medicina

Article
Orthostatic Symptoms and Reductions in Cerebral Blood Flow
in Long-Haul COVID-19 Patients: Similarities with Myalgic
Encephalomyelitis/Chronic Fatigue Syndrome
C. (Linda) M. C. van Campen 1, * , Peter C. Rowe 2 and Frans C. Visser 1
1 Stichting CardioZorg, Planetenweg 5, 2132 HN Hoofddorp, The Netherlands;
fransvisser@stichtingcardiozorg.nl
2 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA;
prowe@jhmi.edu
* Correspondence: info@stichtingcardiozorg.nl

Abstract: Background and Objectives: Symptoms and hemodynamic findings during orthostatic stress
have been reported in both long-haul COVID-19 and myalgic encephalomyelitis/chronic fatigue
syndrome (ME/CFS), but little work has directly compared patients from these two groups. To
investigate the overlap in these clinical phenotypes, we compared orthostatic symptoms in daily life
and during head-up tilt, heart rate and blood pressure responses to tilt, and reductions in cerebral
blood flow in response to orthostatic stress in long-haul COVID-19 patients, ME/CFS controls, and
healthy controls. Materials and Methods: We compared 10 consecutive long-haul COVID-19 cases
with 20 age- and gender-matched ME/CFS controls with postural tachycardia syndrome (POTS)
during head-up tilt, 20 age- and gender-matched ME/CFS controls with a normal heart rate and
blood pressure response to head-up tilt, and 10 age- and gender-matched healthy controls. Identical



symptom questionnaires and tilt test procedures were used for all groups, including measurement of


cerebral blood flow and cardiac index during the orthostatic stress. Results: There were no significant
Citation: Campen, C.(.M.C.v.; Rowe,
differences in ME/CFS symptom prevalence between the long-haul COVID-19 patients and the
P.C.; Visser, F.C. Orthostatic
Symptoms and Reductions in
ME/CFS patients. All long-haul COVID-19 patients developed POTS during tilt. Cerebral blood
Cerebral Blood Flow in Long-Haul flow and cardiac index were more significantly reduced in the three patient groups compared with
COVID-19 Patients: Similarities with the healthy controls. Cardiac index reduction was not different between the three patient groups.
Myalgic Encephalomyelitis/Chronic The cerebral blood flow reduction was larger in the long-haul COVID-19 patients compared with the
Fatigue Syndrome. Medicina 2022, 58, ME/CFS patients with a normal heart rate and blood pressure response. Conclusions: The symptoms
28. https://doi.org/10.3390/ of long-haul COVID-19 are similar to those of ME/CFS patients, as is the response to tilt testing.
medicina58010028 Cerebral blood flow and cardiac index reductions during tilt were more severely impaired than
Academic Editor: Olli J. Polo in many patients with ME/CFS. The finding of early-onset orthostatic intolerance symptoms, and
the high pre-illness physical activity level of the long-haul COVID-19 patients, makes it unlikely
Received: 18 November 2021
that POTS in this group is due to deconditioning. These data suggest that similar to SARS-CoV-1,
Accepted: 21 December 2021
SARS-CoV-2 infection acts as a trigger for the development of ME/CFS.
Published: 24 December 2021

Publisher’s Note: MDPI stays neutral Keywords: long-haul COVID-19; chronic fatigue syndrome (CFS); myalgic encephalomyelitis (ME);
with regard to jurisdictional claims in cerebral blood flow (CBF); orthostatic intolerance; tilt testing; postural orthostatic tachycardia syn-
published maps and institutional affil- drome (POTS)
iations.

1. Introduction
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland. From the early stages of the SARS-CoV-2 virus pandemic, it has become clear that
This article is an open access article affected subjects can experience long-lasting, exhausting fatigue accompanied by post-
distributed under the terms and exertional malaise (PEM), cognitive dysfunction, and an early-onset symptoms of ortho-
conditions of the Creative Commons static intolerance [1,2]. In a large, international survey of adults with persistent symptoms
Attribution (CC BY) license (https:// following suspected or confirmed COVID-19 illness, the three most commonly reported
creativecommons.org/licenses/by/ symptoms were fatigue, PEM, and cognitive dysfunction [2]. Several studies have identi-
4.0/). fied orthostatic intolerance—defined as a group of clinical conditions in which symptoms

Medicina 2022, 58, 28. https://doi.org/10.3390/medicina58010028 https://www.mdpi.com/journal/medicina

Medicina 2022, 58, 28 2 of 18

worsen upon assuming and maintaining upright posture and are ameliorated by recum-
bency [3,4]—after COVID-19, with particular emphasis on the early-onset of postural
orthostatic tachycardia syndrome (POTS) [2,5–9].
These chronic symptoms following COVID-19 illness are also core symptoms of
myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) [4,10,11]. Fatigue is the
cardinal symptom in CFS, post-exertional malaise in ME. Cognitive dysfunction is a highly
prevalent and classifying symptom in both the CFS and ME criteria [12,13]. Orthostatic
intolerance is also highly prevalent, affecting up to 90% of adults and >95% of pediatric
patients in the ME/CFS population [14,15]. Petracek et al. reported that their patients
satisfied criteria for ME/CFS six months after SARS-CoV-2 infection, suggesting that the
virus may trigger ME/CFS, similar to SARS-CoV-1 and other viral infections [16–20].
To further explore whether the similarity in chronic symptoms of patients after SARS-
CoV-2 infection (long-haul COVID-19) and ME/CFS extends to objective hemodynamic
abnormalities, we measured orthostatic symptoms in daily life and during head-up tilt,
heart rate and blood pressure responses to tilt, and reductions in cerebral blood flow during
orthostatic stress testing, comparing 10 consecutive long-haul COVID-19 patients to 20
ME/CFS patients without POTS, and 20 ME/CFS patients with POTS.

2. Materials and Methods

2.1. Participants
The case-control study was conducted in the outpatient clinic of the Stichting Cardio-
Zorg, a cardiology clinic in the Netherlands that specializes in diagnosing and treating
adults with ME/CFS. Cases were eligible if the start of their illness was associated with
confirmed SARS-CoV-2 (COVID-19) infection, or if their acute symptoms were consis-
tent with SARS-CoV-2 in early 2020 (from February to June 2020), during a period where
COVID-19 testing was not recommended, or not available. For probable cases, the clinical
diagnosis of SARS-CoV-2 virus infection had to be made by pulmonologists, internists,
general practitioners, and doctors of the GGD (Municipal Health Service).
The controls were identified from the clinic database of ME/CFS patients who visited
our clinic between November 2015 and July 2021, in whom a tilt test was performed
for quantification of orthostatic intolerance (OI). ME/CFS controls were matched to the
long-COVID-19 cases first by gender, then by age (+/− 1 years), selecting the closest
matching patient to the case. Because our previous research [21] showed that patients
with hypermobility have a larger cerebral blood flow reduction during head-up tilt, and
with 3/10 of long-haul COVID-19 patients being diagnosed with hypermobility, we also
ensured that 30 percent or the ME/CFS patients also met criteria for joint hypermobility. It
was not possible to match this variable by gender, given the small number of hypermobile
males in our ME/CFS database. Patients were considered hypermobile if the diagnosis of
joint hypermobility, or hypermobile Ehlers-Danlos Syndrome (hEDS) had been made by
a geneticist, rheumatologist, or specialized rehabilitation physician. In all other patients
seen during the study period, in whom a formal diagnosis of hypermobility had not been
established, we asked whether they were highly flexible or were hypermobile. In the event
of a positive answer, the Beighton score was obtained [22]. For this study, we chose a
conservative, elevated Beighton score of 6 or higher as the threshold for confirming the
diagnosis of hypermobility [22,23]. The diagnosis of ME/CFS was made according to the
ME/CFS criteria of the International Consensus Criteria (ICC) [10,11], and we excluded
those with any other illnesses that could explain the symptomatology. Moreover, we scored
ME/CFS symptoms based on the Institute of Medicine (IOM) criteria [4]. We noted if study
participants were using medications that could alter heart rate (HR) or blood pressure (BP),
and these drugs were discontinued before performing the tilt test. The ME/CFS controls
became ill at least 2 years before the start of the SARS-CoV-2 pandemic. In light of the
reported occurrence of POTS following COVID-19, we selected 20 ME/CFS controls with
POTS and 20 without POTS. We also selected a third control group of 20 gender- and
age-matched healthy adults without ME/CFS.
Medicina 2022, 58, 28 3 of 18

The study was carried out in accordance with the Declaration of Helsinki. All ME/CFS
participants and healthy controls gave informed, written consent. The study was approved
by the medical ethics committee of the Slotervaart Hospital, Amsterdam, the Netherlands
(P1450).

2.2. ME/CFS Criteria by International Consensus Criteria, Fukuda and Institute of Medicine
In order to study whether daily symptoms of long-haul COVID-19 and ME/CFS
were comparable, we used a questionnaire to systematically ascertain whether patients
satisfied the criteria for CFS described by Fukuda et al. [10], the ME criteria described in the
International Consensus Criteria by Carruthers et al. [11], and the ME/CFS criteria derived
from the report of the Institute of Medicine [4]. Based on the ME criteria, patients were
categorized as having typical ME or atypical ME; based on the Fukuda criteria patients
were categorized as having CFS or chronic fatigue; based on the IOM criteria patients were
categorized as having ME/CFS present or absent.
Using questionnaires we have employed in earlier studies for the evaluation of
ME/CFS patients, we ascertained the presence of the following symptoms as outlined in
the ME/CFS criteria: symptoms present more than 6 months; fatigue/exhaustion; physical
and or mental exercise intolerance; symptom increase after physical and/or mental exercise
(called PEM); prolonged recovery from PEM; memory problems; headaches; muscle pain;
joint pain; unrefreshing sleep; sensory hypersensitivity (light, sound, smells, vibrations,
touch); neuromotor impairment (muscle weakness, disturbed coordination, fasciculations,
ataxia); flu-like symptoms; sore throat; tender lymph nodes; increased sensitivity to viral
infections; gastrointestinal symptoms; genito-urinary symptoms; hypersensitivity to food
and chemicals; orthostatic intolerance; respiratory symptoms; thermal instability including
sweating, and extreme temperature intolerance. For comparison of symptoms of the long-
haul COVID-19 patients, the ME/CFS patients with POTS and with a normal HR and BP
response were combined. Moreover, we asked about the triggers that led to the ME/CFS
symptoms.

2.3. Tilt Test with Extracranial Doppler Cerebral Blood Flow Measurements
Measurements were performed as described previously [15,24]. Briefly, all participants
were positioned for 20 min supine before being having their head tilted up to 70 degrees
for a maximum of 30 min (mainly in healthy controls). The process of tilting upright
took approximately 30 s. HR, systolic blood pressure, and diastolic blood pressure were
continuously recorded by finger plethysmography. Heart rate, systolic blood pressure
and diastolic blood pressure were extracted from the device and imported into an Excel
spreadsheet. The test ended after 30 min or earlier, in case of orthostatic hypotension or
pre-syncope, or at the request of patients if they were unable to tolerate the upright position
any longer. In healthy controls two upright measurements were available: at mid-tilt and
at the end of the tilt period. As the mid-tilt period of healthy controls was similar to the
end-tilt period of patients (13 ± 4 min in healthy controls and 13 ± 7 min in patients), the
mid-tilt data of the healthy controls was used for comparison with patients.
Internal carotid artery and vertebral artery Doppler flow velocity frames were acquired
by one operator (FCV), using a Vivid-I system (GE Healthcare, Hoevelaken, The Nether-
lands) equipped with a 6–13 MHz linear transducer. High resolution B mode images, color
Doppler images and the Doppler velocity spectrum (pulsed-wave mode) were recorded in
one frame. At least two consecutive series of six frames per artery were recorded. Image
acquisition for all 4 vessels at each time point (supine and end-tilt) lasted 3 (1) min. Blood
flow of the internal carotid and vertebral arteries was calculated offline by an investigator
(CMCvC), who was unaware of the patient case or control status. Blood flow in each vessel
was calculated from the mean blood flow velocities x the vessel surface area and expressed
in mL/min. Vessel diameters were manually traced by CMCvC on B-mode images, from
the intima to the opposite intima. Surface area was calculated as follows: the peak systolic
and end diastolic diameters were measured, and the mean diameter was calculated as:
Medicina 2022, 58, 28 4 of 18

mean diameter = (peak systolic diameter × 1/3) + (end diastolic diameter × 2/3) [25]. Flow
in the individual arteries was calculated in 3–6 cardiac cycles, and data were averaged.
Total cerebral blood flow was calculated by adding the flow of the four arteries. End-tidal
PCO2 (PETCO2 ) was monitored using a Lifesense device (Nonin Medical, Minneapolis
USA).

2.4. Doppler Measurements for the Determination of the Cardiac Index

Cardiac Index (CI) is the cardiac output corrected for body surface area. Measurements
were performed as described previously [26]. Briefly, the time–velocity integral (VTI) of
the aorta was measured using a continuous-wave Doppler pencil probe connected to a
Vivid I machine (GE, Hoevelaken, NL) with the transducer positioned in the suprasternal
notch. A maximal Doppler signal was assumed to be the optimal flow alignment. At least
2 frames of 6 s were obtained. Time–velocity integral frames were obtained in the resting
supine position, and at the end of tilt test phase. From an echocardiogram performed
earlier, the diameter of the outflow tract was obtained. The aortic time velocity integral
was measured by manual tracing of at least 6 cardiac cycles, using the GE EchoPac post-
processing software. This was done by one operator (CMCvC). Stroke volumes indices (SVI)
were calculated from the time–velocity integral and the outflow tract area, corrected for the
aortic valve area [27,28], and divided by the body surface area (Du Bois formula). Stroke
volume index of the separate cycles were averaged. The cardiac index was calculated from
the heart rate and stroke volume index. We have previously validated this methodology
by a direct comparison with CI measurements using transthoracic time–velocity integral
images from the apical 4-chamber view [26].

2.5. Hemodynamic Classification of Heart and Blood Pressure Changes during Tilt Testing
The changes in heart rate and blood pressure during the tilt were classified according
to the consensus statement and guidelines [29–31] as follows: (a) normal heart rate and
blood pressure response; (b) postural orthostatic tachycardia syndrome (POTS), defined
as a sustained increase in HR of 30 bpm or more within 10 min of standing, without an
abnormal blood pressure response; and (c), syncope or near-syncope. For comparison
purposes, with COVID-19 cases all having POTS, 20 ME/CFS POTS patients were analyzed
as a control group, as well as a group of ME/CFS patients with a normal heart rate and
blood pressure response (n = 20), and a control group of 20 healthy controls.

2.6. Orthostatic Symptoms during Tilt

Orthostatic symptoms during tilt testing were ascertained using a written question-
naire that elicited whether 15 orthostatic intolerance symptoms were present, as described
previously [15]. Directly after attaining the upright position, a clinician (FCV) read the
questionnaire items to the patients and healthy controls, and participants were asked to
respond with yes or no. The questionnaire is available in the Appendix A.

2.7. Statistical Analysis

Data were analyzed using Graphpad Prism version 6.05 (Graphpad software, La Jolla,
CA, USA). All continuous data were tested for normal distribution using the D’Agostino–
Pearson omnibus normality test, and presented as mean with standard deviation (SD)
or as median with the interquartile range (IQR), where appropriate. Nominal data were
compared using the Chi-square test. Between-group comparison was done by the one-way
analysis of variance (ANOVA). Where significant, results were then explored further using
the post-hoc Tukey’s multiple comparison test. In both the long-haul COVID-19 patients
and in the ME/CFS patients (groups 2 and 3) disease duration was not normally distributed,
and between-group comparison was done using the Kruskal–Wallis test. Where significant,
results were then explored using a post-hoc Dunn’s multiple comparison test. Criteria
symptom clusters were scored as present or absent. The percentage of present symptoms
was calculated for each symptom cluster of the long-haul COVID-19 subjects and for
Medicina 2022, 58, 28 5 of 18

ME/CFS subjects, and 95% confidence intervals were calculated. These nominal data were
also compared with Chi-square (2 × 2 table). Due to the multiple comparisons, we chose to
use a p value of < 0.01 to be significant.

3. Results
The first long-haul COVID-19 patient was evaluated in November 2020. Since then,
nine more long-haul COVID-19 patients were seen at the clinic with a disease duration
between 6 months and 15 months. Those 10 patients were the cases. Respiratory symptoms
were present in 8/10 immediately after the onset of acute infectious symptoms; in two
patients respiratory symptoms developed at three weeks after the onset of other acute
infectious symptoms. None of the patients were admitted to hospital, and thus none
were admitted to the intensive care unit. All 10 long-haul COVID-19 cases had a tilt
test consistent with POTS. The onset of orthostatic intolerance/POTS symptoms started
2.1 ± 0.7 weeks after the onset of viral symptoms. From the database of 452 ME/CFS
patients with normal heart rate and blood pressure responses, we selected 20 controls,
matched on age, then gender. From the database of 302 ME/CFS patients with POTS,
we selected 20 controls, also age- and gender-matched. From the database of 61 healthy
adults, we selected 20 age- and gender-matched controls. Table 1 shows the baseline
demographic and clinical characteristics of the long-haul COVID-19 cases and control
participants (ME/CFS patients and healthy controls). The matching process was successful.
All ME/CFS patients fulfilled the criteria for CFS and the Institute of Medicine criteria. One
long-haul COVID-19 patient and two ME/CFS patients with normal heart rate and blood
pressure responses had atypical ME, whereas the others had ME. As expected, disease
duration differed significantly between the long-haul COVID-19 patient group and the
2 ME/CFS comparison groups. No difference was found in disease duration between
the ME/CFS patients with POTS or ME/CFS patients with a normal heart rate and blood
pressure response during the tilt test.

Table 1. Baseline characteristics.

COVID-19 ME/CFS
Healthy Controls ME/CFS normHRBP
POTS POTS ANOVA and Post-Hoc
(n = 20) (n = 20)
(n = 10) (n = 20) Tukey
Group 1 Group 4
Group 2 Group 3
Male/female (n) 6/14 3/7 6/14 6/14 ns
Age (years) 30 (7) 30 (7) 30 (7) 30 (7) F (3, 66) = 0.010; p = 0.99
Fulfilling typical ME
9 (90%) 20 (100%) 18 (90%)
criteria Chi-square 2128.2
Fulfilling atypical ME p = 0.35
1 (10%) 0 (0%) 2 (10%)
criteria
Fulfilling CFS criteria 10 (100%) 20 (100%) 20 (100%) ns
Fulfilling IOM criteria 10 (100%) 20 (100%) 20 (100%) ns
X2 (2)= 21.03; p < 0.0001.
Disease duration, years,
NA 1 (1–1.8) 9.5 (4–14.5) 10 (7–13.8) Post-hoc tests: 2 vs. 3
#(range)
p = 0.0002; 2 vs. 4 p < 0.0001
BSA (m2 ) 1.88 (0.19) 1.85 (0.17) 1.90 (0.22) 1.75 (0.12) F (3, 66) = 2.86; p = 0.048
BMI (kg/m2 ) 24.8 (4.5) 23.2 (5.4) 22.8 (3.8) 23.4 (4.1) F (3, 66) = 0.79; p = 0.50
BMI: body mass index; BSA: body surface area; CFS: chronic fatigue syndrome; IOM: Institute of Medicine:
ME: myalgic encephalomyelitis; normHRBP: normal heart rate and blood pressure response; POTS: postural
orthostatic tachycardia syndrome; SEID: systemic exertion intolerance disease; # median (IQR) and Kruskal–Wallis
test with Dunn’s multiple comparisons test BMI: body mass index; BSA: body surface area; CFS: chronic fatigue
syndrome; ME: myalgic encephalomyelitis; normHRBP: normal heart rate and blood pressure response; POTS:
postural orthostatic tachycardia syndrome; SEID: systemic exertion intolerance disease.

Table 2 displays the self-reported daily symptom cluster scores for the long-haul
COVID-19 cases and the ME/CFS controls. Figure 1 provides a graphical representation of
Medicina 2022, 58, 28 6 of 18

the data. No significant differences were found in any of the ME/CFS symptom clusters
between long-haul COVID-19 patients and ME/CFS patients.

Table 2. Symptom cluster data of ME, CFS, and IOM ME/CFS criteria.

Symptom/Symptom COVID-19 Cases ME/CFS Controls

95% CI COVID-19 95% CI ME/CFS p-Value #
Cluster % Present % Present
Fatigue 100 100–100 100 100–100 1.0 *
Exercise intolerance
100 100–100 97.5 93–102 1.0 *
physical/mental
PEM post physical/mental
100 100–100 100 100–100 1.0 *
exercise
Prolonged recovery 100 100–100 100 100–100 1.0 *
Memory problems 90 71–109 92.5 84–101 0.80 #
Headache 100 100–100 92.5 84–101 1.0 *
Muscle pain 100 100–100 75 62–88 0.18 *
Joint pain 80 55–105 70 56–84 0.53 #
Unrefreshing sleep 100 100–100 100 100–100 1.0 *
Sensory hypersensitivity 100 100–100 87.5 77–98 0.57 *
Neuromotor abnormalities 100 100–100 92.5 84–101 1.0 *
Sore Throat 80 55–105 77.5 65–90 0.86 #
Tender lymph nodes 90 71–109 60 45–75 0.07 #
Viral infection
70 42–98 57.5 42–73 0.47 #
hypersensitivity
Gastro-intestinal problems 100 100–100 90 81–99 0.57 *
Genito-urinary problems 60 30–90 42.5 27–58 0.32 #
Food/chemical
40 10–70 75 62–88 0.03 #
hypersensitivity
Orthostatic intolerance 100 100–100 97.5 93–102 1.0 *
Respiratory symptoms 100 100–100 87.5 77–98 0.57 *
Thermal instability 80 55–105 72.5 59–86 0.63 #
Extreme temperature
90 71–109 77.5 65–90 0.50 #
intolerance
95% CI: 95 percent confidence intervals; # Chi-square (2 × 2 table) or * Fisher’s exact test (if one of the columns
shows 100%).

The trigger for the development of ME/CFS symptoms was the confirmed or probable
SARS-CoV-2 virus in long-haul COVID-19 patients. In the 40 ME/CFS patients, reported
triggers were an infection (bacterial, viral, borreliosis) in 23 (58%), trauma in 3 (8%), surgery
in 2 (5%), burnout in 2 (5%), and pregnancy in 1 (3%). The onset of symptoms was insidious
in 9 (23%).
Table 3 shows the tilt test measurements of heart rate, systolic blood pressure, diastolic
blood pressure, PetCO2 , cerebral blood flow, and cardiac index for each group. Compared
with long-haul COVID-19 cases and the two ME/CFS patient groups, healthy controls had
a lower end-tilt heart rate, a lower end-tilt diastolic blood pressure, and a lower supine
cardiac index. By definition, the HR at end-tilt in ME/CFS POTS patients was higher
than in the ME/CFS patients with a normal heart rate and blood pressure response. The
difference in PETCO2 (end-tilt minus supine) was significantly less in healthy controls than
in the three patient groups. This was also observed for the percent reduction in cardiac
index at end-tilt.
Medicina 2022, 58, 28 7 of 18

Figure 1. Number of positive symptom clusters derived from ME/CFS/Institute of Medicine criteria
in the long-haul COVID-19 patients and all ME/CFS patient. Legend Figure 1 ME/CFS: myalgic
encephalomyelitis/chronic fatigue syndrome; Exerc: exercise; Intol: intolerance: Phys: physical; Ment:
mental; PEM: post-exertional malaise; Prol: prolonged; Probl: problems; Unrefr: unrefreshing; Sens:
sensory; Hypersens: hypersensitivity; Abn: abnormality; Sympt: symptoms: Infect: infection; GI:
gastro-intestinal; GenitoUr: genito-urogenital; Respir: respiratory; Instab: instability; Extr: extreme;
Temp: temperature.

Figure 2 shows the percent reduction in cerebral blood flow (end-tilt minus supine/supine
x100%) for the long-haul COVID-19 case group and three control groups. All patient groups
had a significantly larger reduction in end-tilt cerebral blood flow compared with the healthy
controls. ANOVA analysis among the three patient groups showed a significant difference
(p = 0.005); the post-hoc analysis identified a significant difference between the long-haul
COVID-19 group and the ME/CFS group with a normal heart rate and blood pressure re-
sponse (p = 0.0011). Those with long-haul COVID-19 and POTS, and ME/CFS and POTS, did
not differ (p = 0.49).
Medicina 2022, 58, 28 8 of 18

Table 3. Tilt table test data.

COVID-19 ME/CFS
Healthy Controls ME/CFS normHRBP
POTS POTS
(n = 20) (n = 20) ANOVA and Post-Hoc Tukeys
(n = 10) (n = 20)
Group 1 Group 4
Group 2 Group 3
Heart rate supine (bpm) 68 (12) 73 (15) 78 (16) 79 (14) F (3, 66) = 2.59; p = 0.06
F (3, 66) = 20.67; p < 0.0001. Post-hoc
Heart rate end-tilt
79 (12) 108 (16) 113 (19) 92 (12) tests: 1 vs. 2 p < 0.0001; 1 vs. 3 p <
(bpm)
0.0001 and 3 vs. 4 p = 0.0001
Systolic BP supine
138 (18) 133 (16) 132 (24) 133 (17) F (3, 66) = 0.42; p = 0.74
(mmHg)
Systolic BP end-tilt
134 (15) 136 (15) 129 (18) 133 (17) F (3, 66) = 0.64; p = 0.59
(mmHg)
Diastolic BP supine
79 (10) 85 (12) 81 (19) 78 (12) F (3, 66) = 0.68; p = 0.57
(mmHg)
Diastolic BP end-tilt F (3, 66) = 4.68; p = 0.0051. Post-hoc
83 (8) 100 (11) 89 (17) 86 (8)
(mmHg) tests: 1 vs. 2 p = 0.0032
CBF supine (mL/min) 617 (83) 629 (70) 637 (121) 605 (86) F (3, 66) = 0.43; p = 0.73
F (3, 66) = 15.74; p < 0.0001. Post-hoc
CBF end-tilt (mL/min) 591 (84) 418 (64) 455 (95) 451 (69) tests: 1 vs. 2 p < 0.0001; 1 vs. 3 p <
0.0001 and 1 vs. 4 p < 0.0001
PET CO2 supine (mmHg) 37 (2) 39 (3) 38 (3) 37 (2) F (3, 66) = 1.76; p = 0.16
F (3, 66) = 16.19; p = 0.0002. Post-hoc
PET CO2 end-tilt
36 (2) 29 (3) 27 (6) 29 (4) tests: 1 vs. 2 p < 0.0001; 1 vs. 3 p <
(mmHg)
0.0001 and 1 vs. 4 p < 0.0001
F (3, 66) = 37.18; p < 0.0001. Post-hoc
Delta PET CO2 (mmHg) −1 (1) −10 (3) −10 (3) −8 (4) tests: 1 vs. 2 p < 0.0001; 1 vs. 3 p <
0.0001 and 1 vs. 4 p < 0.0001
F (3, 66) = 8.08; p = 0.0001. Post-hoc
CI supine (L/min/m2 ) 2.29 (0.30) 2.86 (0.36) 2.82 (0.46) 2.65 (0.39) tests: 1 vs. 2 p = 0.0016; 1 vs. 3
p = 0.0003
CI end-tilt (L/min/m2 ) 2.08 (0.24) 2.20 (0.54) 2.19 (0.48) 1.99 (0.30) F (3, 66) = 1.25; p = 0.30
F (3, 66) = 12.22; p < 0.0001. Post-hoc
Perc reduction CI (%) −9 (5) −23 (14) −22 (12) −25 (5) tests: 1 vs. 2 p = 0.0008; 1 vs. 3
p = 0.0002 and 1 vs. 4 p < 0.0001
BP: blood pressure; CBF: cerebral blood flow; CI: cardiac index (cardiac output indexed for body surface area);
normHRBP: normal heart rate and blood pressure response; POTS: postural orthostatic tachycardia syndrome;
Pet CO2 : end tidal carbondioxide pressure.

Figure 2. Percent reduction in cerebral blood flow (end-tilt minus supine/supine × 100%) in the
long-haul COVID-19 patients, ME/CFS patients with POTS, ME/CFS patients with a normal heart
rate and blood pressure response, and healthy controls. Legend Figure 2 CBF: cerebral blood flow;
ME/CFS: myalgic encephalomyelitis/chronic fatigue syndrome; BP: blood pressure; HR: heart rate;
POTS: postural orthostatic intolerance syndrome.
Medicina 2022, 58, 28 9 of 18

Figure 3 shows the mean number of the 15 questions addressed directly after tilting to
the upright position where patients answered with yes. A significant difference was found
in the number of complaints between healthy controls and the three patient groups. The
long-haul COVID-19 cases and the two ME/CFS patient control groups did not differ on a
one-way ANOVA analysis. As palpitations are prominent in the daily life of patients with
POTS, we compared the palpitation question from the orthostatic intolerance questionnaire
in the three patient groups. Six of 10 in the long-haul COVID-19 group, 8/20 in the ME/CFS
POTS group, and 5/20 in the ME/CFS normal heart rate and blood pressure response group
reported palpitations (Chi square 3523.2; p = 0.17). Similarly, dizziness or lightheadedness
were also compared between the three patient groups. All long-haul COVID-19 patients
and all ME/CFS patients with POTS reported dizziness/lightheadedness directly after the
onset of the upright test phase. In 18/20 ME/CFS patients with a normal heart rate and
blood pressure response, dizziness/lightheadedness was reported after the onset of the tilt
phase. Figure 4 shows an example of cerebral blood flow in the left carotid artery supine
and end-tilt standing. The upper panel shows a long-haul COVID-19 subject and the lower
panel a healthy control. Figure 5 shows an example of cardiac output supine and end-tilt
standing. The upper panel shows a long-haul COVID-19 subject and the lower panel a
healthy control.

Figure 3. Mean number of positive response to 15 questions, obtained directly after tilting to the
upright position, in long-haul COVID-19 patients, ME/CFS patients with POTS, ME/CFS patients
with a normal heart rate and blood pressure response, and healthy controls. Legend Figure 3 ME/CFS:
myalgic encephalomyelitis/chronic fatigue syndrome.
Medicina 2022, 58, 28 10 of 18

Figure 4. Example of cerebral blood flow images of the left carotid artery supine (left side) and
end-tilt standing (right side) of a long-haul COVID-19 subject (upper panel) and a healthy control
(lower panel). Legend Figure 4: CBF: cerebral blood flow.

Figure 5. Example of cardiac output images supine (left side) and end-tilt standing (right side) of a
long-haul COVID-19 subject (upper panel) and a healthy control (lower panel). Legend Figure 5: CO:
cardiac output.

4. Discussion
The main finding of this study is that all long-haul COVID-19 patients met diagnostic
criteria for ME/CFS by 6 months from their initial respiratory illness. Analysis of 21
different symptom clusters that are part of the three different ME/CFS definitions showed
Medicina 2022, 58, 28 11 of 18

no differences in symptom prevalence of long-haul COVID-19 patients compared with the

ME/CFS patients (Figure 1). Our study extends previously reported findings by confirming
that long-haul COVID-19 patients also have objective and significant reductions in cerebral
blood flow during tilt, similar to those with long-standing ME/CFS. In ME/CFS patients
with an abnormal cerebral blood flow reduction, by direct or indirect measures [15,32–39],
and an abnormal cardiac index reduction during a tilt test, have been previously shown by
us and others [40,41].
Surveys exploring the prevalence of 203 symptoms, tracking 66 symptoms in long-haul
COVID-19 patients over seven months [2], confirmed that the majority of the symptoms
are part of the different ME/CFS criteria. The similarity of symptoms between long-haul
COVID-19 and ME/CFS symptoms is indicated as a red X in the Appendix A of the ME, CFS,
and Institute of Medicine criteria. Of interest, many of the long-haul COVID-19 symptoms
that are not part of the ME/CFS criteria were incidentally mentioned by ME/CFS patients
during their visit at our outpatient clinic. Despite the strikingly similar symptoms between
long-haul COVID-19 and ME/CFS patients, the authors of the survey reported that only
118/3762 (3%) patients had been diagnosed with ME/CFS and 155/3762 (4%) with POTS.
The survey is a self-administered questionnaire, which limits the diagnostic accuracy for
ME/CFS, and a prospective study is needed in which the diagnosis of ME/CFS is made
by expert clinicians. Furthermore, long-haul COVID-19 patients may benefit from the
treatment options already published in ME/CFS patients.
It must be remembered that the diagnostic criteria for ME/CFS have changed signifi-
cantly over time. For the diagnosis of CFS the Fukuda criteria contained a limited number
of symptoms. The ICC criteria for ME included a more expansive list of symptoms, whereas
the most recent IOM consensus for ME/CFS simplified the number of criteria when there
was an absence of strong scientific proof that specific symptoms were sufficiently prevalent
in ME/CFS and when those symptoms were inadequate for discriminating ME/CFS from
other diseases [4,10,11]. The present extensive research effort in SARS-CoV-2 symptoma-
tology and the similarity with the ME symptomatology may lead to a reappraisal of the
multi-symptom aspect of ME/CFS, which was lost in the Institute of Medicine ME/CFS
criteria.
Multiple recent reviews on SARS-CoV-2 have shown a range of neurological mani-
festations, supported by imaging and a brain autopsy series [42–48]. This suggests that
the inflammation of the central nervous system plays a role in the pathogenesis of the
neurological manifestations of the disease. Several studies in the past have suggested a
similar neuro-inflammatory basis of ME/CFS, as was shown in several imaging studies and
reviews [49–52]. This similarity—together with the cardiac index and cerebral blood flow re-
duction found in both long-haul COVID-19 cases and ME/CFS controls—supports the view
that long-haul COVID-19, with a symptom duration over 6 months, is a form of ME/CFS,
where SARS-CoV-2 presents as a trigger for the development of the disease. However,
other authors have questioned this trigger–disease relation, stating that there is currently
insufficient evidence to establish COVID-19 as an infectious trigger for ME/CFS [53].
With respect to the presentation of complaints, several points need to be emphasized.
First, patients with long-haul COVID-19 usually have had a mild acute SARS-CoV-2
infection. In contrast, more severely ill SARS-CoV-2 patients, in need of hospitalization
and respiratory assistance, present with more severe respiratory symptoms such as viral
pneumonia, and ultimately acute respiratory distress syndrome (ARDS). This suggests
that the pathogenesis of the chronic SARS-CoV-2 form has a neuro-inflammatory basis
and is less dependent on primary lung injury. Second, orthostatic intolerance symptoms
present early in the COVID-19 illness, in our series between 1 and 3 weeks. Other reports
also show that POTS is an early symptom of SARS-CoV-2 [5,9,54]. The series reported
from the Mayo Clinic shows that POTS is not the only presentation of dysautonomia and
orthostatic intolerance complaints in these patients [54]. Having a normal heart rate and
blood pressure response to orthostatic stress is prevalent in ME/CFS patients, occurring
in 58% of our population [15]. From the available published data on long-haul COVID-19
Medicina 2022, 58, 28 12 of 18

orthostatic intolerance cases, with the cases of the current study included, the majority of
patients presented with POTS: 42 of 71 patients (59%) [6,7,9,54–56]. Given the high number
of case reports, publication bias undoubtedly plays an important role. More prospective
studies on the incidence of orthostatic intolerance abnormalities in long-haul COVID-19
patients are needed.
In the American Heart Association guidelines on the evaluation of patients with
syncope, a distinction is made between POTS and postural tachycardia [31], where POTS
is associated with orthostatic intolerance symptoms, and postural tachycardia is not. The
orthostatic intolerance symptoms are a complex of symptoms considered to result from
cerebral hypoperfusion and/or sympathetic overdrive [3,35]. At present, the objective
demonstration of the cerebral hypoperfusion is not part of the definition of POTS in the
guidelines, although we have demonstrated this cerebral hypoperfusion in the ME/CFS
population and others in other POTS populations [57–60]. Therefore, we also administered
to patients and healthy controls 15 orthostatic intolerance questions directly after onset of
the tilt phase. This questionnaire has been previously validated [15]. In all three patient
groups (long-haul COVID-19 patients, ME/CFS patients with POTS and with normal HR
and BP responses) the number of positively answered questions were significantly higher,
compared with the healthy controls (see Figure 3). Therefore, we are confident that our
long-haul COVID-19 patients had POTS and not postural tachycardia.
In previous studies, orthostatic intolerance and especially POTS, have been consid-
ered to be associated with cardiovascular deconditioning [3,61–63]. We recently described
cerebral blood flow reductions in ME/CFS patients without deconditioning, mild decondi-
tioning, and with moderate/severe deconditioning as measured by the peak VO2 assessed
during cardiopulmonary exercise testing (the maximum amount of oxygen you can utilize
during exercise). This is commonly used to test the aerobic endurance or cardiovascular
fitness of subjects [63]. No significant difference was found in the extent of cerebral blood
flow reduction between no, mild, and moderate/severe deconditioning groups; moreover,
no difference in VO2 was found in ME/CFS patients presenting with POTS, delayed or-
thostatic hypotension, or with a normal heart rate and blood pressure response on tilt
testing [64]. In the present study, in the long-haul COVID-19 patients with POTS, the
orthostatic intolerance/POTS complaints began early after the start of the viral infection
symptoms (1–3 weeks), consistent with other published case reports [5,7,9,56]. All cases
described were patients who were very fit before the start of the infection, participating in
sports activities for multiple hours per week. In light of the early-onset of orthostatic intol-
erance/POTS, and the high physical fitness before the start of the SARS-CoV-2 infection, it
is also unlikely in this patient group that deconditioning plays an important role in their
orthostatic intolerance and POTS.
An important question is whether the long-haul COVID-19 patients will ultimately
recover from the infection. A few studies in ME/CFS have addressed this question [65–70].
Complete recovery in adults was observed between 4 and 31%. However, many follow-up
studies were limited, in that they either relied on a retrospective self-report at a single
point in time, or they consisted of longitudinal data that were analyzed in a cross-sectional
manner without taking into account the influence of baseline findings. Moreover, many
ME/CFS follow-up studies employed medical care samples instead of random community
samples of socioeconomically and ethnically diverse populations [66]. For the long-haul
COVID-19 cohort in the study by Davis et al. [2], 257 respondents (6.8%) recovered after
day 28 of illness. The data suggest that recovery in the long-haul COVID-19 is limited;
however, the follow-up duration so far is short, and longer follow-up data are needed.

Limitations
We acknowledge that referral bias by the general practitioner may have played a role,
selectively referring patients with orthostatic symptoms. Furthermore, as the hypothesis
of long-haul COVID-19 as a trigger for ME/CFS is still a topic of discussion, only a small
population has been studied as of yet. Larger patient groups need to be prospectively
Medicina 2022, 58, 28 13 of 18

studied, as well as an extensive follow-up of one or more years to determine whether

the cerebral blood flow abnormalities disappear in time, together with the recovery of
complaints and improvements in physical/mental functioning. Conversely, we did not
investigate patients who were partly or completely recovered from the SARS-CoV-2 infec-
tion. Finally, in 8/10 patients, the SARS-CoV-2 infection was not confirmed by antigen
testing because of the limited availability of tests at that time, when testing was only done
in patients presenting at the emergency room, or admitted to hospital. In all 10 patients,
the diagnosis of a SARS-CoV-2 infection was made by experienced physicians before they
were referred to us.

5. Conclusions
This study demonstrates that symptoms of long-haul COVID-19 patients are very
similar to ME/CFS symptoms. All long-haul COVID-19 patients had orthostatic intolerance
symptoms and developed POTS during a tilt test. The heart rate abnormalities were
accompanied by a reduction in both cerebral blood flow and cardiac index. Given the
findings of comparable symptoms, hemodynamic, and cerebral blood flow abnormalities in
long-haul COVID-19 and ME/CFS patients, our data support the notion that SARS-CoV-2
infection acts as a trigger for the development of ME/CFS in long-haul COVID-19 patients.
Furthermore, the very early onset of orthostatic intolerance complaints in a previously
physically fit population makes it highly unlikely that POTS in these patients is related to
deconditioning.

Author Contributions: Conceptualization, C.M.C.v.C., P.C.R. and F.C.V.; data collection, C.M.C.v.C.
and F.C.V.; primary data analysis, C.M.C.v.C.; secondary data analysis, F.C.V. and P.C.R. All authors
were involved in the drafting and review of the manuscript. All authors have read and agreed to the
published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: The study was carried out in accordance with the Declaration
of Helsinki. All ME/CFS participants and healthy controls gave informed, written consent. The
study was approved by the medical ethics committee of the Slotervaart Hospital, Amsterdam, the
Netherlands (P1450).
Informed Consent Statement: Informed consent was obtained from all subjects involved in the
study.
Data Availability Statement: The data presented in this study are available on request from the
corresponding author. The data are not publicly available due to privacy reasons.
Acknowledgments: Peter C. Rowe is supported by the Sunshine Natural Wellbeing Foundation
Professorship.
Conflicts of Interest: The authors declare no conflict of interest.

Appendix A
Orthostatic Symptoms Questionnaires
A written questionnaire was used and a clinician (FCV) read the questions to the
patients and healthy controls. Participants were asked to respond with yes or no. The
questionnaire was obtained immediately after reaching the upright position.

Questionnaire at the First Minute of Tilt

1. Did you develop, after being tilted, complaints of dizziness or lightheadedness?
2. Are you, after being tilted, more fatigued in comparison to when you were lying
down?
3. Did you develop, after being tilted, muscle weakness of your legs?
4. Did you develop, after being tilted, a feeling of dyspnea or breathlessness?
5. Do you see less sharp after being tilted?
Medicina 2022, 58, 28 14 of 18

6. Do you hear me differently, after being tilted, in comparison to when you were lying
down?
7. Are you less concentrated while standing, compared to when you were lying down?
8. Did you develop, after being tilted, pain in the muscles of your neck or shoulders?
9. Did you develop, after being tilted, a feeling of nausea?
10. Did you develop, after being tilted, a tingling feeling in your right hand *?
11. Did you develop, after being tilted, a feeling of chest pain or pressure on your chest?
12. Did you develop, after being tilted, low back pain?
13. Did you start to sweat after being tilted?
14. Did you develop, after being tilted, palpitations?
15. Did you develop, after being tilted a feeling of a pressure in your head or headache?
*: the left hand was not asked for as the finger plethysmography cuff was placed around
the middle finger of the left hand.

Table A1. Symptoms in the ME, CFS, and SEID criteria.

ME:
Symptom ME CFS SEID
Specificsymptoms
Chronic fatigue >6 month X X
Reduction physical and mental activities * X X
Reduction memory or concentration X X X
Confusion X
Disorientation X
Cognitive overload X
Decision making problems X
Slowed speech X
Dyslexia X
Short-term memory loss X
Slowed thought X
Sore throat X# X
Tender lymph nodes X# X
Muscle pain X X
Generalized hyperalgesia X
Wide-spread pain (fibromyalgia) X
Myofascial pain X
Abdominal pain X
Chest pain X
Multi joint pain X X
Headache X X
Generalized headache X
Focal headache X
Migraine X
Tension headache X
Sleep disturbance/unrefreshing sleep X X X
Disturbed sleep patterns:
Insomnia X
Prolonged sleep X
Day-night sleep reversal X
Frequent awakenings X
Awaking earlier compared to pre-illness X
Vivid dreams/night mares X
Unrefreshing sleep X
Medicina 2022, 58, 28 15 of 18

Table A1. Cont.

ME:
Symptom ME CFS SEID
Specificsymptoms
PEM or PENE >24 h X X X
Rapid physical and/or mental fatigability during exercise X
Post-exertional flare-up symptoms X
Post-exertional exhaustion X
Prolonged recovery X
Reduction pre-illness physical and mental activity X
Orthostatic intolerance X X
Postural orthostatic tachycardia syndrome X
Neurally mediated hypotension X
Palpitations X
Dizziness/lightheadedness X
Sensory hypersensitivity X
Hypersensitivity:
Light X
Sound X
Vibrations X
Odor X
Taste X
Touch X
Eye focus problems X
Depth perception problems X
Motor disturbance X
Coordination problems X
Ataxia X
Muscle weakness X
Fasciculations X
Susceptibility viral infection with prolonged recovery X
Gastrointestinal problems X
Nausea X
Abdominal pain X
Bloating X
IBS X
Genitourinary problems X
Increased urgency X
Increased polyuria X
Increased nocturia X
Sensitivity to food, medication, odors, chemicals X
Respiratory problems X
Thermostatic instability X
Subnormal body temperature X
Marked diurnal fluctuations temperature X
Sweating episodes X
Feeling of feverishness with/without low grade fever X
Cold extremities X
Extremes of temperature intolerance X
ME: myalgic encephalomyelitis; CFS: chronic fatigue syndrome; SEID: systemic exertion intolerance disease; *:
shared under PEM in ME criteria; # Sore throat and tender lymph nodes are taken as one: flu-like symptoms in
the ME criteria; X: symptoms described by Davis et al. [2].

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