Decreased Exercise Tolerance and Chronotropic Incompetence in Long COVID Patients with Cardiopulmonary Symptoms


Association with Epstein-Barr virus reactivation sets the need for an antiviral clinical trial with cardiopulmonary exercise testing as an endpoint.

What You Should Know

Long COVID is estimated to occur in approximately 10% of individuals who have been infected with SARS-CoV-2. A study cited in the information suggests that 18% of patients who tested positive for SARS-CoV-2 still experienced at least one persistent symptom 12 months after infection, indicating the long-lasting nature of these symptoms.

The complexity of Long COVID symptoms, including fatigue and exercise intolerance, makes it challenging to develop effective treatments.

A recent study mentioned in the information suggests a potential link between EBV reactivation and Long COVID symptoms. The study found that a significant percentage of Long COVID patients with cardiopulmonary symptoms had evidence of recent EBV reactivation, compared to those without such symptoms.

The Post-Acute Sequalae of COVID- 19 infection (PASC) also known as Long COVID-19 is estimated to occur in 10% of those infected with SARS-CoV-2 infection.1 An MMWR study by Montoy et al demonstrated that 18% of patients who test positive for SARS-CoV-2 infection have at least one persistent symptom at 12 months.2 The symptoms of Long COVID are numerous and the underlying mechanisms resulting in these symptoms remain unknown.

The US government has granted over a billion dollars in research money and yet no treatments for Long COVID have been developed. Current efforts appear to be focused on the development of new vaccines aimed at new variants while those suffering from Long COVID are left to their own devices. A recent patient-centered FDA meeting was notable in that afflicted patients stated that the most troubling symptoms were fatigue and exercise intolerance. They also stated that current treatment attempts amounted to “Band-Aids” without addressing mechanisms of disease. A recent study performed by investigators at UCSF Medical Center is an advance in understanding the underpinnings of these symptoms and suggests a possible strategy for an interventional clinical trial.

In the September 1, 2023, issue of the Journal of Infectious Disease, Durstenfeld and colleagues performed a sub study in the San Francisco post-COVID cohort known as Long-Term Impact of Infection with Novel Coronavirus (LIINC) to elucidate mechanisms underlying cardiopulmonary symptoms occurring >1 year after SARS-CoV-2 infection.3

Patients chosen were those who had SARS-COV-2 infection by PCR and had completed an echocardiogram regardless of the presence or absence of symptoms. Patients completed a questionnaire regarding cardiopulmonary symptoms including chest pain, dyspnea, palpitations and fatigue, and had blood-based markers performed including troponin, brain natriuretic protein (BNP), and C- reactive protein (CRP) at < 90 days and 90-150 post- infection. These patients also had Epstein-Barr Virus (EBV) antibodies including early antigen diffuse immunoglobulin and nuclear antigen IgG collected 90-150 days after infection. cardiopulmonary exercise testing (CPET), cardiac magnetic resonance imaging (CMR) and ambulatory cardiac rhythm monitoring were performed. The main comparison was between those with and without cardiopulmonary symptoms.

The study was impressive in the number of observations that came from it. A full 67% of 60 patients in the study had cardiopulmonary symptoms at 6 months and 63% had symptoms at a median of 17.6 months. Of note in this study was that self-reported reduced exercise capacity was associated with the presence of symptoms. Both reduced exercise capacity (defined as peak oxygen consumption < 85% predicted) and the presence of chronotropic incompetence (defined as peak oxygen consumption < 85% predicted, adjusted heart rate reserve < 80%, and no alternative reason for limitation) on CPET testing were statistically higher in the group with symptoms vs. those without symptoms. Cardiac magnetic resonance scanning did not reveal cardiac dysfunction, scar, or myocarditis to explain symptoms. Likewise, dysrhythmia was not present in symptomatic Long COVID patients during ambulatory cardiac monitoring.

Somewhat buried among the vast amount of cardiac testing in this paper is the EBV reactivation data. Eighty percent of Long COVID patients with cardiopulmonary symptoms had some evidence of recent EBV reactivation compared to 40% in those without symptoms (OR 9.3[95%CI, 2.02-43.6]; P=.004). Furthermore all 11 patients with chronotropic incompetence had evidence of EBV reactivation. This study builds on the body of evidence associating EBV reactivation to Long COVID symptoms.

Gold and colleagues found evidence of EBV reactivation by early antigen -diffuse IgG or EBV VCA IgM vs 10% of control subjects; p,.0010.4 The authors of the current publication from UCSF have previously shown a strong association of early EBV early antigen diffuse IgG positivity and the presence of fatigue in Long COVID patients.5 Most recently, Klein and colleagues presented results in Nature on September 25, 2023, indicating that Long COVID patients had elevated levels of EBV antibodies to lytic antigens indicating recent reactivation compared with healthy or convalescent controls despite a similar EBV seroprevalence in all 3 groups.6

The accumulating literature raises the hypothesis that treating EBV reactivation may impact Long COVID symptoms including fatigue and reduced exercise capacity. The current study indicates that Cardiopulmonary exercise testing would serve as a viable endpoint in a clinical trial assessing an anti-EBV agent in Long COVID.


  1. Ford ND, Slaughter D, Edwards D, et al. Long COVID and Significant Activity Limitation Among Adults, by Age - United States, June 1-13, 2022, to June 7-19, 2023. MMWR Morb Mortal Wkly Rep. 2023 ;72(32):866-870. doi: 10.15585/mmwr.mm7232a3.
  2. Montoy JCC, Ford J, Yu H, et al. Innovative Support for Patients with SARS-CoV-2 Infections Registry (INSPIRE) Group. Prevalence of Symptoms ≤12 Months After Acute Illness, by COVID-19 Testing Status Among Adults - United States, December 2020-March 2023. MMWR Morb Mortal Wkly Rep. 2023 ;72(32):859-865. doi: 10.15585/mmwr.mm7232a2.
  3. Durstenfeld MS, Peluso MJ, Kaveti P, et al. Reduced Exercise Capacity, Chronotropic Incompetence, and Early Systemic Inflammation in Cardiopulmonary Phenotype Long Coronavirus Disease 2019. J Infect Dis. 2023 ;228(5):542-554. doi: 10.1093/infdis/jiad131.
  4. Gold JE, Okyay RA, Licht WE, Hurley DJ. Investigation of Long COVID Prevalence and Its Relationship to Epstein-Barr Virus Reactivation. Pathogens. 2021;10(6):763. doi: 10.3390/pathogens10060763.
  5. Peluso MJ, Deveau TM, Munter SE, et al. Chronic viral coinfections differentially affect the likelihood of developing long COVID. J Clin Invest. 2023;133(3): e163669. doi: 10.1172/JCI163669.
  6. Klein J, Wood J, Jaycox J, et al. Distinguishing features of Long COVID identified through immune profiling. [published online September 25,2023]. Nature. doi: 10.1038/s41586-023-06651-y.
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