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
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