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European Association of Spa Rehabilitation (ESPA) recommends spa rehabilitation for patients with post-COVID-19 syndrome. We tested the hypothesis that a high-altitude environment with clean air and targeted spa rehabilitation (MR — mountain spa rehabilitation) can contribute to the improving platelet mitochondrial bioenergetics, to accelerating patient health and to the reducing socioeconomic problems. Fifteen healthy volunteers and fourteen patients with post-COVID-19 syndrome were included in the study. All parameters were determined before MR (MR1) and 16–18 days after MR (MR2). Platelet mitochondrial respiration and OXPHOS were evaluated using high resolution respirometry method, coenzyme Q 10 level was determined by HPLC, and concentration of thiobarbituric acid reactive substances (TBARS) as a parameter of lipid peroxidation was determined spectrophotometrically. This pilot study showed significant improvement of clinical symptoms, lungs function, and regeneration of reduced CI-linked platelet mitochondrial respiration after MR in patients with post-COVID-19 syndrome. High-altitude environment with spa rehabilitation can be recommended for the acceleration of recovery of patients with post-COVID-19 syndrome.
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Mountain spa rehabilitation improved health ofpatients
withpost‑COVID‑19 syndrome: pilot study
AnnaGvozdjáková1 · ZuzanaSumbalová1· JarmilaKucharská1· ZuzanaRausová1· EleonóraKovalčíková2·
TimeaTakácsová2· PlácidoNavas3· GuillermoLópez‑Lluch3· ViliamMojto4· PatrikPalacka5
Received: 4 May 2022 / Accepted: 5 September 2022
© The Author(s) 2022
European Association of Spa Rehabilitation (ESPA) recommends spa rehabilitation for patients with post-COVID-19 syn-
drome. We tested the hypothesis that a high-altitude environment with clean air and targeted spa rehabilitation (MR —
mountain spa rehabilitation) can contribute to the improving platelet mitochondrial bioenergetics, to accelerating patient
health and to the reducing socioeconomic problems. Fifteen healthy volunteers and fourteen patients with post-COVID-19
syndrome were included in the study. All parameters were determined before MR (MR1) and 16–18 days after MR (MR2).
Platelet mitochondrial respiration and OXPHOS were evaluated using high resolution respirometry method, coenzyme
Q10 level was determined by HPLC, and concentration of thiobarbituric acid reactive substances (TBARS) as a parameter
of lipid peroxidation was determined spectrophotometrically. This pilot study showed significant improvement of clinical
symptoms, lungs function, and regeneration of reduced CI-linked platelet mitochondrial respiration after MR in patients with
post-COVID-19 syndrome. High-altitude environment with spa rehabilitation can be recommended for the acceleration of
recovery of patients with post-COVID-19 syndrome.
Keywords High-altitude environment, Mountain spa rehabilitation· Post-COVID-19 syndrome· SARS-CoV-2·
Pulmonary function· Clinical symptoms· Platelet mitochondrial metabolism· Coenzyme Q10· Oxidative stress
Responsible Editor: Lotfi Aleya
* Anna Gvozdjáková
Zuzana Sumbalová
Jarmila Kucharská
Zuzana Rausová
Eleonóra Kovalčíko
Timea Takácsová
Plácido Navas
Guillermo López-Lluch
Viliam Mojto
Patrik Palacka
1 Faculty ofMedicine, Pharmacobiochemical Laboratory
of3rd Department ofInternal Medicine, Comenius
University inBratislava, Sasinkova 4, 81108Bratislava,
2 Sanatorium ofDr. Guhr, 059 81 High Tatras, Tatranská,
Polianka, Slovakia
3 Centro Andaluz de Biología del Desarrollo, Universidad
Pablo de Olavide-CSIC-JA, andCIBERER, Instituto de
Salud Carlos III, Sevilla, Spain
4 Faculty ofMedicine andUNB, 3rd Department ofInternal
Medicine, Derer’s Hospital inBratislava, Comenius
University inBratislava, Limbová 5, 83305Bratislava,
5 Faculty ofMedicine, 2nd Department ofOncology, Comenius
University inBratislava, Klenová 1, 83310Bratislava,
/ Published online: 23 September 2022
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The first new coronavirus originated from southeast
China in 2003 (SARS—severe acute respiratory syn-
drome), and the second originated from Middle East
in 2012 (MERS—Middle East respiratory syndrome)
(Hilgefeld and Peiris 2013). In March 11, 2020, the
World Health Organization (WHO) declared a global
pandemic caused by the SARS-CoV-2 beta-coronavi-
rus responsible for a new type of acute respiratory
infection and an atypical pneumonia. WHO named the
diseases caused by SARS-CoV-2 virus as “COVID-
19” (Corona Virus Diseases 2019) (Wu etal. 2020).
Persisting signs or symptoms related to SARS-CoV-2
infection can be divided into two categories. The
first, subacute COVID-19 including symptoms pre-
sent from 4 to 12 weeks beyond acute COVID-19 and
second, post-COVID-19 syndrome (or chronic) includ-
ing symptoms over 12 weeks after the SARS-CoV-2
infection (Fugazzaro etal. 2022). The main symptoms
include shortness of breath, general fatigue, exhaus-
tion, headaches, muscle and joint pain, cough, hair,
taste and smell loss, sleep and memory disturbances,
depression, sensitivity to sound and light, impaired
quality of life and reduced daily activity (35%),
reduced mobility (33%), and pain (33%) (Walle-Hansen
etal. 2021). Taboada etal. (2021) reported limitations
of everyday life near 50% of patients 6 months after
hospitalization for COVID-19. In patients with severe
SARS-CoV-2 infection, dyspnea develops that manifest
as acute coronary distress syndrome (ACDS) and can
lead to death (Wu etal. 2020).
SARS-CoV-2 viral infection occurs with higher inci-
dence in patients with comorbidities such as diabetes
mellitus type 2, obesity, cardiovascular disease, chronic
lung disease, and cancer (Zhang and Liu 2020; Shi etal.
2018; Huang etal. 2020; Li etal. 2020). In aged people,
dysfunctions of immune system and mitochondrial health
are key factors in COVID-19 disease (Lopez-Lluch 2017;
Fernandez-Ayala etal. 2020; Ganji and Reddy 2021).
Mechanical ventilation is required primarily in patients
with comorbidities (Siddiq etal. 2020). In patients with
post-COVID-19 syndrome, individualized rehabilitation
programs are recommended, focused to pulmonary reha-
bilitation of individuals with post-COVID-19 syndrome
(NICE 2022). ESPA, Wang etal. (2020), and Maccarone
and Mesiero (2021) recommend spa pulmonary rehabilita-
tion for patients with post-COVID-19 syndrome.
Virus proteins need mitochondria for their survival
and replication. Mitochondria play the central role in the
primary host defense mechanisms against viral infec-
tions (Gvozdjáková etal. 2020). Many viruses modulate
mitochondrial function, producing more reactive oxygen
species, (ROS), cytokine storm, and stimulate inflamma-
tion (Ganji and Reddy 2021; Gordon etal. 2020). SARS-
CoV-2 infection caused oxidative stress, mitochondrial
dysfunction, platelet dysfunction and coagulation (Ohta
and Nishiyama 2011; Archer etal. 2020), and high mor-
bidity and mortality. SARS-CoV-2 virus may manipulate
mitochondrial dynamics, metabolism, mitochondrial
bioenergetics, apoptosis and antiviral immunity and alter
intracellular distribution of mitochondria.
In 2020, we published the hypothesis that mitochondrial
bioenergetics and endogenous coenzyme Q10 (CoQ10) level
could be targets of the new SARS-CoV-2 virus (Gvozd-
jáková etal. 2020). Currently, this hypothesis was proved
by authors who showed reduced mitochondrial bioenerget-
ics in monocytes (Gibellini etal. 2020) and in peripheral
blood mononuclear cells of patients with COVID-19 (Ajaz
etal. 2021). Our pilot study show reduced platelet mito-
chondrial function with deficit of endogenous CoQ10 level
in non-hospitalized, non-vaccinated patients 3–6 weeks
after acute COVID-19 (Sumbalová etal. 2022). The effect
of SARS-CoV-2 virus on mitochondrial respiratory chain
was named “Mitochondrial COVID-19” (Gvozdjáková
etal. 2022) (Fig.1).
New strategies for COVID-19 prevention and therapy
are being sought to reduce the negative effects of SARS-
CoV-2 virus in society. Environmental strategies play a
vital role in pandemic prevention similar to COVID-19.
Reduction of air quality can support the transmission
dynamics of infectious disease in society with conse-
quential socioeconomic problems (Coccia 2021; Coccia
2021b; Coccia 2022). To the best of our knowledge, the
effect of SARS-CoV-2 and high-altitude environment with
targeted spa rehabilitation on pulmonary function, platelet
mitochondrial bioenergetics, coenzyme Q10 level (CoQ10),
(a key mitochondrial component for energy production),
and lipid peroxidation of patients with post-COVID-19
syndrome has not been described. MR is beneficial for
chronic pulmonary diseases, improving fatigue, joint pain,
psychological stress, sleep disorders, and quality of life in
patients with various diseases (Gvozdjáková etal. 2021).
We tested other hypothesis and strategy for patients
with post-COVID-19 syndrome that a high-altitude envi-
ronment with clean air and targeted spa rehabilitation
of patients with post-C-19 syndrome can contribute to
improving platelet mitochondrial bioenergetics, to accel-
erating patients’ health and to the reducing socioeconomic
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Materials andmethods
The control group (C)
The control group (C) consisted of fifteen healthy individu-
als (6 men and 9 women), aged 38 to 67 years with a mean
age of 51.3 ± 2.3 years, BMI 25.2 ± 0.9 kg/m2. The inclu-
sion criteria for healthy subjects were absence of chronic
medication and no history of COVID-19. Exclusion crite-
ria were lung and heart diseases, diabetes, cancer, obesity,
smoking, and regular alcohol consumption.
The group ofpatients withpost‑COVID‑19 syndrome (MR)
In May and June of 2021, fourteen patients with post-
COVID-19 syndrome, from Sanatorium of Dr. Guhr, High
Tatras, Tatranská Polianka in Slovakia, were included in
this study (MR group—mountain spa rehabilitation). Ten
of them returned questionnaire of clinical symptoms before
and after MR. The group of patients at the time of admission
to mountain spa rehabilitation are marked as MR1 group,
the same group of patients after mountain spa rehabilitation
is marked as MR2 group. The mean age of the patients was
58.69 ± 2.64 years, (8 men and 6 women), BMI 29.85 ±
1.54 kg/m2.
COVID‑19 history ofthepatients withpost‑COVID‑19
The patients were hospitalized for three weeks in the period
from November 2020 to April 2021 for COVID-19. The
causes for hospitalization of these COVID-19 patients were
increased body temperature between 37.5 and 39.4°C (n =
8), bilateral pneumonia (n = 9), asthma bronchiale (n = 2),
dyslipoproteinemia (n = 8), and the necessity of oxygen
therapy (n = 8). In the patients, many clinical and psycho-
logical symptoms persisted during next 3–6 months after
hospitalization classified as post-COVID-19 syndrome. The
main symptoms on admission to MR were fatigue, cough,
loss of smell, impaired breathing during exercise, loss of
hair, and depression. In some patients, the loss of appetite
was accompanied with considerable weight loss.
Fig. 1 Effect of SARS-CoV-2
on platelet mitochondrial
respiratory chain and oxidative
phosphorylation in patients
after acute COVID-19. Legend:
SARS-CoV-2 in platelet mito-
chondria of patients after over-
coming the disease COVID-19
decreased the function of
mitochondrial respiratory chain
at complex I, endogenous level
of coenzyme Q10 in Q-CYCLE,
ATP production by oxidative
phosphorylation — Complex
V.; respiratory chain com-
plexes: I, II, III, IV, V; Q-cycle
of coenzyme Q10; cyt c —
cytochrome c; e — electron;
NADH — reduced nicotinamide
adenine dinucleotide; NAD+
nicotinamide adenine nucleo-
tide; FADH2 — flavin adenine
dinucleotide reduced; FAD+
flavin adenine nucleotide; O2
— superoxide radical; H2O2
— hydrogen peroxide; proteins;
lipids, DNA — deoxyribonu-
cleic acid; O2 — oxygen; H2O
— water; ADP — adenosine
diphosphate; ATP — adenosine
triphosphate; Pi — inorganic
Cyt C
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Functional capacity ofthelungs
The functional capacity of the lungs was evaluated in ten of
the fourteen patients by 6-min walking test (6MWT) (Brooks
etal. 2002; Casanova etal. 2011), exercise dyspnea during
6MWT by Borg scale (BS) (Borg 1982), and blood oxygen
saturation (SpO2) before and after 6MWT. The results are
summarized in Table1. These tests were performed before
(MR1) and after mountain spa rehabilitation (MR2). Blood
samples were collected the first morning after admission
to the mountain spa before (MR1) and after 16–18 days of
mountain spa rehabilitation (MR2).
Clinical symptoms ofpatients withpost‑COVID‑19
Patients completed a questionnaire (21 questions) before and
after MR. The results are summarized in Table2.
Blood count andbiochemical parameters
In all patients with post-COVID-19 syndrome blood counts,
blood lipid parameters, glucose, and CRP were determined
in Hospital of Dr. Vojtech Alexander in Kežmarok, High
Tatras, Slovakia. The determined parameters are summa-
rized in Table3.
Coenzyme Q10 determination
Total coenzyme Q10 concentration (ubiquinol + ubiqui-
none) in whole blood, plasma, and isolated platelets were
estimated using an isocratic HPLC method (Lang etal.
1986; Kucharská etal. 1998). For the oxidation of ubiqui-
nol to ubiquinone, 1,4-benzoquinone was added to blood
or plasma sample (Mosca etal. 2002). The concentrations
of CoQ10-TOTAL were calculated in μmol/L. The isolated
platelets were disintegrated with methanol (Niklowitz etal.
Table 1 Effect of MR on lungs function of patients with post-
COVID-19 syndrome
6MWT 6-min walking text; BS Borg scale; SpO2 blood oxygen satura-
tion; MR1 the patients with post-COVID-19 syndrome at the begin-
ning of the study; MR2 the patients with post-COVID-19 syndrome
after 16–18 days of MR; xp<0.05, xxp<0.01 vs MR1
Parameter MR1 (n = 10) MR2 (n = 10) MR2 vs
MR1 p
6MWT (m) 479 ± 40.9 566.2 ± 23.3 0.018x
BS (number) 5.9 ± 0.8 3.8 ± 0.5 0.004xx
SpO2 (%)
Before 6MWT 94.1 ± 0.59 94.1 ± 0.72 ns
After 6MWT 94.9 ± 0.60 93.9 ± 0.78 ns
Table 2 Effect of MR on
clinical symptoms of patients
with post-COVID-19 syndrome
Clinical symptom Before MR (MR1)
(number of symptoms)
After MR (MR2)
(number of symptoms)
Dry cough 3 3
Difficulty breathing 6 3
Shortness of breath in rest 4 3
Elevated temperature 2 0
Chills 2 1
Heart palpitations 3 1
Respiratory support with oxygen 0 0
Weakness 0 0
Overall fatigue 7 2
Malaise 2 2
GIT problems 0 0
Diarrhea 1 1
Chest pain 3 1
Muscle and joint pain 10 5
Back pain 0 0
Headache 4 0
Loss of taste and smell 0 0
Weight loss 1 1
Hearing impairment 2 0
Visual disturbance 3 1
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2004). Concentrations of CoQ10-TOTAL in platelets were cal-
culated in pmol/109 cells.
A parameter of oxidative stress — an indicator of lipid per-
oxidation in plasma — was determined spectrophotometri-
cally by measuring the formation of thiobarbituric acid reac-
tive substances (TBARS) (Janero and Bughardt 1989). The
concentration in μmol/L was calculated.
Platelets preparation
Platelets were isolated from whole blood as described pre-
viously (Sumbalova etal. 2018; Palacka etal. 2022) and
counted on hematological analyzer Mindray BC-3600 (Min-
dray, China).
High‑resolution respirometry
The mitochondrial bioenergetics in platelets was evaluated
by high-resolution respirometry (HRR) method (Pesta and
Gnaiger 2012; Sjovall etal. 2013). For the respirometric
assay, 250×106 platelets were used in a 2-mL chamber of
an O2k-Respirometer (Oroboros Instruments, Austria). The
respiration was measured at 37°C in mitochondrial respi-
ration medium MiR05 with addition of 20 mM creatine,
and under continuous stirring at 750 rpm. The data were
collected with DataLab software (Oroboros Instrument,
Austria) using a data recording interval of 2s (Pesta and
Gnaiger 2012; Doerrier etal. 2016). For evaluation of plate-
let mitochondrial bioenergetics, substrate-uncoupler-inhib-
itor (SUIT) protocol 1 (Doerrier etal. 2016) was applied
(Gvozdjáková etal. 2019). The representative trace is in
The cell suspension volume containing 250 × 106 plate-
lets was added to the 2-mL chamber of O2k-Respirometer
filled with the respiration medium. After stabilization at
ROUTINE respiration of intact platelets, digitonin (0.20
μg/106 cells) was added for plasma membrane permea-
bilization. Next, the chemicals were added in following
order: 1PM–CI-linked substrates pyruvate (5 mM) and
malate (2mM) were added to fuel CI-linked LEAK res-
piration; 2D — saturating ADP (1 mM) was added for
determination of CI-linked respiratory capacity of oxida-
tive phosphorylation (OXPHOS); 2D; c — cytochrome
c (10 μM) was added for testing the outer mitochondrial
membrane integrity; 3U — uncoupler FCCP (0.5 μM)
was added at optimum concentration for determination of
electron transfer (ET) capacity with CI-linked substrates
Table 3 Effect of MR on
blood count and metabolites of
patients with post-COVID-19
MR1 The patients before mountain spa rehabilitation; MR2 the patients after mountain spa rehabilita-
tion; WBC white blood cells, RBC red blood cells, HCT hematocrit, PLT platelets, MVC mean corpus-
cular volume, MCH mean corpuscular hemoglobin, MCHC mean corpuscular hemoglobin concentration,
HgB hemoglobin, CHOL total cholesterol, HDL-CH HDL cholesterol, LDL-CH LDL cholesterol, TAG
triacylglycerols, CRP c-reactive protein, GLU glucose. Data are presented as mean ± sem. The differ-
ences between MR1 and the control group, and between MR2 and MR1 group are statistically evaluated,
*p<0.05 vs control, XXp<0.01 vs MR1
Control (n = 15) MRl (n = 14) MR2 (n = 14) MR1 vs C p
MR2 vs MR1
p value
Blood count
WBC (109/L) 6.23 ± 0.47 6.99 ± 0.72 6.59 ± 0.64 0.396 0.327
RBC (109/L) 4.66 ± 0.12 4.62 ± 0.12 4.80 ± 0.09 0.717 0.008 xx
HCT (ratio) 0.410 ± 0.100 0.418 ± 0.01 0.438 ± 0.008 0.813 0.003 xx
PLT (109/L) 247.5 ± 16.1 213.9 ± 14.9 219.1 ± 11.2 0.154 0.556
MCV (fL) 87.14 ± 0.65 90.31 ± 1.26 91.21 ± 1.26 0.024* 0.009 xx
MCH (pg) 29.95 ± 0.28 31.58 ± 0.49 31.10 ± 0.41 0.014* 0.079
MCHC (g/L) 343.71 ± 2.53 349.61 ± 2.00 341.08 ± 1.21 0.273 0.002 xx
HgB (g/L) 140.67 ± 3.32 145.46 ± 3.44 149.23 ± 2.89 0.520 0.056
Lipid parameters
CHOL (mmol/L) 5.32 ± 0.27 5.507 ± 0.299 5.76 ± 0.397 0.707 0.264
HDL-CH (mmol/L) 1.41 ± 0.13 1.100 ± 0.086 1.121 ± 0.099 0.031* 0.632
LDL-CH (mmol/L) 3.09 ± 0.25 3.368 ± 0.287 3.344 ± 0.316 0.319 0.904
TAG (mmol/L) 2.05 ± 0.49 2.489 ± 0.555 3.224 ± 0.954 0.055 0.142
Other parameters
CRP (mg/L) 0.90 ± 0.20 1.80 ± 0.45 1.81 ± 0.53 0.721 0.950
GLU (mmol/L) 5.13 ± 0.17 6.17 ± 0.63 5.20 ± 0.26 0.139 0.069
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pyruvate+malate; 4G — glutamate (10 mM) was added
for evaluation of ET capacity with CI-linked substrates
pyruvate+malate+glutamate; 5S — CII-linked sub-
strate succinate (10 mM) was added for determination
of CI&CII-linked ET capacity. For evaluation of mito-
chondrial pathway–related rates (here labeled according
to titration steps), the rate after digitonin representing
residual oxygen consumption (ROX) was subtracted from
all respiratory rates (Fig.2).
Citrate synthase
The activity of citrate synthase as mitochondrial marker was
evaluated spectrophotometrically according to the method of
Srere (1969a, 1969b), described in detail by Eigentler etal.
(2020). The activity of CS is evaluated in μmol/min/106
Data analysis
The differences between parameters of the post-COVID-19
MR1 group and the control group were evaluated using
unpaired Student’s t test. For evaluation, the difference
between MR1 and MR2 paired Student’s t test was used. P
values <0.05 were considered statistically significant. The
results are shown as individual points and the mean ± stand-
ard error of mean (sem).
Pulmonary function of patients with post-COVID-19 syn-
drome was evaluated by 6-min walking test (6MWT), exer-
cise dyspnea by Borg scale (BS), and blood oxygen satu-
ration (SpO2). By 6MWT, the distance that a patient can
quickly walk in a period of 6 min is measured, reflecting
the functional pulmonary capacity. In our patients, 6MWT
test improved significantly after MR (from 479 ± 40.9 m
to 566.2 ± 23.3 m, p = 0.018), the walked distance dur-
ing the 6MWT increased by 87.2 m. Exercise dyspnea was
measured by BS points from 0 to 10. Zero on BS means
no dyspnea and 10 points on BS reflect maximal dyspnea
after 6MWT. Exercise dyspnea measured by BS statistically
significantly improved in patients with post-COVID-19 syn-
drome after MR by 2.1 points (from 5.9 ± 0.8 points to 3.8
± 0.5 points, p = 0.004). Physiological levels of SpO2 are
between 95 and 100%. SpO2 before 6MWT and after 6MWT
were without significant changes after MR (Table1).
Effect ofMR onclinical symptoms ofpatients
withpost‑COVID‑19 syndrome
From fourteen patients, ten patients filled out the question-
naire for evaluation of clinical symptoms before and after
MR. Several patients had more than three clinical symp-
toms of COVID-19 before MR. Many clinical symptoms
have improved after MR, as breathing difficulty, shortness
of breath, chills, heart palpitations, overall fatigue, muscle
Fig. 2 The trace from the measurement of platelet mitochondrial
respiration in freshly isolated platelets (Doerrier et al. 2016). Leg-
end: The blue line shows oxygen concentration (μM) and the red
trace oxygen consumption (pmol O2/s/106 cells). 250 × 106 platelets
were added into a 2-mL chamber of an O2k-Respirometer with mito-
chondrial respiration medium MiR05 plus 20 mM creatine at 37 °C
and continuous stirring (750 rpm). The titration steps are cells (ce),
digitonin (Dig); pyruvate plus malate (PM); adenosine diphosphate
(ADP); cytochrome c (cyt c); uncoupler FCCP (U); glutamate (G);
and succinate (S). All substrates were added in kinetically saturating
concentrations; FCCP was titrated in optimum concentration to reach
the maximum O2 flow. ce — intact cells; ROX — residual oxygen
consumption; CI — complex I pathway; CI&II — complex I and
complex II pathway; LEAK — non-phosphorylating resting state of
respiration (L); OXPHOS — the phosphorylating state of respiration
(P); ET — noncoupled state of respiration at optimum concentration
of uncoupler
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and joint pain, chest pain, headache, hearing impairment,
and visual disturbance (Table2).
Effect ofMR onblood count andmetabolites
ofpatients withpost‑COVID‑19 syndrome
MR significantly improved blood count, as the count of RBC
(p = 0.008), HCT (p = 0.003), MCV (p = 0.009), and HgB
(p = 0.056) were higher in MR2, and MCHC was lower
(p = 0.002) compared to MR1. Mean of lipids parameters
(CHOL, HDL-CH, LDL-CH, TAG) of post-COVID-19
patients showed dyslipoproteinemia. These parameters were
not influenced by mountain spa rehabilitation (Table3). CRP
was higher in patients with post-COVID-19 syndrome vs
control and did not improve after MR. Slightly higher blood
glucose level of the patients improved after MR (p = 0.069,
Effect ofMR onimpaired platelet mitochondrial
bioenergetics inpatients withpost‑COVID‑19
We used freshly isolated platelets from patients with post-
COVID-19 syndrome before MR (MR1) and after 16–18
days of special MR (MR2). All platelet respiratory param-
eters are expressed as JO2/CS (pmol/s/IU). The results of
platelet mitochondrial bioenergetics analysis are shown in
Fig.3 and in supplementary material Fig. S3A-S3H.
Detailed results are shown in supplementary material,
Fig. S3A–S3H. Routine respiration of intact platelets (ce)
was similar in all groups (Fig.3, Fig. S3A). The rate of
mitochondrial LEAK respiration with CI-linked substrates
(1PM) in MR1 group was lower (by 14.2%), although not
statistically significant in comparison with control group.
In MR2 group, mitochondrial LEAK respiration with CI-
linked substrates was significantly increased vs MR1 (by
47.8%, p = 0.029, Fig.3; Fig. S3B). CI-linked respiration
coupled with ATP production (2D — CI-linked oxidative
phosphorylation (OXPHOS) capacity) in the MR1 group
was significantly reduced (p = 0.0004) by 45.8% vs con-
trol group values. In MR2 group, this parameter associated
with ATP production was slightly improved (by 12.3% vs
MR1) (Fig.3; Fig. S3C). The respiration after addition of
cytochrome c (2D;c) in the MR1 group was decreased by
50.6% vs control group values (p = 0.00002), in MR2 group,
this parameter was slightly improved vs MR1 group (by
15.3%) (Fig.3; Fig. S3D). Maximal mitochondrial oxidative
capacity (the electron transfer capacity, ET) after uncoupler
titration (3U) was significantly reduced in MR1 group vs
control group (by 45.7%, p = 0.0002). In MR2 group, this
parameter was slightly improved vs MR1 (by 8.8%) (Fig.3;
Fig. S3E). After addition of CI-linked substrate glutamate
(4G), the ET capacity was significantly lower in MR1 group
vs control group (by 40.0%, p = 0.0005). This respiration
was slightly increased in MR2 group vs MR1 (by 15.6%,
Fig.3; Fig. S3F). ET capacity with CI&II-linked substrates
(5S) was lower in MR1 group vs control group (by 9.7%, p =
0.060). This parameter was slightly higher in MR2 vs MR1
group (by 4.8%, Fig.3; Fig. S3G). The mean improvement
of mitochondrial parameters representing OXPHOS and ET
capacity was 11.4% (from 4.8 to 15.6%) in comparison with
MR1 group, which was taken as 100% (Fig.3; Fig. S3C
– S3G).
The mitochondrial marker — the activity of citrate syn-
thase — was increased in patients with post-COVID-19
syndrome in comparison with control group (by 34.7%, p =
0.0004). After MR, the activity of citrate synthase in plate-
lets slightly decreased vs MR1 (by 10.8%, p = 0.092, Fig.4).
Effect ofMR onTBARS andendogenous CoQ10
inpatients withpost‑COVID‑19 syndrome
There was no significant difference in TBARS concentration
between control group and patients with post-COVID-19
syndrome. Endogenous concentration of CoQ10-TOTAL
(ubiquinone + ubiquinol) in platelets, blood, and plasma of
the post-COVID-19 syndrome group did not significantly
Fig. 3 Effect of mountain with spa rehabilitation on platelet mito-
chondrial bioenergetics in patients with post-COVID-19 syndrome.
Legend: ce: ROUTINE respiration of intact platelets; 1PM: com-
plex I-linked LEAK (state 4) respiration with substrates (pyru-
vate + malate); 2D: complex I-linked OXPHOS (state 3) respira-
tion capacity associated with CI-linked ATP production; 2D;c: The
OXPHOS capacity after cytochrome c addition; 3U: The respiration
after uncoupler FCCP titration represents CI-linked electron trans-
fer (ET) capacity with substrates pyruvate+malate; 4G: ET capacity
with substrates pyruvate+malate+glutamate; 5S: CI&CII-linked ET
capacity with substrates pyruvate + malate + glutamate + succinate,
(Doerrier etal. 2016; Gvozdjáková etal. 2019). The respiratory rates
are marked according the steps in the SUIT protocol 1 (see Fig.2).
Control — the control group; MR1 — patients before mountain spa
rehabilitation; MR2 — patients after mountain spa rehabilitation. CI
— complex I pathway; CI&CII — complex I and complex II path-
way; LEAK — the non-phosphorylating resting state of respiration;
OXPHOS — the phosphorylating state of respiration; ET — the non-
coupled state of respiration at optimum uncoupler concentration
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differ from the control group and did not change after MR
WHO recommended rehabilitation (WHO 2022) and ESPA
recommended spa rehabilitation of the patients with post-
COVID-19 syndrome. The rehabilitation improved pul-
monary function, exercise capacity, and quality of life of
patients with post-acute phase of COVID-19 (Nalbandian
etal. 2021; Schaeffer etal. 2022). Other authors used reha-
bilitation based on respiratory physiotherapy techniques, on
exercise training or in combination with yoga (Srinivasan
etal. 2021; Herrera etal. 2021).
The current pilot study was undertaken to determine
the effect of high-altitude environment and targeted reha-
bilitation in spa on pulmonary function, clinical symp-
toms, endogenous coenzyme Q10 levels, oxidative stress,
and platelet mitochondrial oxidative phosphorylation
(OXPHOS) function in patients with post-COVID-19
syndrome. In high-altitude environment of High Tatras
in Slovakia, spa rehabilitation in Sanatorium of Dr. Guhr,
Tatranská Polianka is used for curing chronic pulmonary
diseases for many years. The Sanatorium is located at alti-
tude of 1005 m above sea level, in the zone of forests with
dry air, favorable solar radiation, reduced partial oxygen
pressure and air pressure, and with a mild, relatively stable
daily temperature (Gvozdjáková etal. 2019). For patients
with post-COVID-19 syndrome in high-altitude environ-
ment and spa rehabilitation program include walking,
breathing exercises, oxygen therapy, exercise, water pro-
cedures, massages, psychological support, and education
(Jendrichovsky etal. 2021; Tiku etal. 2020). The reha-
bilitation program is individualized for the improvement
of mental health, to prevent skeletal muscle hypotrophy
with a focus on increasing the rate of daily movement and
overall patient activity.
Beneficial effect of pulmonary rehabilitation was docu-
mented in patients with chronic respiratory disease (Spruit
etal. 2013). Improvements in exercise capacity, dyspnea,
fatigue, anxiety, and depression after a pulmonary rehabilita-
tion were reported by Soril etal. (2022). We evaluated pulmo-
nary function of patients with post-COVID-19 syndrome by
6MWT, BS, and SpO2. By 6-min walking test, the distance
that a patient can quickly walk in a period of 6 min (6MWT)
is measured, reflecting the functional pulmonary capacity
(Brooks etal. 2002; Casanova etal. 2011). After MR2 6MWT
improved significantly (p = 0.018), the walking distance
increased by 87.2 m. The increase in 6MWT by 70 m is con-
sidered clinically important for patients. Exercise dyspnea was
evaluated by Borg scale (Borg 1982). After MR2, the exercise
dyspnea was significantly improved (p = 0.004). An improve-
ment by 0.5 point on BS is considered as an improvement of
lung function. Oxygen saturation (SpO2) levels before and after
6MWT were without significant changes after MR (Table1).
Rehabilitation of patients in a high-altitude environment
reduced the extent of physical, cognitive, and mental impair-
ment (as breathing, total fatigue, muscle, joint and chest
pain, headache, memory impairment, depression, hearing
impairment, visual disturbances), and improved the quality
of life of patients with post-COVID-19 syndrome (Table2).
Although special rehabilitation in the Sanatorium lasted only
16–18 days, the positive effect of MR was manifested in
patients with post-COVID-19 syndrome.
Fig. 4 Effect of MR on citrate synthase activity in platelets of patients
with post-COVID-19 syndrome. Legend: CS — citrate synthase;
MR1 — before mountain spa rehabilitation; MR2 — after mountain
spa rehabilitation
Table 4 Effect of MR on lipid
peroxidation and CoQ10-TOTAL
concentration of patients with
post-COVID-19 syndrome
TBARS indicator of lipid peroxidation; CoQ10-TOTAL ubiquinol + ubiquinone; MR1 before mountain spa
rehabilitation; MR2 after mountain spa rehabilitation;
Parameter Control (n = 15) MR1 (n = 14) MR2 (n = 14)
TBARS in plasma (μmol/L) 4.80 ± 0.18 4.65 ± 0.16 4.52 ± 0.17
CoQ10-TOTAL in:
Platelets (pmol/109 cells) 84.14 ± 5.56 93.92 ± 5.92 91.47 ± 7.11
Blood (μmol/L) 0.313 ± 0.020 0.366 ± 0.035 0.315 ± 0.017
Plasma (μmol/L) 0.516 ± 0.032 0.516 ± 0.045 0.509 ± 0.035
14207Environmental Science and Pollution Research (2023) 30:14200–14211
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Several pathobiochemical mechanisms participate in
virus infection on cellular and subcellular level. Mitochon-
dria (subcellular particles) play a central role in the primary
host defense mechanisms against viral infections, and in
these processes, a number of novel viral and mitochondrial
proteins are involved. One possible mechanism of SARS-
CoV-2 effect is a manipulation of mitochondrial bioenerget-
ics indirectly, by ACE2 regulation, and the other possibility
is manipulation by localizing ORF-9b (open reading frame)
protein to mitochondria. Manipulations of host mitochon-
dria by viral ORFs can release mtDNA in the cytoplasm,
activate mtDNA-induced inflammasome, and suppress
innate and adaptive immunity (Singh etal. 2020; Singh
etal. 2021). In the pathological conditions, as by virus acti-
vated cells, their request for energy production is increased
(Singh etal. 2020). Under physiological conditions, plate-
lets receive approximately 60% of energy from glycolysis
and 40% energy from OXPHOS (Gatti etal. 2020; Warburg
etal. 1927). Other mechanism of SARS-CoV-2 virus is its
role in manipulating mitochondrial function. SARS-CoV-2
hijacks of host mitochondria of immune cells in COVID-
19 disease (Singh etal. 2020), and impairs mitochondrial
dynamics leading to cell death (Ganji and Reddy 2021; Seth
etal. 2005). Mitochondrial “hijacking” by SARS-CoV-2
virus could be a key factor in the pathogenesis of this virus
and induction of COVID-19 (Saleh etal. 2020; Singh etal.
2021). A good mitochondrial fitness could be considered
as a protective factor against viral infections, including
COVID-19 (Maccarone and Mesiero 2021; Burtscher etal.
2021; Jimeno-Almazán etal. 2021).
Mitochondrial antiviral signaling protein (MAVS), asso-
ciated with the outer mitochondrial membrane, mediates
the activation of NFK-B and the induction of interferons in
response to viral infection (Sun etal. 2006; Seth etal. 2005).
Many viruses target mitochondrial metabolism, dynamics,
mitochondrial bioenergetics, membrane potential, ion per-
meability, induce reactive oxygen species production, alter
the Ca2+ regulatory activity, and cause oxidative stress in
host cells (Anand and Tikoo 2013; Elesela and Lukacs
2021). Viruses can modulate apoptosis and mitochondrial
antiviral immunity, alter intracellular distribution of mito-
chondria, cause host mitochondrial DNA depletion for their
survival in the cell (Ohta and Nishiyama 2011; Ripoli etal.
2010; Di Gennaro etal. 2020). Progression of the disease
in COVID-19 patients involves “cytokine storm” with iron
dysregulation (as hyperferritinemia) which induces ROS
production and oxidative stress (Saleh etal. 2020).
The regeneration of mitochondria impaired by SARS-
CoV-2 viruses can be achieved by various means including
breathing exercises, increased physical activities, reduction
of daily calories intake, enhanced daily intake of food with
antioxidants properties (Ganji and Reddy 2021), spa rehabili-
tation (Wang etal. 2020; Maccarone and Mesiero 2021), and
targeted coenzyme Q10 supplementation (Gvozdjáková etal.
2019). This pilot study showed significant deficit of platelet
mitochondrial complex I-linked ET capacity and OXPHOS
respiration associated with ATP production in patients with
post-COVID-19 syndrome which were improved by spa
rehabilitation in a high-altitude environment.
An essential component of the mitochondrial respira-
tory chain for energy (adenosine triphosphate) production
is coenzyme Q10 (CoQ10) with antioxidant properties. In
physiological conditions, CoQ10 transports electrons from
complex I and complex II to complex III. Complexes of
respiratory chain (CI, CIII, and IV) are organized in super-
complexes minimizing the distance for electron transfer. In
the pathological conditions, electron flux from CoQ can be
reversed to CI reducing NAD+ — the phenomenon known as
the reverse electron transfer (RET) (Hidalgo-Gutiérrez etal.
2021; Scialo etal. 2017). We suppose that impaired platelet
mitochondrial metabolism in patients with post-COVID-19
syndrome can contribute to the reprogramming of mitochon-
drial OXPHOS toward glycolysis.
Viral infections induce production of reactive oxygen spe-
cies, which can contribute to the alterations of mitochon-
drial bioenergetics. Different viruses are able to modulate
antioxidant enzymes (Singh etal. 2021; Hidalgo-Gutiérrez
etal. 2021). In our patients, the endogenous CoQ10 levels
and TBARS in plasma of patients with post-COVID-19 syn-
drome were similar to control data, probably as a result of
therapy with oxygen and drugs with antioxidant properties
before starting MR.
High-altitude of the mountain spa environment improved
mitochondrial fitness as could be seen from improved CI-
linked OXPHOS and ET capacity of platelet mitochondria
of patients with post-COVID-19 syndrome (Fig.3, Fig.
S3E – S3G). In MR2 group, platelet mitochondrial CI-
linked LEAK respiration (L) was significantly increased
vs MR1 (Fig.3, Fig. S3B). The parameter P-L control effi-
ciency (Gnaiger 2020) calculated from ADP-stimulated and
LEAK reaspiration as (P-L)/P was slightly lower in the MR1
group vs controls, and after MR declined by 9.5% vs MR1
(p = 0.055) (Fig.3, Fig. S3H). This parameter with values
from 0 to 1 is a measure of coupling control efficiency. The
mechanisms leading to decreased P-L control efficiency
after MR in patients with post-COVID-19 syndrome could
be a matter of further research. It could be speculated that
increased physical activity in MR could induce oxidative
stress mediating higher proton conductance of inner mito-
chondrial membrane at high proton motive force (at LEAK
state), preventing this way increased ROS production by
platelet mitochondria. An increase in LEAK respiration and
a decrease in P-L control efficiency was found in platelets
of ultramarathon runners after the race, reflecting increased
proton leakage across the inner mitochondrial membrane
(Hoppel etal. 2021). The increased CS activity in platelets
14208 Environmental Science and Pollution Research (2023) 30:14200–14211
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Content courtesy of Springer Nature, terms of use apply. Rights reserved.
of patients with post-COVID-19 syndrome may indicate
increased density of mitochondria as a compensation for
their decreased function.
Comprehensive strategy for virus pandemic has to be based
on medical evidence, on effective vaccines to decrease
mortality, to improve economic growth and socioeconomic
system. Spa rehabilitation in high-altitude environment
contributes to the acceleration of patients’ health and to the
reduction of socioeconomic problems. Our pilot findings
contribute to the understanding of the role of mitochondria
in the pathogenesis of COVID-19. Mountain spa rehabilita-
tion can be recommended for the acceleration of recovery
of patients with post-COVID-19 syndrome.
Limitations of these pilot results include relatively short
time of mountain spa rehabilitation (16–18 days) paid by
the insurance company and number of patients with post-
COVID-19 syndrome (n = 14).
Supplementary Information The online version contains supplemen-
tary material available at https:// doi. org/ 10. 1007/ s11356- 022- 22949-2.
Acknowledgements We thank the National Institute for Pediatric Res-
piratory Diseases and Tuberculosis, n.o., Dolný Smokovec, Slovakia,
for collaboration in counting of isolated platelets. Technical assistance,
Anna Štetková and Jana Bertalanová, from Pharmacobiochemical Lab-
oratory of 3rd Department of Internal Medicine, Faculty of Medicine,
Comenius University in Bratislava, Slovakia.
Author contribution Anna Gvozdjáková and Eleonóra Kovalčíková
designed the study. The first draft of the manuscript was written by
Anna Gvozdjáková, and all authors commented of previous versions of
the manuscript. Patrik Palacka and Timea Takácsová collected clinical
data. Zuzana Sumbalová and Zuzana Rausová measured and evalu-
ated platelet mitochondrial function; Jarmila Kucharská measured and
evaluated antioxidants. Zuzana Sumbalová performed the statistical
analysis and created figures. Viliam Mojto reviewed the manuscript.
Plácido Navas and Guillermo López-Lluch reviewed and completed
the manuscript. All authors read and approved the final manuscript.
Funding This research was partially funded by the Comenius Univer-
sity in Bratislava, Faculty of Medicine and by OncoReSearch, Rovinka,
Data availability The supporting data are available from the authors
upon request.
Institutional review board statement The study was carried out accord-
ing to the principles expressed in the Declaration of Helsinki (World
Medical Association 2022), and the study protocol was approved by
the Ethics Committee of Dérer’s Hospital in Bratislava, Limbová 5, 833
05 Bratislava, Slovakia, Code: 12/2021. The randomized controlled
clinical trials registration number is NCT05178225.
Consent to participate Written informed consent form was obtained
from each participant before including to the study group.
Consent for publication The authors declare that they have all rights
to publish the presented anonymous data.
Competing of interest The authors declare no competing interests.
Open Access This article is licensed under a Creative Commons Attri-
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... A meta-analysis of studies of mountain climate therapy (HACT) for asthma confirmed its efficacy in improving lung function [9,12]. According to the current pilot research study conducted by Gvozdjakova et al. in 2022 [13], pulmonary rehabilitation in a mountain environment may improve platelet mitochondrial bioenergetics, improve functional capacity (dyspnoea), and accelerate patient recovery. A previous study showed that platelet mitochondrial respiration parameters were improved in patients with post-COVID-19 syndrome following this rehabilitation method [13]. ...
... According to the current pilot research study conducted by Gvozdjakova et al. in 2022 [13], pulmonary rehabilitation in a mountain environment may improve platelet mitochondrial bioenergetics, improve functional capacity (dyspnoea), and accelerate patient recovery. A previous study showed that platelet mitochondrial respiration parameters were improved in patients with post-COVID-19 syndrome following this rehabilitation method [13]. Similarly, in an experimental study involving climate therapy, improvements in mitochondrial complex I (CI) capacity parameters associated with oxidative phosphorylation (OXPHOS) and electron transfer (ET) in platelets were found [14]. ...
... These modalities have been introduced into medical practice largely on the basis of empirical findings as well as assumptions about the beneficial effects of environmental modification; despite this, up to this time we have no satisfactory experience and scientific information about the influence of environmental and climatic conditions on human health [12]. Therefore, researchers are looking for as much experimental [11,13,14] and clinical evidence [15,32] as possible on the effectiveness of this therapy. This study aimed to determine whether there is a difference in the predictors of clinically significant improvement between the traditional (value of 4) and newly proposed MCID SGRQ (value of 7) after climatic rehabilitation treatment. ...
Full-text available
Background: The minimum clinically important difference (MCID) for the St George's Respiratory Questionnaire (SGRQ) is debated in chronic obstructive pulmonary disease (COPD) quality-of-life (QoL) assessments. This study aimed to determine whether there is a difference in predictors of clinically significant improvement between the traditional (value of 4) and newly proposed MCID SGRQ (value of 7) after climatic rehabilitation treatment. Climatic rehabilitation treatment consists of two main parts: climatotherapy, which typically involves the controlled exposure of individuals to natural environmental elements, and climatic rehabilitation, which includes other therapeutic factors such as physical activities as well as educating the patient to change their lifestyle. Methods: This study included 90 consecutive patients diagnosed with COPD who underwent structured complex pulmonary rehabilitation in High Tatras, part of the Carpathian Mountains. The examination before and after treatment included spirometry, QoL assessment using the SGRQ, 6 min walk test (6-MWT), and the Borg, Beck and Zung scale. Results: Patients showed statistically significant improvement after the intervention in FEV1, FEV1/FVC, 6-MWT, (p < 0.001), anxiety scores, depression, and improvement in dyspnoea both before and after the 6-MWT (p < 0.001). For both MCID for SGRQ levels 4 and 7, we confirmed the same predictors of clinical improvement for bronchial obstruction grade (spirometry) and exercise capacity (6-MWT), for quality of life in activity score and total score. Conclusion: The results suggest that both the proposed MCID for SGRQ values could be sufficient to assess the clinical significance of the achieved change in health status when assessing the need for pulmonary rehabilitation comprising climatotherapy in patients with COPD.
... The virus may modulate antiviral immunity signaling, alter the intracellular distribution of mitochondria, induce platelet dysfunction and aggregation, increase oxidative stress, and reduce antioxidant protection [10]. In 2020 we hypothesized that mitochondria and endogenous coenzyme Q10 (CoQ10) biosynthesis may be the targets of the SARS-CoV-2 virus [11], and two years later we documented platelet mitochondrial bioenergy dysfunction, reduced endogenous CoQ10 level and oxidative stress in patients with post-COVID-19 syndrome [12,13]. ...
... The importance of endogenous CoQ10 biosynthesis for immune response and reducing the severity of SARS-CoV-2 virus infection has been published [12,25]. CoQ10 is an integral part of the mitochondrial respiratory chain in the inner membrane and a key substance for ATP production. ...
... Cytochrome c transfers the electrons to oxygen through Complex IV (cytochrome c oxidase). Protons are pumped to the mitochondrial intermembrane space and proton motive force is produced, which is used for ATP synthesis at Complex V (by ATP synthase) via oxidative phosphorylation [12,27]. ...
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Background: Mitochondrial dysfunction and redox cellular imbalance indicate crucial function in COVID-19 pathogenesis. Since 11 March 2020, a global pandemic, health crisis and economic disruption has been caused by SARS-CoV-2 virus. Vaccination is considered one of the most effective strategies for preventing viral infection. We tested the hypothesis that preventive vaccination affects the reduced bioenergetics of platelet mitochondria and the biosynthesis of endogenous coenzyme Q10 (CoQ10) in patients with post-acute COVID-19. Material and methods: 10 vaccinated patients with post-acute COVID-19 (V + PAC19) and 10 unvaccinated patients with post-acute COVID-19 (PAC19) were included in the study. The control group (C) consisted of 16 healthy volunteers. Platelet mitochondrial bioenergy function was determined with HRR method. CoQ10, γ-tocopherol, α-tocopherol and β-carotene were determined by HPLC, TBARS (thiobarbituric acid reactive substances) were determined spectrophotometrically. Results: Vaccination protected platelet mitochondrial bioenergy function but not endogenous CoQ10 levels, in patients with post-acute COVID-19. Conclusions: Vaccination against SARS-CoV-2 virus infection prevented the reduction of platelet mitochondrial respiration and energy production. The mechanism of suppression of CoQ10 levels by SARS-CoV-2 virus is not fully known. Methods for the determination of CoQ10 and HRR can be used for monitoring of mitochondrial bioenergetics and targeted therapy of patients with post-acute COVID-19.
... Therefore, hot-spring scenic spots should provide different tourism products and adopt different marketing strategies in different seasons (Grossi and Mussini 2021;Li and Chi 2014). The marketing departments could also develop some cultural and entertainment products to weaken the seasonality of hot-spring scenic spots (Gvozdjáková et al. 2022;Zhang et al. 2022). ...
... Second, tourism enterprises should adjust and upgrade their products and services and conduct more publicity to minimise the adverse effects of climate change. For hot-spring spots, health and entertainment elements can be integrated according to the climate to attract potential visitors (Gvozdjáková et al. 2022). Finally, tourists should change their stereotypical attitude of travelling only in fine weather and choose their preferred scenic spots according to different weather conditions. ...
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Hot-spring tourism refers to entertainment, health preservation, commercial conferences, and other leisure activities at hot-spring locations. This tourism often shows periodic variability, which may be due to seasonal temperature variations. However, studies on the effects of temperature variations on tourist arrivals at hot springs are limited. Therefore, this study aimed to evaluate this relationship in 31 provincial capital cities and 13 s-tier cities in China. Using the Baidu Index, we obtained data for tourist arrivals to hot springs in each city and constructed a generalised additive model to explore the associations between temperature variations and tourist arrivals. We also analysed the statistical significance of the estimated effects during different seasons to explore potential effect modification. A 1 °C increase in temperature was associated with a 1.81% (95% confidence interval (CI): 1.69–1.93) decrease in daily tourist arrivals for hot-spring tourism. Significant positive associations between the abovementioned factors were observed in summer (2.18% change, 95% CI: 1.32–3.04). The effect of temperature on the volume of tourist arrivals may last for approximately 2 months. Robustness analysis confirmed the data reliability. The results indicate that significant relationships exist between temperature variations and hot-spring tourism arrivals, which vary seasonally. This study has significant implications for travel agencies to effectively manage tourist visits to hot spring locations.
... The evaluated respiratory capacities are marked according to the titration steps in the reference protocol 1 and correspond to following respiratory states: ce-routine respiration of intact cells; Dig-residual oxygen consumption (ROX) after permeabilization with digitonin; 1PM-LEAK respiration with CI-linked substrates pyruvate + malate; 2D-CI-linked OXPHOS capacity; 2D; c-CI-linked OXPHOS capacity after addition of cytochrome c; 3U-CI-linked electron transfer (ET) capacity with pyruvate + malate; 4G-CI-linked ET capacity with pyruvate + malate + glutamate; 5S-CI&II-linked ET capacity. (Author ZS, published in Gvozdjáková et al., 2022). ...
... It should be emphasized that all these patients were with depressed mitochondrial function lasting for 3-7 months and this enormous improvement was seen within 1 month of a spa rehabilitation supported by CoQ 10 supplementation. In platelets of patients of the MR group the mean increase of mitochondrial CI-linked OXPHOS and ET capacity after the rehabilitation program was +13.8% and +12.2% (Gvozdjáková et al., 2022), in both cases representing only half of that achieved during the same time in patients simultaneously supplemented with CoQ 10 . ...
Full-text available
European Association of Spa Rehabilitation recommend spa rehabilitation for patients with post COVID-19 syndrome (post C-19). We studied effects of special mountain spa rehabilitation program and its combination with ubiquinol (reduced form of coenzyme Q 10 —CoQ 10 ) supplementation on pulmonary function, clinical symptoms, endogenous CoQ 10 levels, and platelet mitochondrial bioenergetics of patients with post C-19. 36 patients with post C-19 enrolled for rehabilitation in mountain spa resort and 15 healthy volunteers representing the control group were included in this study. 14 patients with post C-19 (MR group) were on mountain spa rehabilitation lasting 16–18 days, 22 patients (MRQ group) were supplemented with ubiquinol (2 × 100 mg/day) during the rehabilitation and additional 12–14 days at home. Clinical symptoms and functional capacity of the lungs were determined in the patients before and after the spa rehabilitation program. Platelet bioenergetics by high-resolution respirometry, plasma TBARS concentration, and CoQ 10 concentration in blood, plasma and platelets were evaluated before and after the spa rehabilitation program, and in 8 patients of MRQ group also after additional 12–14 days of CoQ 10 supplementation. Pulmonary function and clinical symptoms improved after the rehabilitation program in both groups, 51.8% of symptoms disappeared in the MR group and 62.8% in the MRQ group. Platelet mitochondrial Complex I (CI)-linked oxidative phosphorylation (OXPHOS) and electron transfer (ET) capacity were markedly reduced in both groups of patients. After the rehabilitation program the improvement of these parameters was significant in the MRQ group and moderate in the MR group. CI-linked OXPHOS and ET capacity increased further after additional 12–14 days of CoQ 10 supplementation. CoQ 10 concentration in platelets, blood and plasma markedly raised after the spa rehabilitation with ubiquinol supplementation, not in non-supplemented group. In the MRQ group all parameters of platelet mitochondrial respiration correlated with CoQ 10 concentration in platelets, and the increase in CI-linked OXPHOS and ET capacity correlated with the increase of CoQ 10 concentration in platelets. Our data show a significant role of supplemented ubiquinol in accelerating the recovery of mitochondrial health in patients with post C-19. Mountain spa rehabilitation with coenzyme Q 10 supplementation could be recommended to patients with post C-19. This study was registered as a clinical trial: ID: NCT05178225.
... Currently, the European SPA Association (European SPA Association) is emphasizing the importance of spa treatment for the prevention and prophylaxis of health and maintenance of an adequate status of the immune system (Katsarova (2022)). Balneotherapy (SPA-therapy) is recommended by the European SPA association after COVID-19, for better recovery of health and limitation of long-term symptoms in patients with post-COVID-19 syndrome (PCS) (Gvozdjáková et al. (2023)). This therapeutic approach could be effective in patients whose main symptoms include: general fatigue, decreased physical activity, muscle and joint pain, shortness of breath, cough, augesia and anosmia, sleep problems and cognitive and memory disorders, depression, impaired quality of life. ...
Full-text available
Balneotherapy is one of the most used therapies, where natural factors are applied for treatment and prevention. It is used in various pathological conditions, with evidence of a good effect in rheumatic and neurological diseases, and in recent years also in patients recovering from COVID-19. The therapeutic factors that are used include: natural mineral or thermal waters, natural peloids (mud) and other environmental therapeutic factors. The pandemic of COVID-19 turned out to be a significant factor that led to changes in lifestyle and habits and, accordingly, the use of balneotherapy procedures for prevention and treatment. Balneotherapy (SPA-therapy) is recommended by the European SPA association after COVID-19, for better recovery of health and limitation of long-term symptoms in patients with post-COVID-19 syndrome (PCS). It is suggested that balneo-climate-treatment can improve lung function, increase the physical activity capacity and the performance of therapeutic exercises as well as the quality of life of patients in the recovery phase after COVID-19. The purpose of the present review is to investigate the benefits and effectiveness of both balneo and mud therapy in patients with long-term post-COVID-19 sequelae. Materials and methods: For the purpose of the present study, a review was made of the known scientific articles published in the world databases (Google Scholar, Pubmed, Science Direct Web of Science, Scopus, and literary sources in Cyrillic). The results were searched for the following keywords: post-COVID-19 condition, long-term effects of COVID-19, post-COVID-19 syndrome (PCS), rehabilitation, balneotherapy, SPA therapy, peloidotherapy, mud treatment, lye therapy, treatment with Rapa (highly concentrated solution of salts (most often NaCl)). Results: The review of the scientific literature published in specific medical journals found evidence for the therapeutic effectiveness and benefits of balneo and mud therapy in patients with long-term consequences of COVID-19. The described application methods are characterized by variety in the application methodology, both for external (baths, bathtubs, showers, therapeutic SPA applications) and for internal application (mainly through inhalations). On the other hand, different recommendations were found regarding the type and chemical characteristics of mineral (thermal) water and therapeutic mud that are preferred for therapy. Overwhelmingly, studies recommend combining balneo (SPA) and mud therapy with resort and climate treatment, moderate physical activity and a dietary regimen tailored to the individual characteristics of patients. Conclusion: Balneo (SPA) treatment, therapies with natural and preformed physical factors could have a preventive role, in order to improve the body’s reactivity to the adverse factors of the external environment and pathogenic microorganisms and to increase insusceptibility to infectious diseases.
... Regeneration of mitochondria damaged by SARS-CoV-2 virus can be achieved by a variety of means, including respiratory exercise, increased physical activity, reduction in daily caloric intake, increased daily intake of food with antioxidant properties (Ganji and Reddy (2021)), balneo-rehabilitation (Maccarone, Mesiero (2021)), and targeted supplementation with coenzyme Q 10. (Gvozdjáková et al. (2019)). Gvozdjáková et al. (2022)) conducted a study in sanatorium conditions at an altitude of 1005m ((Tatranská Polianka High Tatras in Slovakia) on healthy volunteers and PCS patients whose symptoms included: breathing difficulties, shortness of breath, chills, heart palpitations, general fatigue, muscle and joint pain, chest pain, headaches, hearing impairment and visual disturbances (Gvozdjáková et al. (2023)). As a result of the study, Gvozdjáková et al. (2022) found that mountain climatotherapy reduced: the extent of physical, cognitive and mental impairment; general fatigue, muscle, joint and chest pain, headaches, memory impairment and depression; increased red blood cell (RBC) count, MCV and HgB, MCHC was reduced compared to baseline; as well as the blood glucose level. ...
Full-text available
Medical Climatotherapy in sanatorium conditions is a traditional method applied by Physical and Rehabilitation Medicine in the convalescent period, after infectious and non-infectious diseases. Rehabilitation is an essential part of long-term medical care after COVID-19 and is a very important element in the recovery process. A large number of patients in the recovery phase after SARS-CoV-2 infection have prolonged clinical symptoms that can persist for weeks and months after the acute phase of illness. In conjunction with the increasing number of patients who have survived coronavirus infection, the need for post-coronavirus care to recover and overcome residual clinical symptoms is also increasing. The long-lasting effects of COVID-19 can be manifested by respiratory system impairments, but also any other system in the body, including musculoskeletal symptoms, decreased physical capacity, reduced quality of life and psycho-emotional symptoms. In resort settings, natural physical factors are combined with preformed physical factors together with appropriate physical activity, nutritional and dietary regime. The main resort factors are: climate, mineral waters and healing mud. There is a growing need to develop an effective strategy and management of post-acute rehabilitation measures for post-COVID-19 patients to address a large contingent of those in need with a focus on older people with co-morbidities. Medical rehabilitation provides opportunities for a continuum of care that can be successfully delivered in a resort setting in the absence of contraindications. Aim: to investigate the potential benefits of the application of climato-resort treatment in patients in period of recovery with symptoms of Long COVID-19 or post COVID-19 syndrome (PCS). Materials and Methods: a review of the available scientific literature was conducted, covering global databases (Pubmed, Google Scholar, Science Direct) using keywords that included the terms: post COVID-19 condition, SPA/Resort treatment, mountain climatotherapy, thalassotherapy, rehabilitation, functional recovery. Results: A review of the specialist literature found evidence for the therapeutic benefits of conducting rehabilitation in a resort setting. The application of natural and preformed physical factors resulted in overcoming residual symptoms on the broncho-pulmonary system, improving the functional capacity of the respiratory system and skeletal musculature, increasing the tolerance to exercises and physical activity, and influencing the psycho-emotional consequences of COVID-19. Conclusions: Resort and climatotherapy can be an important factor in the recovery process after COVID-19, for prevention and improvement of the body's resistance to the adverse effects of environmental factors, infectious agents, and the negative effects of modern lifestyle.
... The control of chronic inflammation is key in the progression of aging and in the response to damages produced by pathogens. For example, recent studies on COVID-19 patients have demonstrated a protective effect of CoQ 10 on the sequelae produced by the disease reducing oxidative damage and inflammation Kucharska et al., 2023;Sumbalova et al., 2022). ...
Mitochondrial dysfunction is one of the main factors that affects aging progression and many age-related diseases. Accumulation of dysfunctional mitochondria can be driven by unbalanced mito/autophagy or by decrease in mitochondrial biosynthesis and turnover. Coenzyme Q is an essential component of the mitochondrial electron transport chain and a key factor in the protection of membrane and mitochondrial DNA against oxidation. Coenzyme Q levels decay during aging and this can be considered an accelerating factor in mitochondrial dysfunction and aging progression. Supplementation with coenzyme Q is successful for some tissues and organs but not for others. For this reason, the role of coenzyme Q in systemic aging is a complex picture that needs different strategies depending on the organ considered the main objective to be addressed. In this chapter we focus on the different effects of coenzyme Q and related compounds and the probable strategies to induce endogenous synthesis to maintain healthy aging.
Full-text available
Mitochondrial bioenergetics reprogramming is an essential response of cells to stress. Platelets, an accessible source of mitochondria, have a crucial role in cancer development; however, the platelet mitochondrial function has not been studied in urothelial carcinoma (UC) patients. A total of 15 patients with UC and 15 healthy controls were included in the study. Parameters of platelet mitochondrial respiration were evaluated using the high-resolution respirometry method, and the selected antioxidant levels were determined by HPLC. In addition, oxidative stress was evaluated by the thiobarbituric acid reactive substances (TBARS) concentration in plasma. We demonstrated deficient platelet mitochondrial respiratory chain functions, oxidative phosphorylation (OXPHOS), and electron transfer (ET) capacity with complex I (CI)-linked substrates, and reduced the endogenous platelet coenzyme Q10 (CoQ10) concentration in UC patients. The activity of citrate synthase was decreased in UC patients vs. controls (p = 0.0191). γ-tocopherol, α-tocopherol in platelets, and β-carotene in plasma were significantly lower in UC patients (p = 0.0019; p = 0.02; p = 0.0387, respectively), whereas the plasma concentration of TBARS was increased (p = 0.0022) vs. controls. The changes in platelet mitochondrial bioenergetics are consistent with cell metabolism reprogramming in UC patients. We suppose that increased oxidative stress, decreased OXPHOS, and a reduced platelet endogenous CoQ10 level can contribute to the reprogramming of platelet mitochondrial OXPHOS toward the activation of glycolysis. The impaired mitochondrial function can contribute to increased oxidative stress by triggering the reverse electron transport from the CoQ10 cycle (Q-junction) to CI.
Full-text available
Background: After an acute treatment for coronavirus disease (COVID-19), some symptoms may persist for several weeks, for example: fatigue, headaches, muscle and joint pain, cough, loss of taste and smell, sleep and memory disturbances, depression. Many viruses manipulate mitochondrial function, but the exact mechanisms of SARS-CoV-2 virus effect remain unclear. We tested the hypothesis that SARS-CoV-2 virus may affect mitochondrial energy production and endogenous biosynthesis of coenzyme Q10 (CoQ10). Methods: Ten patients after COVID-19 and 15 healthy individuals were included in the study. Platelets isolated from peripheral blood were used as an accessible source of mitochondria. High-resolution respirometry for the evaluation of platelets mitochondrial function, and HPLC method for CoQ10 determination were used. Oxidative stress was evaluated by TBARS concentration in plasma. Results: Platelet mitochondrial respiratory chain function, oxidative phosphorylation and endogenous CoQ10 level were reduced in the patients after COVID-19. Conclusion: We assume that a reduced concentration of endogenous CoQ10 may partially block electron transfer in the respiratory chain resulting in a reduced adenosine triphosphate (ATP) production in the patients after COVID-19. Targeted mitochondrial therapy with CoQ10 supplementation and spa rehabilitation may improve mitochondrial health and accelerate the recovery of the patients after COVID-19. Platelet mitochondrial function and CoQ10 content may be useful mitochondrial health biomarkers after SARS-CoV-2 infection (Tab. 3, Fig. 3, Ref. 46).
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Mitochondria are vital intracellular organelles that play an important role in regulating various intracellular events such as metabolism, bioenergetics, cell death (apoptosis), and innate immune signaling. Mitochondrial fission, fusion, and membrane potential play a central role in maintaining mitochondrial dynamics and the overall shape of mitochondria. Viruses change the dynamics of the mitochondria by altering the mitochondrial processes/functions, such as autophagy, mitophagy, and enzymes involved in metabolism. In addition, viruses decrease the supply of energy to the mitochondria in the form of ATP, causing viruses to create cellular stress by generating ROS in mitochondria to instigate viral proliferation, a process which causes both intra- and extra-mitochondrial damage. SARS-COV2 propagates through altering or changing various pathways, such as autophagy, UPR stress, MPTP and NLRP3 inflammasome. Thus, these pathways act as potential targets for viruses to facilitate their proliferation. Autophagy plays an essential role in SARS-COV2-mediated COVID-19 and modulates autophagy by using various drugs that act on potential targets of the virus to inhibit and treat viral infection. Modulated autophagy inhibits coronavirus replication; thus, it becomes a promising target for anti-coronaviral therapy. This review gives immense knowledge about the infections, mitochondrial modulations, and therapeutic targets of viruses.
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Pulmonary rehabilitation is essential in post-COVID subjects, reporting respiratory impairment after the discharge from the hospital. Because the number of patients with respiratory outcomes is high and there are few facilities available, we wonder if a spa setting could represent a valid out-of-hospital alternative. We aim to explore recent evidence related to respiratory rehabilitation in the spa environment to understand if it can represent an appropriate setting for respiratory rehabilitation interventions in post-COVID subjects. Studies were found by screening PubMed, MEDLINE, and Google Scholar databases from 2011 up to February 2021. Studies were eligible if they were reviews, randomized controlled trials (RCTs), or clinical trials, investigating respiratory interventions in the spa environment. Recent evidence has shown that inhalations and mineral-rich water immersions are effective in fighting and preventing multiple chronic respiratory tract diseases. Therefore, these treatments could also be applied to post-COVID patients with medium long-term respiratory outcomes.
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Background Covid 19 infection has severe impact in various systems of the body, but primarily it affects the respiratory system by destroying the lung tissues, and thus leading to an acute medical emergency. There is an alarming sign to be noted, on the raise of post covid patient's numbers, who arrive at post covid follow up special clinic with persistent breathing difficulty. Hence this study focuses on post hospitalization pulmonary rehabilitation with an effective home exercise to improve the pulmonary ventilation. Aim This study aims to explore the efficacy of combining various breathing exercise to improve the pulmonary ventilation. Methods An Experimental study was carried out with 48 participants. On the basis of inclusion and exclusion criteria, all of these participants were categorized into experimental and control group. Experimental group received pursed lip breathing exercise with bhastrika pranayama and the control group receivedIncentive spirometry.The FVC & FEV1 parameters in PFT were recorded pre and post to the intervention by blinded tester who was not aware about group allotment. Result: Post test FEV1 experimental group shows a mean value of 75.75 and standard deviation of 3.7997 and showing a T value of 5.2756 with a p value of <0.0001.Post test FEV1 shows significant improvement among both groups. The present study analyzed efficacy of intervention for patients with dyspnea in post covid follow up clinic. The patients are not only having respiratory complaints but also had complaints of various dysfunctions. So the other factors should also need to be assessed and a proper intervention should be rendered in order to prevent re-hospitalization.
Fatigue is a common, debilitating, and poorly understood symptom post-COVID-19. We sought to better characterize differences in those with and without post-COVID-19 fatigue using cardiopulmonary exercise testing. Despite elevated dyspnoea intensity ratings, V̇O2peak (ml/kg/min) was the only significant difference in the physiological responses to exercise (19.9±7.1 fatigue vs. 24.4±6.7 ml/kg/min non-fatigue, p=0.04). Consistent with previous findings, we also observed a higher psychological burden in those with fatigue in the context of similar resting cardiopulmonary function. Our findings suggest that lower cardiorespiratory fitness and/or psychological factors may contribute to post-COVID-19 fatigue symptomology. Further research is needed for rehabilitation and symptom management following SARS-CoV-2 infection.
Background Multi-disciplinary rehabilitation is recommended for individuals with post-acute sequelae of COVID-19 infection (i.e., symptoms 3–4 weeks after acute infection). There are emerging reports of use of pulmonary rehabilitation (PR) in the post-acute stages of COVID-19, however the appropriateness of PR for managing post-COVID symptoms remains unclear. To offer practical guidance with regards to post-COVID PR, a greater understanding of the clinical effectiveness literature is required. Methods A rapid review of the published literature was completed. An electronic database search of the literature published between July 1, 2020 and June 1, 2021 was performed in MEDLINE, Pubmed, and EMBASE. Primary studies evaluating the clinical effectiveness of PR for individuals with post-COVID symptoms were included. Results Nine studies evaluating the effectiveness of PR were identified; most were small, experimental or quasi-experimental studies, including 1 RCT, and were primarily of low quality. After attending PR, all studies reported improvements in exercise capacity, pulmonary function, and/or quality of life for individuals with post-COVID symptoms who had been hospitalized for their acute COVID-19 infection. Few studies evaluated changes in post-COVID symptom severity or frequency and, of these, improvements in dyspnea, fatigue, anxiety and depression were observed following PR. Further, no studies evaluated non-hospitalized patients or long-term outcomes beyond 3 months after initiating PR. Conclusions With limited high-quality evidence, any recommendations or practical guidance for PR programmes for those with post-COVID symptoms should consider factors such as feasibility, current PR capacity, and resource constraints.
The Coronavirus Disease 2019 (COVID-19) continues to generate a constant pandemic threat with new mutations of the viral agent that create socioeconomic issues. One of the fundamental problems is the evaluation of the preparedness of countries to cope with COVID-19 pandemic crisis to detect factors associated with the reduction of infectious disease and rollout of vaccinations in society. The study here confronts this problem by developing two basic indexes, which measure the performance to face pandemic threats by countries. In particular, the Index r (as resilience) detects which countries have had the best performance to reduce the negative impact of mortality related to COVID-19 pandemic and the Index p (as preparedness and prevention) assesses best-performer countries to support COVID-19 vaccinations to constrain future pandemic threats and support the recovery of socioeconomic systems. Index of resilience is a composite measure based on three indicators, given by average mortality, hospital occupancy and Intensive Care Units occupancy per 100 000 people, producing an overall score; Index of prevention is also a composite measure of two indicators related COVID-19 vaccinations (doses of vaccines administrated and total vaccinates per 100 000 people), producing an overall score. The application of these indexes on a case study of European countries, having a homogenous socioeconomic area, shows strategic positioning of countries to cope with a major pandemic threat. Findings reveal that all countries have some weaknesses and no country has a high preparedness to cope with a major epidemic or pandemic. Moreover, results suggest that best-performer countries to cope with COVID-19 pandemic crisis have a smaller size of population and better public governance, associated with high expenditures in health system. These indexes can help policymakers for designing strategies to improve preparedness to face future pandemic threats.