2.1. Case Histories
Demographics and more detailed medical histories are presented in Table 1.
2.1.1. Patient A
Patient A is 38-year-old Caucasian female with a past medical history of infrequent childhood seizures beginning at age eight, which co-occurred with vasovagal syncope between ages 25-30, and Lyme disease, which was diagnosed and treated with IV ozone therapy and supplements in 2018, two years after initial symptom onset.
She contracted COVID-19 and tested positive by PCR in the second week of March 2020 and subsequently showed the presence of antibodies. Patient A initially experienced cold-like symptoms, including fever (103 F), dyspnea both at rest and upon exertion, rhinitis, and pharyngitis, followed by an initially productive, then dry, cough, nausea, diarrhea, and visual and auditory hallucinations that lasted for approximately three weeks.
Over the next several months she experienced periods of symptom remission for several weeks, followed by recurrence of dyspnea, chest tightness, anxiety, and panic attacks, and . She also experienced post-exertional malaise, increased dyspnea, and chest pressure within 24-48 hours of taking an hour-long walk or yoga class. She reported mild symptom relief with albuterol sulfate but tried to limit its use due to increased jitteriness. Medications at the time of her initial evaluation included daily hydroxychloroquine, prednisone, Topamax, and Adderall as needed, as well as multiple non-prescription anti-inflammatory supplements.
2.1.2. Patient B
Patient B is a 38-year-old Caucasian female with a medical history of allergic rhinitis, allergic reaction to penicillin, amoxicillin, and tetracycline, degenerative disc disease, and three hospitalizations in 2002 for medical complications associated with anorexia nervosa, which has been in partial-to-full remission since 2004. Her psychiatric history also includes premorbid diagnoses of persistent depressive disorder, generalized anxiety disorder and attention-deficit hyperactivity disorder. She was a nationally competitive swimmer and exercised regularly prior to her illness.
Patient B contracted COVID-19 mid-March 2020, and initially experienced rhinitis, dry cough, and chest tightness. Those symptoms resolved completely three days later which coincided with sudden onset anosmia, ageusia, and dysgeusia. The following week she developed fever (102 F) with intermittent borderline hypothermia (95 F), return of cough, dyspnea on exertion and at rest, chills, and myalgias, at which time she was clinician-diagnosed with COVID-19 as PCR testing was unavailable. She also experienced olfactory hallucinations on three occasions and had multiple dermatologic issues including transient “white” hives and “canker-like” sores that would last two to three hours at a time.
The second week of April, Patient B was admitted to the ER at which time chest x-ray revealed “possible mild pleural effusions.” She remained ineligible for PCR testing but was again clinician-diagnosed with COVID-19 and discharged without further testing or treatment. Her dyspnea, cough, and fatigue worsened over the next month and she began experiencing oxygen desaturation (low 80’s and high 70’s) after speaking for more than 10-15 minutes or climbing a flight of stairs, which coincided with heart rate lability (40 to 154 bpm within 60 seconds). Other symptoms included brain fog, impaired memory, nightmares, and night sweats. Patient B had two more ER admissions in June for oxygen desaturation, chest pain and dyspnea on exertion, at which time she was diagnosed with hypertension. Her last ER admission, in late July, was for chest pain which, was attributed to a cough-induced muscle strain. Pulmonary function tests, echocardiogram, and cardiac stress test were all normal. Holter monitor showed inappropriate sinus tachycardia. She continued to experience daily fevers (99.5-102) until early October.
Medications at the time of her initial evaluation included Zoloft, Adderall XR, and TriNessa Lo daily, as well as Singulair (for allergic rhinitis), trazadone, and albuterol as needed. After her evaluation she was diagnosed with coronary vasospasms for which daily Procardia XL was prescribed.
2.1.3. Patient C
Patient C is 34-year-old Black female who has a medical history significant for sickle-cell trait (carrier only), HSV-1, and a childhood history of Tourette's syndrome (in remission). She was a regular runner prior to her illness.
Patient C began experiencing dyspnea on exertion in mid-April 2020. She was clinician diagnosed with COVID-19 in the emergency department the following day and subsequently released without treatment. She continued to experience dyspnea without oxygen desaturation for months and suspected pneumonia but continued to run 1-2 miles several times a week. An August chest CT was "mostly normal," but per medical records showed some post-viral inflammation and “damage to approximately 30% of smaller blood vessels in the lungs.”
In early August, Patient C experienced severe laryngeal spasms for seven days, after using albuterol and Advair. She discontinued those medications but continued to experience persistent inflammation in her throat and larynx. A January CT scan was normal with the exception of mildly dilated distal esophagus. After endoscopic evaluation was normal, her ENT suggested her symptoms might indicate irritable larynx syndrome and/or possible nerve damage.
Medications at the time of Patient C’s initial evaluation included Albuterol, Advair Naproxen, Celebrex, and non-prescription supplements.
2.2. Exercise Tolerance Testing
Exercise tolerance was tested pre- and post-treatment using the Bensen22 treadmill protocol (see Supplemental Table 1). The Bensen protocol was selected because MET increase at each stage is more gradual and consistent than other more frequently utilized maximal and sub-maximal protocols and is therefore less likely to induce post-exertional malaise or exacerbate PCS symptoms. The protocol begins at a speed of 1.0 MPH with a 0% incline (1.77 METs) for two minutes, after which intensity is increased by approximately 25% every two minutes, alternating between increases in speed and incline until age-adjusted (200 - age) heart rate or blood pressure maximum is reached, moderate (somewhat hard to hard) symptom burden is reported, or the patient requests to stop.
The exercise tolerance tests were performed on room air. Heart rate and rhythm were monitored continuously via ECG. Blood pressure and oxygen saturation were measured at rest, during each exercise stage, and five-minutes post exercise. Rate of Perceived Exertion (RPE) and Breathlessness were obtained at peak exercise using the Borg scales.23
2.3. Treatment Protocol
After initial testing, patients underwent two (A & C) or three (B) exercise sessions per week for a total of 22 treatment sessions. The initial sessions were approximately 25% longer in duration and lower in intensity than the exercise tolerance test, such that 80-100% of peak exercise intensity was achieved within three to six sessions. In subsequent sessions, time and intensity were increased by no more than 0.5 METS, as tolerated based upon vital signs and patient-reported symptoms following the previous session and during exercise.
The patients received 6 liters per minute of continuous oxygen via nasal cannula regardless of oxygen saturation 5 minutes prior to, during, and 5 minutes post-exercise. Heart rate and rhythm were monitored continuously via ECG, and blood pressure and oxygen saturation were measured at rest, every 3-5 minutes during exercise, and five-minutes post exercise.