York, New York
Renslow Sherer, MD
Director
International HIV Training Center
Professor of Medicine
University of Chicago
Chicago, Illinois
Faculty Disclosures
Arthur Kim, MD, has disclosed that he is on the drug and safety monitoring board of
Kintor Pharmaceuticals.
Sharon F. Lewin, AO, FRACP, PhD, FAHMS, has disclosed that she has received
consulting fees from AbbVie, Gilead Sciences, and ViiV Healthcare; funds for research
support from Leidos; and other financial or material support from Gilead Sciences,
Merck, and ViiV Healthcare.
Kristen Marks, MD, has disclosed that she has received funds for research support
paid to Weill Cornell Medicine from Gilead Sciences.
Renslow Sherer, MD, has disclosed an unrestricted research grant from Gilead
Sciences.
Natural History, Symptom Spectrum,
and Possible Sequelae
 Primary Symptoms of COVID-19
Headache
Congestion or runny nose,
new loss of taste or smell
Cough, sore throat
“Symptoms may
appear 2-14 days Shortness of breath
after exposure to Fatigue, muscle or difficulty breathing
or body aches,
the virus” fever or chills

Nausea or
vomiting, diarrhea

Li. J Med Virol. 2020;92:577.

cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html Slide credit: clinicaloptions.com
 Pulmonary Sequelae
 Diffuse alveolar damage noted in Macroscopic and Histologic Lung Findings2
multiple, small postmortem
studies of COVID-19
‒ N = 38 from northern Italy1
‒ N = 10 from Germany2
 Platelet–fibrin thrombi indicative
of coagulopathy observed in
small arterial vessels of some
patients1

1. Carsana. Lancet Infect Dis. 2020;20:1135. 2. Schaller. JAMA. 2020;323:2518. Slide credit: clinicaloptions.com
 Long-term Lung and Bone Ramifications of
Hospital-Acquired SARS Infection
 Prospective, observational cohort study of medical staff infected with SARS in
2003; 15-yr follow-up of lung and bone outcomes via pulmonary CT scans
and function tests, hip joint MRIs and function questionnaires (N = 71)
‒ Percentage of lung area with pulmonary lesions diminished from 9.4% to
3.2% in first yr (P <.001), then stabilized until last assessment in 2018
‒ Percentage of osteonecrotic volume by MRI of femoral head declined
substantially from 38.8% to 30.4% in first 2 yr (P = .0002), then slowly to
2013 and plateaued until last assessment in 2018
“Pulmonary interstitial damage and functional decline caused by SARS mostly
recovered, with a greater extent of recovery within 2 yr after rehabilitation.
Femoral head necrosis induced by large doses of steroid pulse therapy in
SARS patients was not progressive and was partially reversible.”
Zhang. Bone Res. 2020;8:8. Slide credit: clinicaloptions.com
 Extrapulmonary Manifestations of COVID-19
Neurologic
Dermatologic  Headaches  Ageusia
 Petechaie  Urticaria  Dizziness  Myalgia
 Livedo reticularis  Vesicles  Encephalopathy  Anosmia
 Erythematous rash  Pernio-like lesions  Guillain-Barré  Stroke

Cardiac Thromboembolism
 Takotsubo cardiomyopathy  Cardiogenic shock  Deep vein thrombosis
 Myocardial injury/myocarditis  Myocardial ischemia  Pulmonary embolism
 Cardiac arrhythmias  Acute cor pulmonale  Catheter-related thrombosis

Hepatic
Endocrine  Elevated ALT/AST
 Hyperglycemia  Elevated bilirubin
 Diabetic ketoacidosis
Renal
Gastrointestinal  Acute kidney injury
 Diarrhea  Abdominal pain  Proteinuria
 Nausea/vomiting  Anorexia  Hematuria

Gupta. Nat Med. 2020;26:1017. Elrobaa. Front Public Health. 2021;9:711616. Slide credit: clinicaloptions.com
 Cardiovasular Sequelae
 Prospective, observational cohort study sourcing recovered patients
from the University Hospital Frankfurt COVID-19 Registry (N = 100)1
‒ CV magnetic resonance performed at median 71 days from diagnosis
‒ Abnormal findings in 78% of patients, myocardial inflammation in 60%;
independent of preexisting comorbidities, severity of acute SARS-CoV-2
infection, and time from diagnosis
‒ Reduced left ventricular ejection fraction, increased left ventricle volumes
and native T1/T2 vs risk-matched controls
“There are no data on how acute treatment of COVID-19 may affect . . . long-term
cardiac recovery and function. Patients with ostensibly recovered cardiac function
may still be at risk of cardiomyopathy and cardiac arrhythmias.”2
1. Puntmann. JAMA Cardiol. 2020;5:1265. 2. Mitrani. Heart Rhythm. 2020;17:1984. Slide credit: clinicaloptions.com
 Neurologic Sequelae

Sensory Deficits: “Respiratory virus infections are

Olfactory and Gustatory Dysfunction associated with neurologic and
 Systematic review and meta-analysis psychiatric sequelae, including
including 24 studies of confirmed Parkinsonism, dementia, depression,
COVID-19 (N = 8438)1
posttraumatic stress disorder, and
‒ Pooled prevalence anxiety . . . Significant long-term
‒ Anosmia: 41.0%; ageusia: 38.2% neurologic and psychiatric sequelae
‒ Decreased among older patients have to be anticipated in COVID-19,
 “Not yet clear whether COVID-19–related
especially in survivors of severe
OGDs are transient or permanent”1 disease.”3
‒ In one prospective cohort (N = 3191),  Cognitive monitoring of recovered
resolution typical within 3 wk2 patients may be necessary
1. Agyeman. Mayo Clin Proc. 2020;95:1621. 2. Lee. J Korean Med Sci. 2020;35:e174. 3. Iadecola. Cell. 2020;183:16. Slide credit: clinicaloptions.com
Long COVID
 Long COVID (PASC) Dermatologic
 Petechaie
 Livedo reticularis Neurologic
 Headaches  Ageusia
 Postacute sequelae of  Erythematous rash
 Urticaria  Dizziness  Myalgia
 Encephalopathy
COVID-19  Vesicles
 Pernio-like lesions  Guillain-Barré


Anosmia
Stroke

 New symptoms that affect Cardiac

 Takotsubo cardiomyopathy
Thromboembolism
 Deep vein thrombosis
everyday function, emerge  Myocardial injury/myocarditis
 Cardiac arrhythmias
 Pulmonary embolism

within 4 wk to 3 mo after first  Cardiogenic shock

 Catheter-related thrombosis

being infected and last for at  Myocardial ischemia

 Acute cor pulmonale
Hepatic
 Elevated ALT/AST
least 2 mo  Elevated bilirubin

Pulmonary
‒ Symptoms may fluctuate over  Chronic cough Renal
 Acute kidney injury
time  Shortness of breath
 Pulmonary fibrosis
 Proteinuria
 Hematuria

‒ Overlap with prolonged

symptoms post hospitalization Endocrine
 Hyperglycemia
 Diabetic ketoacidosis
Gastrointestinal
 Diarrhea  Abdominal pain
 Nausea/vomiting  Anorexia

www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1.
www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html. Slide credit: clinicaloptions.com
 Updated
US Prevalence of Long COVID
Estimated Long COVID Cases Estimated and Cumulative Long COVID Cases

COVID-19 surviving cases Estimated long COVID cases

80,000,000

60,000,000

Cases
40,000,000

20,000,000

0
Jul 2020 Jan 2021 Jul 2021 Jan 2022

 Most patients improve over 6 mo

>2,000,000 cases >100,000-500,000 cases
>1,000,000-2,000,000 cases <100,000 cases  Number of chronically ill patients is smaller
>500,000-1,000,000 cases (1%-5% of all people with COVID-19)
American Association of Physical Medicine and Rehabilitation. pascdashboard.aapmr.org/.
 Potential Causes of Long COVID
 Direct neuro-invasion PULMONARY CARDIOVASCULAR
Alveolar + epithelial damage RAAS dysregulation

 Dysregulated immune response Micro- and macrothrombosis Viral/inflammatory myocarditis

IL-6 and TGF-β damage Conduction system fibrosis
Myofibroblast proliferation Acute MI ± new HF
POTS
 Auto-inflammation Abnormal PFTs
NEUROLOGIC
Viral neurotoxicity
Inflammatory neurotoxicity
 Post-ICU syndrome Microvascular thrombosis
Neurodegeneration?

 Lingering virus in
HEMA-
immunologically privileged sites RENAL
TOLOGIC

 Endothelial injury, ongoing IMMUNOLOGIC

Autoimmune antibodies
ENDOCRINE
Thyroiditis

endothelial dysfunction Change in T-cell subsets

Immunosenescence?
Diabetes type 1 and 2
Menstrual cycle irregularity
Viral persistence? GI dysregulation
MIS-C

Akselrod. IDWeek 2021. Chasing the Sun presentation.

www.sciline.org/covid-19/emerging-challenges/. Proal. Front Microbiol. 2021;12:698169. Slide credit: clinicaloptions.com
 Risk Factors for Long COVID
 Risk factors for long COVID at
the time of COVID-19 diagnosis:
Long COVID
anticipating
factors ‒ Type 2 diabetes
Single-cell
multiomics ‒ Circulating SARS-CoV-2 viremia
Auto- Plasma SARS-CoV-2 RNAemia
antibodies multiomics and other virus viremia ‒ Epstein-Barr virus reactivation
‒ Certain autoantibodies
Viral load
‒ Type I interferons
Symptom surveys Autoantibodies and
Preexisting and EHR SARS-CoV-2 antibodies
conditions ‒ Associated with SLE

Su. Cell. 2022;185:881. Slide credit: clinicaloptions.com

 Long COVID Symptoms
Acute COVID-19
Post COVID-19 Mo 5
Post COVID-19 Mo 9
 N = 96 patients followed 12 mo n.d.
Post COVID-19 Mo 12

post COVID-19 hospitalization Fever Difficulty finding words n.d.

n.d.
Sore throat Sleeping problems
‒ Only 22% symptom free at 12 mo Vomiting/nausea
Headache

 Persistent symptoms: Diarrhea

Vertigo
Decrease in taste n.d.
‒ Poor exercise tolerance Anxiety
Anosmia n.d.
Hair loss
‒ Fatigue Cough
P <.05

Cold
Dyspnea
‒ Dyspnea P <.05
Body aches
Fatigue
P <.05
‒ Poor concentration Reduced exercise capacity
n.d. Shivering
n.d.
‒ Trouble finding words Concentration problems Palpitations

0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 70 80 90 100
Patients (%)
‒ Sleep disruption
Seeßle. Clin Infect Dis. 2022;74:1191. Slide credit: clinicaloptions.com
 Long COVID and COVID-19 Vaccination
Respiratory failure
Intubation/ventilation
Hypoxemia

 Long COVID can occur after a

Seizures
ICU admission
Psychotic disorder
Hair loss

breakthrough infection, but Death

Myocarditis
Urticaria
Myoneural junction/muscle disease

rates are consistently lower in Myalgia

Hypercoagulopathy/DVT/PE
Cerebral hemorrhage
Anosmia
vaccinated vs unvaccinated Nerve/nerve root/plexus disorder
Oxygen requirement
Ischemic stroke
Contribution
1.00

persons
Interstitial lung disease
Coronary disease
Fatigue 0.75
Other pain
Hospitalization
Cardiomyopathy 0.50

 2 doses of SARS-CoV-2 vaccine

Cognitive symptoms
Peripheral neuropathy
Arrhythmia 0.25
Kidney disease

is protective against some

Liver disease
Cardiac failure 0
Sleep disorders
Abnormal breathing

postacute sequelae of COVID- Type 2 diabetes mellitus

Obesity
Chest/throat pain
Joint pain
19, but not all Hypertension
Long COVID feature (any)
Hyperlipidemia
GERD
Abdominal symptoms
Mood disorder
Anxiety disorder
Headache
Anxiety/depression
0.6 0.7 0.8 0.9 1.0 1.2
HR
Kuodi. medRxiv. 2022;[Preprint]. Note: this study has not been peer reviewed.
Taquet. Brain Behav Immun. 2022;103:154. Slide credit: clinicaloptions.com
 Symptom Frequency in Vaccinated and Unvaccinated
Individuals
32 *
30 Uninfected
28 Vaccinated with 2-doses
26 Vaccinated with 1-dose
Symptom Frequency (%)

24 Unvaccinated
22 *
20
18
16 * *
14 *
12
10
8
6
4
2
Fatigue Headache Limb Muscle Loss of Hair Loss Insomnia Dizziness Persistent Shortness
Weakness Pain Concentration Cough of Breath
*Significantly less frequent among those vaccinated with two doses compared to those unvaccinated

Kuodi. medRxiv. 2022;[Preprint]. Note: this study has not been peer reviewed. Slide credit: clinicaloptions.com
 Long COVID Symptoms: Timelines

Majority of cases are self-limited Prolonged, relapsing

and resolve or improve in 3-6 mo symptoms may last >6 mo

0-4 wk >4-12 wk >12 wk >6 mo

 10%-30% of COVID-19 patients have chronic symptoms

‒ More common in younger female patients with mild initial illness
 More severe: post-hospitalization with major end-organ injury
‒ ARDS, AKI or CKD, PE or DVT, myocardial injury

Schmidt. Nat Biotechnol. 2021;39:908. Slide credit: clinicaloptions.com

 Predi-COVID Prospective Cohort Study
 Study goals
‒ Evaluate long COVID symptom frequency at 1 yr after acute SARS-CoV-2
infection according to initial disease severity
‒ Assess symptom co-occurrences
‒ Describe symptom resolution dynamic
‒ Determine long COVID impact on QoL
 289 patients completed a detailed self-reported questionnaire at 1 yr

Fischer. ECCMID 2022. Abstr L0413. Slide credit: clinicaloptions.com

 Predi-COVID: Symptom Frequencies According to
Initial Disease Severity
Overall Asymptomatic Mild Moderate/Severe
Loss of smell
Loss of taste
Runny nose
Pain in the sinuses
Pain in the ears
Sore throat

 59.5% of participants had

Eye tiredness
Memory loss
Mental confusion
Headaches

≥1 long COVID symptom at 1 yr

Migraines
Feeling sick
Tremor of limbs
Balance disorders
Conjunctival inflammation
Photophobia
Epileptic attacks

‒ Most frequent symptoms: fatigue, Fatigue

Irritability
Anxiety
34.3% 58.6%

shortness of breath, irritability

Muscle or joint pain in the lower limbs
Back pain Group
Tingling sensations in the limbs or on the skin ENT symptoms
Muscle or joint pain in the upper limbs Neurologic and
Sweats/chills ocular symptoms
Depression General symptoms
Cardiorespiratory

‒ Moderate/severe acute infection

Recurrent feeling of thirst
Hair loss symptoms or
Weight loss diseases
Gastrointestinal
Loss of appetite symptoms

associated with significantly higher

Walking difficulties Vascular/lymph
Newly appeared allergy node symptoms or
Fever diseases
Shortness of breath Urinary symptoms

rate of having ≥1 long COVID Feeling of tightness in the chest

Arrhythmia
Tachycardia
Skin symptoms

symptom vs asymptomatic
Chest pain
Wheezing
Dry cough
Burning sensation in the chest

infection (82.8% vs 38.6%; P <.001) Fatty cough

Heart failure
Myocarditis
Bloody sputum
Stomach burn
Other abdominal pain

 Symptoms not resolved after Nausea

Diarrhea
Vomiting
Circulation disorders

15 wk were more likely to persist Hypertension

Hematomas
Hypotension
Lymphadenopathy

up to 1 yr Urinary tract infections

Urinary pain
Dry skin
Skin rashes
Blue/purple/white or swollen fingers or toes

0 20 40 60 0 20 40 60 0 20 40 60 0 20 40 60
Participants (%)

Fischer. ECCMID 2022. Abstr L0413. Slide credit: clinicaloptions.com

 Predi-COVID: Co-occurrences of
20 Most Frequent Symptoms

Feeling of tightness in the chest

the limbs or on the skin

Tingling sensations in

Circulation disorders
Muscle or joint pain

Muscle or joint pain

Shortness of breath

in the upper limbs

in the lower limbs
Mental confusion
Eye tiredness

Memory loss

Sweats/chills
Loss of smell
Arrhythmia

Feeling sick
Headaches
Migraines
Irritability

Back pain

Dry skin
Anxiety

Fatigue
Irritability 100 55.8 46.3 43.4 50.8 46.2 40.4 42.3 36.5 32.7 34.6 44.2 32.7 30.8 17.3 38.5 36.5 30.8 25 26.9

Anxiety 55.8 100 35.2 34.3 44.6 43.3 37 45.7 32.6 32.6 37 39.1 32.6 32.6 10.9 39.1 30.4 28.3 23.9 23.9

Shortness of breath 46.3 35.2 100 38.4 47.7 40.7 38.9 38.9 29.6 31.5 37 33.3 48.1 38.9 18.5 22.2 27.8 24.1 20.4 18.5

Fatigue 43.4 34.3 38.4 100 53.5 39.4 38.4 36.4 29.3 30.3 36.4 34.3 24.2 28.3 15.2 28.3 28.3 27.3 25.3 20.2

Eye tiredness 50.8 44.6 47.7 53.5 100 50.8 49.2 49.2 33.8 30.8 32.3 38.5 27.7 33.8 21.5 30.8 29.2 26.2 29.2 29.2

Mental confusion 46.2 43.5 40.7 39.4 50.8 100 73.3 53.3 37.8 37.8 40 40 31.1 33.3 22.2 42.2 26.7 26.7 40 40

Memory loss 40.4 37 38.9 38.4 49.2 73.3 100 48.9 31.1 35.6 37.8 37.8 26.7 35.6 24.4 40 24.4 20 33.3 26.7

Headaches 42.3 45.7 38.9 36.4 49.2 53.3 48.9 100 52.3 34.1 24.4 25 27.3 29.5 20.5 31.8 31.8 29.5 22.7 31.8

Migraines 36.5 32.6 29.6 29.3 33.8 37.8 31.1 52.3 100 36.8 24.4 32.6 28.2 26.3 13.5 36.8 24.3 29.7 25.1 37.8

Muscle or joint pain in the upper limbs 32.7 32.6 31.5 30.3 30.8 37.8 35.6 34.1 36.8 100 68.9 60.5 41 47.4 21.1 50 26.3 31.6 28.9 34.2

Muscle or joint pain in the lower limbs 34.6 37 37 36.4 32.3 40 37.8 24.4 24.4 68.9 100 66.7 42.2 37.8 17.8 48.9 33.3 37.8 28.9 22.2

Back pain 44.2 39.1 33.3 34.3 38.5 40 37.8 25 32.6 60.5 66.7 100 37.2 34.9 18.6 41.9 32.6 37.2 32.6 27.9

Feeling of tightness in the chest 32.7 32.6 48.1 24.2 27.7 31.1 26.7 27.3 28.2 41 42.2 37.2 100 51.3 20.5 28.2 28.2 25.6 12.8 17.9

Arrhythmia 30.8 32.6 18.9 28.3 33.8 33.3 35.6 29.5 26.3 47.4 37.8 34.9 51.3 100 15.8 39.5 31.6 28.9 31.6 26.3

Loss of smell 17.3 10.9 18.5 15.2 21.5 22.2 24.4 20.5 13.5 21.1 17.8 18.6 20.5 15.8 100 10.5 17.6 20.7 16.7 20.7

Tingling sensations in the limbs or on the skin 38.5 39.1 22.2 28.3 30.8 42.2 40 31.8 36.8 50 48.9 41.9 28.2 39.5 10.5 100 39.5 42.1 36.8 36.8

Dry skin 36.5 30.4 27.8 28.3 29.2 26.7 24.4 31.8 24.3 26.3 33.3 32.6 28.2 31.6 17.6 39.5 100 38.2 38.2 23.5

Sweats/chills 30.8 28.3 24.1 27.3 26.2 26.7 20 29.5 29.7 31.6 37.8 37.2 25.6 28.9 20.7 42.1 38.2 100 30 27.6

Circulation disorders 25 23.9 20.4 25.3 29.2 40 33.3 22.7 35.1 28.9 28.9 32.6 12.8 31.6 16.7 36.8 38.2 30 100 30

Feeling sick 26.9 23.9 18.5 20.2 29.2 40 26.7 31.8 37.8 34.2 22.2 27.9 17.9 26.3 20.7 36.8 23.5 27.6 30 100

Fischer. ECCMID 2022. Abstr L0413. Slide credit: clinicaloptions.com

 Predi-COVID: Quality of Life
Disease Severity at Inclusion
QoL Measure, n (%) Overall
Population P
Asymptomatic Mild Moderate/Severe Value
Poor sleep 155 (54.2) 17 (38.6) 93 (54.1) 37 (63.8) .04
Altered respiratory
QoL at 1 yr 37 (12.9) 0 16 (9.3) 18 (31.0) <.001

Could not live in current

health status long term 36 (12.5) 4 (9.1) 22 (12.6) 9 (15.5) .655

Fischer. ECCMID 2022. Abstr L0413. Slide credit: clinicaloptions.com

 Clinical Management of Long COVID
 Long COVID conditions can be managed by primary care providers
‒ Patient-centered approaches to optimize QoL and function
 Laboratory values and imaging are not the only measure of a patient’s well-being
‒ Lack of abnormalities does not invalidate a patient’s symptoms
Conservative diagnostic Majority of cases are self-limited and Prolonged, relapsing symptoms may last >6 mo
approach; most cases will resolve resolve or improve in 3-6 mo

0-4 wk >4-12 wk >12 wk >6 mo

 Set achievable goals via shared decision-making

‒ Specific symptom amelioration
‒ Management plan to improve physical, mental, and social well-being
www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-clinical-eval.html.
www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-management.html. Slide credit: clinicaloptions.com
 Long COVID Treatments Under Consideration
 Investigational agents for long COVID  Currently available drugs being studied to
‒ LYT-100 treat long COVID
‒ Deuterated pirfenidone ‒ Budesonide (inhaled)

‒ Leronlimab ‒ Colchicine
‒ CCR5 antagonist ‒ Fluvoxamine
‒ LMWF5A ‒ Monoclonal antibodies
‒ Anti-inflammatory peptide ‒ NSAIDS
‒ SNG001 ‒ SARS-CoV-2 vaccination
‒ Inhaled interferon beta ‒ Sirolimus
‒ Statins
‒ Vitamin D

Schmidt. Nat Biotechnol. 2021;39:908. Slide credit: clinicaloptions.com

Coagulopathy in COVID-19
 Laboratory Predictors of Thrombosis in COVID-19
No Thrombotic No Thrombotic
Thrombotic Thrombotic
Median Value or Bleeding Complication P Value Median Value or Bleeding Complication P Value
Complication Complication
(n = 347) (n = 38) (n = 347) (n = 38)

D-dimer, ng/mL ESR, mm/hr

 Initial 891 1538 .0002  Initial 38 47 .020
 Minimum 760 1336 .0006  Minimum 36 43 .079
 Peak 1377 4001 <.0001  Peak 56 91 .0077

Fibrinogen, mg/dL Ferritin, μg/L

 Initial 579 696 .0045  Initial 504 825 .015
 Minimum 549 669 .0028  Minimum 453 750 .0056
 Peak 662 828 .0001  Peak 707 1182 .0020

CRP, mg/L
 Initial 63.3 124.7 .0011
 Minimum 35.4 94.2 <.0001
 Peak 130.3 277.7 <.0001

Al-Samkari. Blood. 2020;136:489. Slide credit: clinicaloptions.com

 COVID-19 Coagulopathy: Thromboinflammation

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This research was originally published in Blood. Jackson. Thromboinflammation: challenges of therapeutically targeting
coagulation and other host defense mechanisms. Blood. 2019;133:906. © The American Society of Hematology. Slide credit: clinicaloptions.com
 Endotheliitis
 Postulated to be a central feature of pathophysiology1
 SARS-CoV-2 binds to host cells via the ACE2 receptor1,2
 High density of ACE2 receptors on endothelial cells1,2
 Endotheliitis and viral inclusions in endothelial cells have been reported
in COVID-19 autopsy series2

1. Ackermann. NEJM. 2020;383:120. 2. Varga. Lancet. 2020;395:1417. Slide credit: clinicaloptions.com

 Virchow’s Triad in COVID-19

Platelet activation
Viral RNA
Vascular DNA-NETs
endotheliitis VWF
Factor Xla
Thrombin-fibrin

Endothelial dysfunction
Altered blood flow

Becker. J Thromb Thrombolysis. 2020;15:1. Slide credit: clinicaloptions.com

 Autopsy Evidence of Lung Damage in COVID-19
 Prospective study to compare Alveolar Damage2
clinical findings with data from
autopsy (N = 12)1
‒ 7/12 patients had unsuspected
bilateral DVT
‒ 4/7 died from PE Organizing Microthrombus2

1. Wichmann. Ann Intern Med. 2020;173:268. 2. Carsana. Lancet Infect Dis. 2020;20:1135. Slide credit: clinicaloptions.com
 Anticoagulant Therapy in Patients With
Severe COVID-19 and Coagulopathy
 Single-center, retrospective study in 28-Day Mortality Stratified by SIC Score*
Wuhan, China, compared 28-day and D-Dimer Levels†
mortality with prophylactic heparin 80 Heparin users (n = 99)
or low-molecular-weight heparin for 70 P = .029 Heparin nonusers (n = 350)
P = .011
≥7 days vs no heparin or heparin for 60

Mortality (%)
P = .017
<7 days in patients with severe COVID-19 50
(N = 449) 40
30
‒ Severe COVID-19: RR ≥30 breaths/min, 20
SaO2 ≤ 93% at rest, or PaO2/FiO2 ratio 10
≤300 mm Hg 0

LN

>6 N

>8 N
LN
≥4

<4

>2 N
LN

>4 N
LN
‒ No difference in 28-day mortality between

UL

L
L

UL
xU

xU
xU
xU

xU

xU
SIC
SIC

5x
3x
heparin users and nonheparin users in

≤1

>1

>
>
er

er

er

er
er

er

er

er
overall population (30.3% vs 29.7%; P

m
m

m
Di

Di

Di

Di
Di

Di

Di

Di
= .910)

D-

D-

D-

D-
D-

D-

D-

D-
*SIC score includes PT, platelet count, and SOFA. †ULN = 0.5 μg/mL
Tang. J Thromb Haemost. 2020;18:1094. Slide credit: clinicaloptions.com
 Treatment Dose Anticoagulation and
In-Hospital Survival Among Patients With COVID-19
 Single-center, retrospective study at  Longer duration of TDAC associated
Mount Sinai Health System, New York, with reduced mortality risk (aHR*:
compared survival with treatment 0.86/day; 95% CI: 0.82-0.89; P <.001)
dose anticoagulation vs prophylactic
TDAC No TDAC
dose or no anticoagulation in Outcome
(n = 786) (n = 1987)
hospitalized patients with COVID-19,
In-hospital mortality, % 22.5 22.8
March 14 - April 11, 2020 (N = 2773)
Median survival, days 21 14
‒ Median hospitalization duration: Mechanical ventilation, % 29.8 8.1†
5 days  In-hospital mortality, % 29.1 62.7
 Median survival, days 21 9
‒ Median anticoagulation duration:
Major bleeding, % 3 1.9
3 days

*Adjusted for age, sex, ethnicity, BMI, history of hypertension, heart failure, atrial fibrillation, type 2 diabetes, anticoagulation use prior to
hospitalization, and admission date. †P <.001.

Paranjpe. JACC. 2020;76:122. Slide credit: clinicaloptions.com

 Prophylactic Dose vs Therapeutic Dose
Anticoagulation in COVID-19
 Retrospective, 2-center, cohort study comparing in-hospital mortality with
prophylactic vs therapeutic AC dosing of enoxaparin or heparin begun preemptively
at admission, April 1-25, 2020 (N = 374)
‒ Excluded therapeutic AC for thrombotic indication; prophylactic AC group received only
prophylactic dosing for whole inpatient duration

Outcome Prophylactic Dose AC Therapeutic Dose AC

(n = 299) (n = 75)
In-hospital mortality, % 14.4 38.7
Crude risk ratio (95% CI) 2.7 (1.8-4.0)
 P value <.001
Adjusted risk ratio* (95% CI) 2.3 (1.0-4.9)
 P value .04
*Full logistic model included AC dosage, age, ethnicity, diabetes, history of heart disease or cancer, hyperlipidemia, intensive care, peak CRP,
mechanical ventilation, and antibiotic use.
Motta. Crit Care Explor. 2020;2:e0309. Slide credit: clinicaloptions.com
 High-Dose Anticoagulation in Severe COVID-19:
Retrospective Observational Study Design
 538 consecutive adult patients  French national guidelines
admitted to 8 ICUs in France, for published on April 3, 2021, expanded
PCR-confirmed, severe COVID-19 recommendations for high-dose
thromboprophylaxis to additional risk
 Received thromboprophylaxis during groups, including severe COVID-19
≥1 of 6 predefined time periods from pneumonia requiring oxygen by
ICU admission through ICU Day 14 HFNC or invasive ventilation
 Primary outcome: incidence of ‒ Permitted pre/post comparison
thrombotic complications of standard vs high-dose
thromboprophylaxis with LMWH or
 Data collected from March 21 to UFH in patients with COVID-19 in ICU
April 10, 2021
‒ High-dose arm included
intermediate- or therapeutic-dose
anticoagulation
Tacquard. Chest. 2021;159:2417. Slide credit: clinicaloptions.com
 High-Dose Anticoagulation in Severe COVID-19:
Baseline Characteristics and Thrombotic Events
 538 participants at baseline: Cumulative
Incidents,
Thrombosis Type Incidence, %
n (%)
‒ 389 (73%) males (95% CI)
All thromboses* 122 (100) 22.7 (19.2-26.3)
‒ Median age: 63 yr (IQR: 55-71)  PE 64 (52) 12.0 (9.2-14.7)
 DVT 18 (15) 5.0 (2.7-7.3)
 Catheter 14 (11) 3.9 (1.9-5.9)
‒ Median BMI: 29 (IQR: 26.0-33.0)  Stroke 4 (3) 1.1 (0.1-2.2)
 Other 2 (2) 0.5 (0-1.3)
 At ICU admission, median D-dimer  Infarctions
‒ Mesenteric 1 (2) 0.2 (0-0.8)
levels significantly higher in patients ‒ Myocardial 1 (1) 0.2 (0-0.8)
 Medical device
who developed TC (2.59 mg/L; ‒ CRRT filter 13 (11) 22.8 (11.8-33.7)
IQR: 1.30-7.72) vs those without ‒ ECMO 5 (4) 11.6 (1.9-21.3)
TC (1.5 mg/L; IQR: 0.99-2.97)
‒ Remained significantly higher during *Data from 538 patients; for PE, DVT, catheter, stroke, and other
thromboses, n = 360 (one center did not submit data).
14 days in ICU

Tacquard. Chest. 2021;159:2417. Slide credit: clinicaloptions.com

 High-Dose Anticoagulation in Severe COVID-19:
Results
 High-dose thromboprophylaxis Multivariate
Risk Factors
associated with reduced risk of TC Associated Analysis P Value
Odds Ratio
(HR: 0.81; 95% CI: 0.66-0.99) With TC (95% CI)
‒ No increased risk of bleeding vs Higher D-dimer
standard dose level at ICU 1.45 (1.10-1.91) .01
admission
 Cumulative exposure to high-dose Requiring
2.35 (0.99-5.57) <.05
thromboprophylaxis was associated ECMO*
with reduction in PE incidence
(HR: 0.72; 95% CI: 0.53-0.98) *25 patients received ECMO in those with TC vs 19 in those without TC.

 Cumulative exposure to high-dose  No increased risk of TC in obese

thromboprophylaxis not associated patients, suggesting high-dose
with reduced mortality at Day 14 thromboprophylaxis effective in this
(HR: 1.12; 95% CI: 0.78-1.62) high-risk group
Tacquard. Chest. 2021;159:2417. Slide credit: clinicaloptions.com
 Guidance on Thromboprophylaxis
Recommending Organization*
NIH1
 Hospitalized adults with COVID-19 should receive
prophylactic dose anticoagulation
 Anticoagulant or antiplatelet therapy should not be used
to prevent arterial thrombosis outside of the usual SoC
for patients without COVID-19
 Currently insufficient data to recommend for or against
the use of thrombolytics or increasing anticoagulant
doses for VTE prophylaxis in hospitalized COVID-19
patients outside of clinical trial
 Hospitalized patients should not be routinely discharged
on VTE prophylaxis (extended VTE prophylaxis can be
considered in patients with low bleeding risk and high
VTE risk)
ASH2
 All hospitalized adults with COVID-19 should receive
thromboprophylaxis with low-molecular-weight heparin
over unfractionated heparin, unless bleeding risk
outweighs thrombosis risk
 Fondaparinux is recommended in the setting of
heparin-induced thrombocytopenia
 In patients in whom anticoagulants are contraindicated
or unavailable, use mechanical thromboprophylaxis (eg,
pneumatic compression devices)
 Full-dose, rather than prophylactic dose,
anticoagulation should be used in patients with acute
COVID-19 even if no suspected or confirmed VTE or
other indication for anticoagulation

*Additional recommendations available from the International Society on Thrombosis and Haemostasis, 3 and CHEST.4

1. NIH. COVID-19 Treatment Guidelines. Antithrombotic therapy in patients with COVID-19. Last updated May 31, 2022.
2. American Society of Hematology. COVID-19 and VTE/anticoagulation: FAQs. Last updated February 2, 2022.
3. Spyropoulos. J Thromb Haemost. 2020;18:1859. 4. Moores. Chest. 2020;158:1143. Slide credit: clinicaloptions.com
Duration of Immunity
 Potential Immune Correlates of Protection to
SARS-CoV-2 Infection
SARS-Cov-2 Innate Immune Adaptive Immunity Immune Memory
Infection Response to SARS-CoV-2
TH Cytokine production Memory T-cell
Treg Regulation of inflammation
Memory B-cell
DC activation and CTL Killing of infected cells
uptake of viral
antigens TFH Induction of antibodies

Days/Weeks B-cell Plasma cell

Weeks/Months
Months/Years

Cox. Nat Rev Immunol. 2020;20:581. Slide credit: clinicaloptions.com

 Omicron Neutralization Activity After Vaccination
 28 days after a third vaccine
Victoria Delta Omicron
dose, neutralization titers are

FRNT50 (Reciprocal Serum Dilution)

P <0.0059 (1.9X) P <0.0001 (2.7X) P <0.0001 (2.7X)
lower for omicron compared 104
390 723
104
75 206
104
21 57

with victoria and delta 103 103 103

102 102 102

 Neutralization titers against 101 101 101

omicron are increased after 100

V2+28 V3+28
100
V2+28 V3+28
100
V2+28 V3+28

a third vaccine dose Victoria Delta Omicron

P <0.0001 (4.6X) P <0.0001 (8.3X) P <0.0001 (34.2X)
‒ Booster vaccines should be

FRNT50 (Reciprocal Serum Dilution)

P <0.0001 (22.3X) P <0.0001 (63.2X) P <0.0001 (49.9X)
P <0.0001 (25.4X) P <0.0001 (77.9X) P <0.0001 (59X)

encouraged for protection 105

104
1993 413 363 9219 105
104
282 37 30 2337 105
104
19 13 11 649

against omicron infection 103 103

102
103
102
102
101 101 101
100 100 100
V2+28 V2+6M Pre-V3 V3+28 V2+28 V2+6M Pre-V3 V3+28 V2+28 V2+6M Pre-V3 V3+28

Dejnirattisai. Cell. 2022;185:467. Slide credit: clinicaloptions.com

 T-Cell Response Following Vaccination
 COVID-19 vaccination may provide protection against hospitalization due to the omicron
variant despite decreased antibody neutralization
‒ COVID-19 vaccination elicits highly cross-reactive T-cells capable of recognizing multiple VOC
Ad26.COV2.S BNT162b2
10 1
101
%IFN+ / CD8+ T-Cells

%IFN+ / CD8+ T-Cells

100 100
10-1 10-1
10-2 10-2
10-3 10-3
A a n A a n A on
W Delt icro W Delt icro W ic r
Om Om Om
Month 1 Month 8 Month 8
Time Following Immunization
Liu. medRxiv. 2022;[Preprint]. Note: This study has not been peer reviewed. Slide credit: clinicaloptions.com
Coinfections and COVID-19
 Bacterial Coinfection in SARS-CoV-2 vs Influenza A/B
Cohorts: Retrospective Study in the UK, 2019-2020
 Blood culture positivity and bacteremia SARS-CoV-2 Influenza A/B
rates statistically similar between groups Blood Culture (n = 643) (n = 133)
Results, n
‒ SARS-CoV-2 group: 643/836 patients had CA HCAI CA HCAI
blood cultures Respiratory
1 1 2 0
bacteremias
‒ Blood culture positive: 9.3% (60/643)
Nonrespiratory 11 8 0 0
‒ True bacteremia: 3.3% (21/643) bacteremias
No growth 583 133
‒ 2 respiratory, 3 central line, 16 unrelated
nonrespiratory
Contaminants* 36 6

‒ Influenza group: 133/216 patients had *Coagulase negative Staphylococci.

blood cultures
‒ Blood culture positive: 6% (8/133)
‒ True bacteremia: 1.5% (2/133)
Hughes. Clin Microbiol Infect. 2020;26:1395.
 Among patients with SARS-CoV-2 (pre-
omicron era), relative risk of death with
true pathogens in blood vs baseline
admitted patients: 1.51 (P = .3543)
Slide credit: clinicaloptions.com
 Bacterial Coinfection in SARS-CoV-2 vs Influenza A/B
Cohorts: Outcomes
 Respiratory culture positivity rates Influenza
statistically similar between groups SARS-CoV-2 A/B
Respiratory (n = 112) (n = 38)
‒ SARS-CoV-2 group: 34.8% Culture Results, n
(39/112 tested) CA HCAI CA HCAI
‒ Influenza group: 21.1% (8/38 tested) Bacterial 13 24 4 4
 No patients in SARS-CoV-2 group were Fungal
 Candida spp* 10 14 0 7
coinfected with influenza or RSV (0/250  Aspergillus spp 1 2 0 1
tested)
No growth
*Deemed 64 not treated.
contaminants from the oropharynx; 22
 Among patients with SARS-CoV-2 (pre-
omicron era), relative risk of death with
positive sputum culture vs baseline
admitted patients: 0.90 (P = .8462)
Hughes. Clin Microbiol Infect. 2020;26:1395. Slide credit: clinicaloptions.com
 Community-Acquired vs Hospital-Acquired
Coinfections in Spanish COVID-19 Cohort
 Retrospective analysis of hospitalized patients with COVID-19: N = 989
No Coinfection CA Coinfection Pa Value vs No HA Pb Value vs No
Baseline Characteristic Superinfection*
(n = 917) (n = 31) Coinfection (n = 43) Coinfection

Median age, yr (IQR) 61 (48-74) 63 (54.5-74) .671 67 (55.8-74.3) .006

Male sex, n (%) 51.0 (55.6) 18 (58.1) .956 26 (60.5) .822
Comorbidities,† n (%)
 CKD 47 (5.1) 8 (25.8) <.001 6 (14) .013
 Cancer 77 (8.4) 1 (3.2) .259 8 (18.6) .021

Inflammatory markers,
median (IQR)
 CRP 7.06 (3.3-13.3) 6.8 (3.2-9.8) .714 11.8 (5.6-17.9) .012
 Ferritin 544 (150-1100) 208 (154-432) .042 797 (296-1743) .575
 Lymphocytes 0.9 (0.6-1.2) 0.8 (0.6-1.1) .892 0.783 (0.5-1.1) .088
 Lactate dehydrogenase 287 (233-372) 264 (221-378) .477 311.5 (248-472) .193

*2 patients with CA infection developed HA superinfection. †Other comorbidities (HTN, DM, CVD, COPD) not significantly different between
those with and without coinfection.

Garcia-Vidal. Clin Microbiol Infect. 2021;27:83. Slide credit: clinicaloptions.com

 Community-Acquired vs Hospital-Acquired
Coinfections in Spanish COVID-19 Cohort: Outcomes
 3.1% (31/989) CA coinfection rate  4.3% (43/989) HA superinfection rate
lower than expected from past associated with longer hospital stays,
influenza pandemics1,2 and not more ICU admissions, and higher
associated with higher mortality mortality rate
No Pa Value vs No HA Pb Value vs No
CA Coinfection
Outcome Coinfection (n = 31) Superinfection*
(n = 917) Coinfection (n = 43) Coinfection

Median hospital stay, days (IQR) 9 (5-15) 8 (4.5-11.5) .565 20 (11-27.8) <.001
ICU admission, n (%) 109 (11.9) 8 (25.8) .02 29 (67.4) <.001
Median time in ICU, days (IQR) 3 (1-10) 3 (0-9) .888 5 (0.5-20) .095
Death, n (%) 86 (9.4%) 5 (16.1) .21 8 (18.6) .047
*2 patients with CA infection developed HA superinfection.

1. Garcia-Vidal. Clin Microbiol Infect. 2021;27:83. 2. Martin-Loeches. Chest. 2011;139:555. Slide credit: clinicaloptions.com
Reinfection With SARS-CoV-2
 Duration of Viral Shedding in Patients With COVID-19
Before Omicron Era
 178 patients with confirmed SARS-CoV-2
infections identified by contact screening in Asymptomatic cases (n = 37)
Wanzhou District, China, by April 10, 2020 1.0 Symptomatic cases (n = 37)

Viral RNA Positive Rate (%)

 37/178 (20%) were asymptomatic in 0.8
the preceding 14 days and during the
in-hospital isolation period 0.6

 37 sex-, age-, and comorbidity-matched 0.4

controls identified among symptomatic
infections, also hospitalized for isolation 0.2
HR: 1.69 (1.06-2.70)
 Asymptomatic cases shed virus significantly 0 Log rank P = .028
longer than symptomatic cohorts 0 6 10 15 20 25 30 35 40 45
Duration of Viral Shedding (Days)
‒ Not known how long shed virus
remains infective
Long. Nat Med. 2020;26:1200. Slide credit: clinicaloptions.com
 CDC Remarks on Reinfection

“After recovering from COVID-19, “The risk of reinfection also depends on

most individuals will have some host susceptibility, vaccination status,
protection from repeat infections​ and the likelihood of re-exposure to
.” infectious cases of COVID-19.”
 The probability of reinfection may increase with time after recovery due to:
‒ Waning immunity
‒ Exposure to viral variants

CDC. Reinfection with COVID-19. Last updated January 20, 2022.

CDC. Ending Isolation and Precautions for People with COVID-19: Interim Guidance. Last updated January 14, 2022. Slide credit: clinicaloptions.com
 Assessing Disease Severity
and Risk Factors for Severe Disease
 NIH Guidelines: Defining a COVID-19
Severity Spectrum
Stage Characteristics
Asymptomatic or  Positive virologic test for SARS-CoV-2 (ie, NAAT or antigen test) but
presymptomatic infection no symptoms consistent with COVID-19
 Varied symptoms (eg, fever, cough, sore throat, malaise, headache,
Mild illness muscle pain, nausea, vomiting, diarrhea, loss of taste or smell) but
no shortness of breath, dyspnea, or abnormal chest imaging

Moderate illness  SpO2 ≥94% on room air at sea level and lower respiratory disease
evidenced by clinical assessment or imaging

Severe illness  SpO2 <94% on room air at sea level, PaO2/FiO2 <300 mm Hg,
respiratory rate >30 breaths/ min, or lung infiltrates >50%
Critical illness  Respiratory failure, septic shock, and/or multiorgan dysfunction

NIH COVID-19 Treatment Guidelines. Clinical spectrum of SARS-CoV-2 infection. Last updated August 8, 2022. Slide credit: clinicaloptions.com
Population Mortality and Fatality Trends
 Terminology
Measure Numerator Denominator Reported as
Mortality (general Number of deaths Total population Usually per 100,000 persons
definition) due to specific cause
CDC-reported Number of deaths Total number % (multiplied by 100)
COVID-19 mortality due to COVID-19 of deaths

Case-fatality rate Number of deaths Total COVID-19 % (multiplied by 100)

due to COVID-19 cases

CDC. Principles of Epidemiology in Public Health Practice, Third Edition. An Introduction to

Applied Epidemiology and Biostatistics. cdc.gov/csels/dsepd/ss1978/lesson3/section3.html. Slide credit: clinicaloptions.com
 Updated
Case-Fatality Rates by Country
 Mortality differences among countries Observed Case-Fatality Rates (August 8, 2022)
and time periods could be caused by Peru 5.4

differences in: Mexico

Colombia 2.2
4.8

Russia 2.0
‒ Testing  countries only test people Brazil 2.0
Iran 1.9
with severe symptoms; the case fatality India 1.2
rate will be higher than one with United States 1.1
Spain 0.8
widespread testing for asymptomatic Italy 0.8
cases United Kingdom 0.8
Greece 0.7
Thailand 0.7
‒ Demographics  mortality high Turkey 0.6

for older persons or persons with Germany

France
0.5
0.4
high-risk comorbidities Finland 0.4
Japan 0.2
Taiwan 0.2
‒ Healthcare system characteristics  Australia 0.1
hospital overwhelm, etc 0 1 2 3 4 5
Deaths (%)
‒ Unknown factors
coronavirus.jhu.edu/data/mortality Slide credit: clinicaloptions.com
 Updated
CDC: COVID-19 Reported Cases and Mortality
1.2M 4k
Solid lines depict 7-day moving averages
3.5k
1M
3k
800k
2.5k

Deaths
Cases

600k 2k

1.5k
400k
1k
200k
500

0 0
Jan 20 June 20 Nov 20 Apr 21 Sep 21 Mar 22 Aug 22
cdc.gov/coronavirus/2019-ncov/covid-data/covidview/index.html Slide credit: clinicaloptions.com
 Complexities of Calculating Mortality and
Case-Fatality Rates in Hospitals and ICUs
 Rates should be adjusted for the changing demographics of people
admitted over time, but these detailed data can be difficult to obtain
 Thresholds for hospital admission may have changed over time, with
less severely ill patients being admitted as space became less limited
‒ Potentially adjusted for in NYC dataset by adjusting for clinical and
laboratory values that reflect disease severity (eg, oxygen saturation,
C-reactive protein)

Horwitz. J Hosp Med. 2021;16:90. Slide credit: clinicaloptions.com

 Go Online for More CCO
Coverage of COVID-19!
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Frequently Asked Questions Module containing expert answers to questions on COVID-19

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