Post-Acute COVID-19 SyndromeMichael G. Risbano MD, MA

Co-Director UPMC Post-Covid Recovery Clinic

Director, Invasive Cardiopulmonary Exercise Testing Program

Head, Clinical Operations and Translational Research Pulmonary Hypertension

Pulmonary, Allergy, and Critical Care Medicine

University of Pittsburgh Medical Center

Overview

• Define Post-Acute Sequelae of COVID-19

• Epidemiology and Symptoms

• Pathophysiology

• Phenotyping

• Evaluation and Management

A name is a name is a name

• Long Covid

• Long Tail Covid

• Long Haul Covid-19

• Post-Covid Syndrome

• Post-Acute Sequelae of Covid-19 (PASC)

Post-Acute Sequelae of Covid-19 (PASC)

• No objective tests or biomarkers

• It is not the blood clots, myocarditis, multisystem inflammatory disease or pneumonia (disease states caused by COVID-19 infection)

• CDC, long Covid is “a range of symptoms that can last weeks or months…[that] can happen to anyone who has had Covid-19.”

• Symptoms may affect multiple organ systems, occur in diverse patterns, wax and wane and worsen after physical or mental activity.

Phillips et al. NEJM (2021) PMID: 34192429

Timeline of Post-Acute COVID-19

Nalbandian. Nature Medicine (2021) PMID: 33753937

Epidemiology and Symptoms

Post-Acute COVID-19 Study

Post-acute COVID-19 US study

• 60 days post-hospital discharge

• Gender and age not recorded

• n=488

• 6.7% deceased, 15.1% readmission

• 32.6% persistent symptoms

• 18.9% new or worsening symptoms

• DOE stairs 22.9%, cough 15.4%, loss taste/smell 13.1%

Post-acute COVID-19 Italian study

• n=142 hospitalized patients

• Follow-up 60 days from onset of first symptom

• Persistent symptoms 87.4%• Fatigue 53.1%• Dyspnea 43.4%• Joint pain 27.3%• Chest pain 21.7%• 55% had 3 or more of these symptoms

• 44.1% had a decline in QoL

Carfi. JAMA (2020) PMID: 32644129Chopra. AIM (2020) PMID: 33175566

UK Coronavirus Infection Survey

Post infection survey

• n=26,147 (+)PCR

• April 26, 2020 to August 1, 2021

• Questions• Month 1 weekly questions

• Months 2-12 monthly

• 1:1 match age, gender, pre-existing conditions

Symptoms in the past seven days:

1. Fever

2. Headache

3. Muscle ache

4. Weakness

5. Tiredness

6. Nausea

7. Abdominal pain

8. Diarrhoea

9. Sore throat

10. Cough

11. Shortness of breath

12. Loss of taste / loss of smell

https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/articles/technicalarticleupdatedestimatesoftheprevalenceofpostacutesymptomsamongpeoplewithcoronaviruscovid19intheuk/26april2020to1august2021 Accessed 9/15/2021

Percentage of study participants reporting any of 12 symptoms continuously

Group At least 5 weeks post infection At least 12 weeks post infection

Covid-19 Controls Covid-19 Control

All People 11.4 (7.3-17.7) 2.2 (0.9-5.3) 3.0 (1.9-4.6) 0.5 (0.2-1.1)

Males 9.8 (5.8-16.7) 2.0 (0.8-5.0) 2.6 (1.5-4.6) 0.4 (0.2-0.9)

Females 13.1 (8.1-21.3) 2.4 (1.0-5.8) 3.4 (2.2-5.5) 0.4 (0.2-0.7)

* 95% confidence intervals

https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/articles/technicalarticleupdatedestimatesoftheprevalenceofpostacutesymptomsamongpeoplewithcoronaviruscovid19intheuk/26april2020to1august2021 Accessed 9/15/2021

COVID-19 Infections

• United States 120 million

• Pennsylvania 1.36 million

• Allegheny County 86,280

CDC COVID Data Tracker accessed 9/16/2021

COVID-19 Infections

• United States 120 million x 10 - 30% = 12 - 36 million

• Pennsylvania 1.36 million x 10 - 30% = 136 - 408K

• Allegheny County 86,280 x 10 - 30% = 8.6 - 26K

CDC COVID Data Tracker accessed 9/16/2021

COVID-19 Infections

• United States 120 million x 3% = 3.6 million

• Pennsylvania 1.36 million x 3% = 40.8K

• Allegheny County 86,280 x 3% = 2.6K

CDC COVID Data Tracker accessed 9/16/2021

• Average age PASC 40 years• Affect health care systems

• Affect economic recovery

• Physiologic vs. psychogenic• Disbelieved, marginalized or

shunned by medical community

• May further exacerbate gender and racial inequality

• 3 months after CAP (n=576)1

• 51% fatigue

• 28% dyspnea

• SARS-CoV Hong Kong (n=233)2

• 40% chronic fatigue 40 months post-infection

• MERS-CoV symptoms up to 18 months post-infection3

Gaffney. Am J Med (2021) PMID: 34428463Phillips et al. NEJM (2021) PMID: 34192429

1. Metlay et al. JGIM (1997) PMID: 92292812. Lam et al. AIM (2009). PMID: 200087003. Lee et al. Psych Invest (2019) PMID: 30605995

Pathophysiology PASC

Pathophysiology Acute COVID-19 → PASC

Gupta. Nature Medicine (2021) PMID: 32651579

Ramakrishnan. Frontiers in Immunology (2021) PMID: 34276671

Phenotyping PASC

Physiology Studies on Post-Covid Patients

Cardiopulmonary Exercise Testing (CPET)

• Noninvasive measure of resting and exercise measurements of metabolic rates to identify organ systems limiting exercise capacity.

• +/- arterial line

• Symptoms with exercise, study exercise!

• Identify limitations due to: • Cardiac

• Pulmonary Vascular

• Ventilatory limitation

• Deconditioning / poor effort

AuthorPMID#

Baratto33764166

Rinaldo33926969

Skjørten34210791

Motiejunaite33536937

ReferenceValues

Location Milan, Italy Milan, Italy Oslo, Norway Paris, France

Days post PCR (+) Hospital discharge 97 (26) 90 90

Covid Disease SeverityPost Hospital

Oxygen 22.2%Non-Invasive Vent 50%Mechanical Vent 27.8%

Critical 52%Severe 24%

Mild-Moderate 24%

ICU 20%Non-ICU 80%

Mechanical Vent 13%

ICU 22%Severe 49%

Intubated 18%

n 18 41 156 114

Age (years) 66 (21) 56 (13) 56.2 (12.7) 57 (48-66)

Gender (female) 28% 35% 39% 33%

Residual lung disease (CT Scan) -- 63% -- 65 (57%)

Reduced VO2 peak (n, %) 17 (95%) 41 (54.6%) 49 (31%) 85 (75%)

⩒O2 peak (%Predicted) 59 (32) 72% (9) 84% (19) 71% (60-85) >80 - 85%

DLco (%Predicted) -- 69 (13) 84 (16) 79 (65-90) >80%

Ventilatory Limitation n=2 No No No

Diagnosis AnemiaReduced systemic O2

extraction and delivery

Deconditioning Deconditioning Deconditioning

Mean (SD) Median (IQR)Mean (SD)Mean (SD)

Impact of the severity of the acute phase of COVID-19 on long-term sequalae not clear

• Mild: symptomatic + no PNA

• Mod: PNA + SpO2 >90% on RA

• Severe: PNA + SpO2 <90% on RA

• Critical: ARDS + P/F <300 mmHg on NIV or mechanical ventilation

• Severity of disease does not affect oxygen consumption.

All(n=75)

Mild-Moderate

(n=18)

Severe(n=18)

Critical (n=39)

p-value

Age (years) 57 (12) 50 (9)* 58 (13) 59 (11)* 0.042

Female (n,%) 32 (43) 9 (50) 11 (61) 12 (31) 0.076

CT(abnormal/ total, %)

43/68(63%)

5/16*(31%)

9/18(50%)

29/38 *(76%)

0.006

DLco (%) 71 (14) 72 (13) 67 (12) 73 (15) 0.378

Reduced VO2

peak (n, %)41 (54) 11 (61) 9 (50) 21 (51) 0.79

⩒O2 peak (%Predicted)

83 (15) 83 (17) 82 (16) 84 (15) 0.895

⩒E/⩒CO2 slope 28.4 (3.1) 27.1 (2.6)* 29.8 (3.9)* 28.3 (2.6) 0.028

Ventilatory Limitation

No No No No

Rinaldo. Respiratory Medicine (2021) PMID: 34416618

Cardiopulmonary Exercise Testing (CPET)

• Caveat to the CPET studies:• premorbid/ baseline values are unclear

• What does a normal ⩒O2 peak in a symptomatic patient mean?

• ⩒O2 peak ∆ 104→84%

• What is the physiology of PASC >3 months after initial infection?

• Is there advanced testing beyond CPET?

iCPET

Invasive Cardiopulmonary Exercise Testing (iCPET)

RHC

Radial

Arterial Line

Exercise

Bike

CPET

• Breath-by-breath analysis of ventilatory gas exchange and cardiac function in association with upright cycle ergometer exercise testing.

• Invasive access• Arterial line

• Pressures• Blood gas

• Right heart catheterization• Hemodynamics• Blood gas

• Resting Hemodynamics

• Peak Exercise Hemodynamics and Cardiopulmonary Exercise Testing

Invasive Cardiopulmonary Exercise Testing (iCPET)

• Clinical

• Research• Blood samples: rest, peak and post

exercise

• Diagnoses• Cardiac (ePH 2°↑ LVEDP)• Pulmonary Vascular (PAH, ePH)• Preload insufficiency• Decreased peripheral O2 extraction• Ventilatory limitation• Deconditioning / poor effort

Post-COVID-19 (n=10) Controls (n=10) p-value

Age, years 48 ± 15 48 ± 8 0.87

Female [n(%)] 9 (90) 8 (80) 0.53

Interval infection to iCPET (months) 11 ± 1 --

Inpatient stay 1 (10%) --

⩒O2 peak (%Predicted) 70 ± 11 131 ± 45 0.001

Cardiac Output (% Predicted) 115 ± 44 123 ± 34 0.64

Ventilatory Limitation No No

Rest and peak hemodynamic limitation No No

CaO2 (mL/dL) 18.6 ± 1.3 19.5 ± 2.3 0.29

Hemoglobin (g/dL) 13.4 ± 1.1 14.2 ± 1.4 0.16

SER = C(a-v)O2 /CaO2 0.49 ± 0.1 0.78 ± 0.1 <0.0001

Singh et al. Chest 2021 (PMID 34389297)

Radial Art Line CaO2 Normal20 dL/mL

PA CatheterCvO2 elevated8.5 dL/mL

Systemic Extraction Ratio (%) = C(a-v)O2 /CaO2 x 100= (20-8.5) / 20 x 100 = 57.5%normal >80%

Who Cares?

Fick ⩒O2 = CO x C(a-v)O2

Mechanisms

1) Primary dysfunction of the skeletal muscle mitochondrion

2) Hyperventilation and a left shift of the oxyhemoglobin dissociation curve

3) Limb muscle microcirculatory dysregulation

Reduced Peripheral Oxygen Extraction

Physiologic mechanisms of post-acute sequelae of SARS-CoV-2

infection

Referred to UPMC Post-Covid Clinic Program for persistent symptoms

21 Referred to ACPET Program for exercise intolerance

Excluded1 RER <1.05

1 refused study

12 Reduced VO2 Max6 Normal VO2 Max

1 without peak hemodynamics

2 ePH3 Decreased peripheral oxygen extraction

1 Preload Insufficiency and decreased peripheral Oxygen Extraction

5 Preload Insufficiency

1 incomplete CPET data*

Table 1. Demographics All COVID-19 Post-COVID-19 Normal VO2 Peak

Post-COVID-19 Reduced VO2 Peak p-value

n 17 5 12

Age (years) 43 (39-58) 45 (36-42) 43 (38-60) ns

Female (%) 70.6% 80% 66.6% nsRace (%)

White 100 100 100 nsBlack 0 0 0Asian 0 0 0Hispanic 0 0 0

Height (cm) 172.7 (166.5-184.0) 178 (169.1-191.5) 170 (166-183) nsWeight (kg) 100 (86.5-117.1) 110.2 (91.2-123.7) 98 (85.5-115.5) nsBMI (kg/m2) 33.9 (30.2-39.1) 31.9 (26.4-42.1) 34.3 (30.6-39.9) nsHemoglobin 13.8 (13.0-15.1) 13.8 (13.7-14.7) 13.5 (12.9-15.1) nsDuration of PASC Symptoms (Days) 152.5 (127-324) 145 (82.5-256.5) 170.0 (127-367) ns

Hypertension 8 2 6Hyperlipidemia 3 0 3Obstructive Sleep Apnea 3 0 3Anxiety 4 1 3Beta Blocker 7 1 6Calcium Channel Blocker 4 0 4Diuretics 4 1 3

*Unpublished data

Preload Insufficiency Defined

• VO2 max <80%

• Normal left ventricular ejection fraction

• RAPmax <6.5 mmHg

• COmax <80%

Preload Insufficiency

• Dysautonomia

• Adrenal insufficiency

• Volume depletion

• Medications

Table 2. Peak Exercise Values

All COVID-19 Post-COVID-19 Normal VO2 Peak

Post-COVID-19 Reduced VO2 Peak p-value

n 17 5 12Exercise Values

RER 1.15 (1.1-1.2) 1.15 (1.1-1.2) 1.15 (1.1-1.2) 0.791METS 4.3 (3.3-5.4) 5.9 (5.4-6.8) 3.8 (3.3-4.8) 0.040Watts 111.0 (92.0-148.0) 162 (160-94) 101 (92-119) 0.040

CPET Values⩒O2 Peak (%) 71.6 (65.5-84.0) 100 (84.2-101.9) 66.6 (59.8-73.6) 0.002⩒E/⩒CO2 Slope 31.3 (29.5-35.4) 31.3 (31.1-33.2) 32.2 (27.9-37.5) 0.960⩒E (L/min) 62.4 (51.8-67.1) 90.6 (89.6-96.9) 55.5 (47-64.2) 0.015

Peak Invasive HemodynamicsHR (BPM) 142.5 (131-158) 149 (131-161) 140 (134-145) 0.500RAP (mmHg) 3.0 (2-6) 2.0 (0-6) 3.5 (2-6.5) 0.340CO (L/min) 13.4 (10.8-15.3) 16.0 (14.5-18.9) 12.6 (10.2-13.6) 0.006Peak CO (% Predicted) 82.6 (68.8-106.4) 110.5 (109.6-114.1) 72.0 (60.1-93.6) 0.008Stroke Volume (mL) 92.7 (88.4-106.4) 108.6 (96.0-113.5) 90.6 (87.0-101.2) 0.126DO2 (L/min) 2.73

(2.11-3.11)3.26

(2.95-2.61)2.37

(1.84-2.74)0.008

Blood Gas Values

CaO2 (mL/dL) 19.7 (18.2-20.9) 20.4 (20.3-20.4) 18.9 (17.7-21.5) 0.342

SER = C(a-v)O2 /CaO2 0.64 (0.57-0.68) 0.68 (0.67-0.71) 0.62 (0.57-0.65) 0.250

*Unpublished data Median (IQR)

Evaluation and Management of PASC

• Studies unrevealing

• Symptoms are disproportionate to resting studies

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• Positive COVID-19 test • Symptoms > 2 months post diagnosis

Pulmonary COVID-19 Clinic Evaluation (Telemedor in person)

• Neurocognitive evaluation• Exercise capacity / exercise limitation• Physical Exam

Standard workup

• Full PFTs • Resting TTE • 6MWT

• NT-proBNP• CRP, TSH, ANA

• D-Dimer if (+) or concerning symptoms/history →CTA• If RV abnormal or known acute PE or iCPET c/w chronic

PE →VQ scan

• HRCT scan with inspiratory and expiratory images• ECG

• Invasive Cardiopulmonary Exercise Testing (iCPET)

• Persistent Fevers → ID

• Cardiology to order ischemia work-up

• Cardiac MR testing

• Neurocognitive testing

• Psychiatry• Social Work

(+) DOE >2 months

• Refer to pulmonary rehab• Physical Therapy

• Dysautonomia Testing

• Cardiac MR• VQ Scan

• Research

Treatment

• There are no specific therapies.

• Supportive care • Treat underlying conditions

• Cognitive evaluation and therapy

• Smell therapy

• Increase fluid / volume intake / beta blockers

• Physical therapy / cardiopulmonary rehab

UPMC Centers for Rehab Services

• Fatigue // Generalized Weakness // Decreased Exercise Capacity

• Difficulty Walking // Difficulty with Stairs // Difficulty with Mobility

• Dyspnea with Activity // POTS

• Neuropathy // Balance Problems

• Headaches // Dizziness

• Generalized Pain (Myalgias, Arthralgias)

Outpatient Physical Therapy

Helpful if any cardiac/pulmonary workup is completed pre-rehab if

concerns identified.

Therapists will closely monitor HR, BP and SaO2 in response to

activity/exercise

RxWell is a coaching-enhanced digital cognitive behavioral therapy tool

• Behavioral health challenges are pervasive and under-treated in the general population.

• RxWell is a digital tool that utilizes evidence-basedCognitive Behavioral Therapy (CBT) to help patients better manage anxiety and depression.

• UPMC coaches communicate with patients within RxWell by secure texting to motivate and educate patients and help them personalize techniques to achieve their specific goals.

TECHNIQUES COACH INTERACTIONS

Conclusions

• PASC is a heterogenous condition.

• PASC pathophysiology is likely to be multifactorial

• Signals of deconditioning, preload insufficiency, exercise PH and reduced peripheral oxygen extraction have been identified.

• Severity of initial COVID-19 infection is not associated with differences in exercise capacity.

• Recovery time is variable, but it occurs.

• Best to take a multidisciplinary approach to the management of PASC.

Thank You!

UPMC Post-Covid Recovery Clinic

• Alison Morris, MD

• Danny Dunlap, MD

• Corrine Kliment, MD

• Carl Koch, MD

• Karla Yoney, PA-C

• Emily Joseph

ACPET Program

• Robert Rathbun, EP-C

• David Barber, EP-C

• Karen Barron, RN

• Yasmin Al Aaraj, MD

• Shadyside Cath Lab