Next Article in Journal
Early Diagnosis of Liver Metastases from Colorectal Cancer through CT Radiomics and Formal Methods: A Pilot Study
Previous Article in Journal
Association of COVID-19 with Intracranial Hemorrhage during Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome: A 10-Year Retrospective Observational Study
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Greatly Improved Fatigue Symptoms When Treated with Oxygen-Ozone Autohemotherapy

Umberto Tirelli
Marianno Franzini
Luigi Valdenassi
Sergio Pandolfi
Massimiliano Berretta
Giovanni Ricevuti
2,5 and
Salvatore Chirumbolo
Tirelli Medical Group, 33170 Pordenone, Italy
Italian Society of Oxygen Ozone Therapy (SIOOT), University of Pavia, 27100 Pavia, Italy
Villa Mafalda Clinics, Via Monte delle Gioie 5, 00199 Rome, Italy
Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy
Department of Drug Sciences, School of Pharmacy, University of Pavia, 27100 Pavia, Italy
Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37129 Verona, Italy
Author to whom correspondence should be addressed.
J. Clin. Med. 2022, 11(1), 29;
Submission received: 2 November 2021 / Revised: 29 November 2021 / Accepted: 1 December 2021 / Published: 22 December 2021
(This article belongs to the Section Epidemiology & Public Health)


(1) Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic syndrome characterized by fatigue as its major and most outstanding symptom. Previous evidence has supported the ability of ozone to relief ME/CFS related fatigue in affected patients (2) Methods: A number of 200 ME/CFS previously diagnosed patients, (mean age 33 ± 13 SD years) were consecutively treated with oxygen-ozone autohemotherapy (O2-O3-AHT). Fatigue was evaluated via an FSS 7-scoring questionnaire before and following 30 days after treatment. (3) Results: Almost half (43.5%) of the treated patients evolved their FSS scale from the worst (7) to the best (1) score, assessing the highest improvement from being treated with O2-O3-AHT. Furthermore 77.5% of patients experienced significant ameliorations of fatigue, of 4–6 delta score. No patient showed side effects, yet experienced long lasting fatigue disappearance, by three months follow up (4) Conclusions: Treatment with O2-O3-AHT greatly improves ME/CFS related fatigue, aside from sex and age distribution.

1. Introduction

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which has been thoroughly reviewed very recently [1], is a complex terminology used to identify a multi-systemic, serious and long-term illness characterized by fatigue and debilitating muscular-skeletal pain, which usually compels patients to abruptly shutting down many active aspects of their social lives [2,3,4]. Fatigue is a symptom of the utmost importance in ME/CFS and is usually employed to test the general development of ME/CFS symptomatology upon a defined therapy [5,6,7,8,9,10,11]. The epidemiology of ME/CFS has been widely investigated [12,13,14,15]. Previous studies conducted in Italy as forerunner approaches in treating fatigue date back to nineties [5,6,11,16]. In Italy, a recent study performed on 82 CFS patients living in the Northern areas of the country, reported that the mean age was 32 years, quite half of these patients showed early symptoms between 24 and 40 years and ME/CFS was prevalently (3:1) observed in female subjects [15]. Yet, evaluating a correct prevalence of ME/CFS is a burdensome task, as ME/CFS diagnosis is particularly difficult and often patients with fatigue and other clinical signs are misunderstood with other chronic illnesses [17,18]. The recent diagnostic criteria for ME/CFS from the Centers for Disease Control and Prevention, the so-called IOM 2015 Diagnostic Criteria, which updated the CDC-1994 guidelines [19], encompassed symptoms and signs such as a severe and chronic fatigue usually lasting longer than six months, as well as the presence of at least four of the following physical symptoms: unrefreshing sleep, impaired concentration, attention or memory, post-exertional malaise, headaches, muscular-skeletal pain and polyarthralgia, tender lymph nodes and sore throat [20,21,22,23]. ME/CFS diagnosis is therefore quite completely based on the clinical evidence, where long-lasting, debilitating fatigue represents the major and most outstanding symptom [24,25]
The difficulty in reaching a sound and proper diagnostic evaluation of ME/CFS, hampers somehow the possibility to find an effective therapy for ME/CFS [26]. Commendable attempts were addressed in the past, even by our group [5,7,11], yet ME/CFS remains so far a very complex task for clinics. Individuals with ME/CFS should be investigated for concurrent depression, pain, and even sleep disturbances. To date, the only available treatment options include a kind of cognitive behavior therapy, including graded motor exercise rehabilitation, approaches that have been demonstrated to only slightly improve fatigue and ameliorating also social adjustment, anxiety, and post-exertional malaise. However, no pharmacologic medicine therapies have been proven thoroughly effective, to date.
Encouraging attempts in treating ME/CFS fatigue with oxygen-ozone autohemotherapy (O2-O3-AHT) were successfully accomplished by our groups and others [27,28,29]. Oxygen-ozone therapy is able to modulate many complex aspects of immunity, the majority of which underlie the pathogenetic mechanisms causing ME/CFS [30,31]. Interestingly, as occurring in COVID-19, where O2-O3-AHT resulted particularly effective in treating the oxidative stress associated with the sickness, ME/CFS too might have an oxidative stress causative pathogenesis [32,33]. This evidence, associated with the increasing awareness that ozone is able to modulate inflammation by targeting the oxidative stress signaling [32] and by previous encouraging outcomes on ME/CFS [27], suggested us to treat fatigue in patients with O2-O3-AHT.
In this paper we treated fatigue symptomatology in a large cohort of patients diagnosed as ME/CFS by adopting O2-O3-AHT. Results are herein described and discussed.

2. Materials and Methods

2.1. Patients’ Recruitment

A number of 224 outpatients coming as a whole to the different clinical centers of Pordenone and Gorle (Bergamo) were recruited on the basis of the eligibility criteria assessed for the present research study, 200 entered the study, 19 did not follow up the study design and were excluded from the investigation. 5 formally accepted the research study but never started for different individual reasons. Age distribution reported a mean of 33.08 ± 13.50 SD years [CI95 = 31.20–34.97] and a median of 33.14 years, the cohort was composed of 69 males (34.5%), so the majority of patients was represented by female subjects. All patients were thoroughly informed of the therapy protocol and about the use of data for research purposes, according the recommendations of the Helsinki Declaration.

2.2. Inclusion and Exclusion Criteria

Inclusion criteria were represented by outpatients referring to our clinical healthcare previously diagnosed for ME/CFS [23,34], suffering from fatigue, having accepted and signed the informed consent for therapy and moreover enabled and agreed in sharing data for research. Exclusion criteria were represented by patients with chronic active inflammatory pathologies or neurodegenerative and psychiatric disorders, SARS-CoV2 positivity, having experienced COVID-19 within the previous 6 months, included in the suspicion of a post-COVID symptomatology, intaking pharmaceutical drugs within the previous 72 h, having been diagnosed for autoimmune disorders aside from ME/CFS, having cancer, if pregnant women.

2.3. Sample Size

Sample size was calculated to achieve an error range of about 10%. Referring to a population proportion of 51%, forecast data resulted in a 13.86% error with 50 patients, whereas 9.80% (<10%) with 103 patients, therefore 200 patients were within the minimal sample size with p < 0.001. The Cohen d test for the two separate groups, i.e., before O2-O3-AHT and following O2-O3-AHT was successful, (p = 0.004323 or Hedges’ g value). Moreover, Glass’ delta p = 0.012444 (p < 0.02).

2.4. Patients’ Evaluation of the Fatigue Symptomatology

An anamnestic interview and complete visitation of about 40–60 min was performed. Fatigue was the major symptom evaluated in the study as able to highlight the patient’s overall clinical status in the most sound and reliable approach, due to its optimal performance features, stability over time and scant possibility to be shadowed by other minor symptoms. Each patient was asked to respond to a 7-scoring system Fatigue Severity Scale (FSS) before undergoing therapy and one month following therapy [35,36]. Results were collected as scores and statistically evaluated.

2.5. Patients’ Treatment with Oxygen Ozone Autohemotherapy (O2-O3-AHT)

Patients underwent not less than two weekly sessions of major oxygen-ozone autohemotherapy, according to the protocol previously assessed by the Italian Society of Oxygen-Ozone Therapy (SIOOT) [27]. For each O2-O3-AHT session a treatment time of 30 min was held. Improvements are not immediate but can be observed in the post-treatment period, from 1 week to 1 month following at least one oxygen-ozone therapy session. Therefore, one cannot calculate if more sessions are made, much higher is the improvement. Ozone does not act in a cumulative way but elicits subtle and complex mechanisms in the patient’s physiology. A volume of 200 mL of blood was withdrawn from any patient and collected in a CE certified SANO3 bag, then immediately treated with 45 μg/mL of ozone in a O2-O3 mixture, continuously regulated and tuned by the instrumental device Multioxygen Medical 95 CPS (Gorle, BG, Italy). The Multioxygen® Medical 95 is disposed as an outpatient unit for O2-O3 therapy, allowing operators to customize the gas mixture according to the clinical request. Actually, the O2-O3 mixture generator is managed by a microprocessor that ensures the precision of the ozone delivery, once the O3-O2 mixture amount is selected by the operator. Therefore, it is possible to customize the treatment by selecting the ozone concentration in a continuous range from 1 to 100 μg of O3. Then the 200 mL of ozonized blood was reintroduced into the circulatory blood directly, from the sterile bag. Therefore, the therapy required an ozone generator, medical grade oxygen, a sterile syringe and a certified bag endowed with an intravenous cannula, for the O2-O3-AHT. If following one week from the O2-O3 -AHT treatment, the FSS delta score was 0, a second session of O2-O3-AHT will be performed with 150 mL treated blood at 45 μg/mL of ozone in a O2-O3 mixture. A median of 155 mL, CI95 = 135–245 mL of blood was ozonized and reintroduced for each treated patient [27,37]. Patients were followed up at 30 days subsequently to the second O2-O3-AHT session and asked to complete the FSS questionnaire, as previously agreed.

2.6. Statistics

Data were collected and expressed as mean ± standard deviation, for quantitative values. Sample size was evaluated by assessing data and forecasting evaluations with Cohen d test and a Glass’ delta. Statistical inference, if any, was evaluated following non-parametric tests. Scores were evaluated by a Kruskall-Wallis test with p < 0.05. Data were elaborated with a SPSS v 24 software and Stata software for graphs.

3. Results

Table 1 summarizes the results obtained in the present study.
When treated with O2-O3-AHT fatigue symptoms within the first one-two weeks ameliorated from a score value of 7 (meaning the worst) to 1 (meaning the best, i.e., completely absent symptoms) in almost half of the oxygen-ozone treated patients (43.5%), whose only 24.64% were males and more than 75% females.
The percentage of patients experiencing a delta scoring of 4–6 points were higher than 75%. Anyway, only 5% reported very small, quite negligible improvements in fatigue symptoms. Age distribution did not show any difference in the whole randomized patients’ population (p = 0.38765), therefore age did not affect significantly the results of this investigation. About 6.5% of patients diagnosed with ME/CFS, with fatigue symptoms and treated with O2-O3-AHT were teen agers. The Kruskall-Wallis (KW test) for this cohort of subjects was 18.7778 (p = 0.00001). Neither age nor sex distribution affected the correct evaluation of the FSS questionnaire, as KW tests were significant at p < 0.05 (Table 1)), and when this ratio was referred to the number of subjects recruited on the total, the rate of males responding to the therapy for about 60% (59.48%) was 1.5 higher than females, responding for about 75% (74.58%) to the therapy.
This might indicate that male patients are particularly sensitive to O2-O3-AHT despite their age range and that female are much more responsive but with higher variability. Quite 80% of patients responded optimally to O2-O3-AHT (77.5%) and more than half (51%) responded with the maximal FSS delta score. Figure 1 shows the impressive difference in fatigue score before and after the O2-O3-AHT.
No patient reported adverse manifestation upon O2-O3-AHT and following the next 3 months from the treatment.

4. Discussion

The results here described assess that O2-O3-AHT is able to relief fatigue in almost half of the whole cohort of ME/CFS patients. The study of ME/CFS was pioneered in Italy by Tirelli and coworkers [11], when several theories about the concurrent viral origin of ME/CFS and the immune impairment in T cell activation and NK cell functional depression were addressed [11]. Immune modulation, even via the tuning of cell survival with the oxidative stress response, might be a solution to address ME/CFS symptomatology, mainly represented by fatigue, and ozone may be a possible approach [5,6,27]. So far, no reliable explanation has been forwarded to elucidate how ozone is able to restore wellness in patients suffering from ME/CFS-related fatigue [27]. The recent evidence associating COVID-19 with ME/CFS pathogenesis as a manifestation of an impaired stress response is particularly intriguing [33]. The ability of ozone to modulate the Nrf2/Keap1/ARE system and the NO/eNOS signaling pathways may provide insightful suggestions to highlight possible mechanisms underlying the effect of O2-O3-AHT in ME/CFS-caused fatigue symptomatology [27]. During ME/CFS mitochondria functionality may be greatly disturbed, so generating an impairment in many mitochondria-related activities, including ROS signaling [38] and in inflammation disorders [39,40]. ME/CFS is characterized by an increase in CD4+CD25+Foxp3+ T regulatory (Treg) cells [41], which may be modulated and lowered by ozone [42]. Another impairment in ME/CFS regards Th17 cells. The CCR6+ Th17 cells in ME/CFS were reported to secrete less IL-17 respect to healthy subjects, circulating cell frequency is significantly lower, whereas ozone can restore their amount, even with IL-17A [43,44]. The immune micro-environment in ME/CFS is of the utmost importance to elucidate how ME/CFS- associated fatigue develops and how treating the same [9,10,11]. To date, the mechanisms with which O2-O3-AHT may restore physical activity and relief fatigue-related discomfort and myalgia or arthralgia, is far to be fully elucidated. A dysregulated Treg immune response and an impaired Th2 and Th17 cytokine pattern, may be modulated and tuned by ozone and its oxidized metabolites. This activity is closely linked with the cell anti-oxidant endowment and the machinery deputed to the optimal stress response. Noticeably, the major ozone-induced blood byproduct, the 4-hydroxynonenal (4-HNE) induces the thioredoxin reductase 1, via the Nrf2 pathway, then increasing the level of Tregs [45,46].
Although the scant evidence able to tailoring a speculative hypothesis on how O2-O3-AHT can relief fatigue in ME/CFS patients may regard cells and functional models either than ME/CFS, the ability of ozone to modulate immunity and inflammation via the Nrf2 system is particularly documented [32].
Furthermore, ozone may regulate nitric oxide (NO) and the activity of the endothelial nitric oxide synthase (eNOS) [32]. Yet, ME/CFS patients seem to have normal NO alongside with normal IL-6 levels, before and after a physical exercise upon fatigue symptoms but exhibit high levels of F2-isoprostanes, which are oxidative stress biomarkers, probably quenched by the activity of ozone on the Nrf2/Keap1/ARE system [47,48,49].
The ability of ozone to modulate the complex interplay between oxidative stress and chronic inflammation may be the key to comprehend how ME/CFS patients felt a rapid relief in their fatigue symptoms following O2-O3-AHT.

5. Conclusions

Patients suffering from ME/CFS fatigue and treated with O2-O3-AHT experienced rapid relief of their symptoms. Further insights are needed to elucidate the mechanism by which about 95% of treated patients recovered their ability to move without pain and discomfort.

Author Contributions

Conceptualization, U.T. and S.C.; methodology, U.T., M.F., L.V. and S.C.; software, S.C.; validation, U.T., G.R., M.B. and S.C.; formal analysis, S.C. and S.P.; investigation, U.T. and M.F.; resources, U.T., M.F. and L.V.; data curation, S.C. and S.P.; writing—original draft preparation, S.C.; writing—review and editing, U.T., S.C. and S.P.; visualization, U.T.; supervision, U.T., M.F., L.V., S.P., M.B., G.R. and S.C.; project administration, U.T.; funding acquisition, M.F. and L.V. All authors have read and agreed to the published version of the manuscript.


This research was funded by SIOOT, Gorle (BG).

Institutional Review Board Statement

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of the Tirelli Clinical Group.

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

Not applicable.


A special thank to all the caregivers and health personnel involved in the management of the study.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Deumer, U.S.; Varesi, A.; Floris, V.; Savioli, G.; Mantovani, E.; López-Carrasco, P.; Rosati, G.M.; Prasad, S.; Ricevuti, G. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): An Overview. J. Clin. Med. 2021, 10, 4786. [Google Scholar] [CrossRef]
  2. Barhorst, E.E.; Boruch, A.E.; Cook, D.B.; Lindheimer, J.B. Pain-related post-exertional malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia: A systematic review and three-level meta-analysis. Pain Med. 2021, pnab308. [Google Scholar] [CrossRef]
  3. Noor, N.; Urits, I.; Degueure, A.; Rando, L.; Kata, V.; Cornett, E.M.; Kaye, A.D.; Imani, F.; Narimani-Zamanabadi, M.; Varrassi, G.; et al. A Comprehensive Update of the Current Understanding of Chronic Fatigue Syndrome. Anesthesiol. Pain Med. 2021, 11, e113629. [Google Scholar] [CrossRef]
  4. Lim, E.J.; Son, C.G. Prevalence of Chronic Fatigue Syndrome (CFS) in Korea and Japan: A Meta-Analysis. J. Clin. Med. 2021, 10, 3204. [Google Scholar] [CrossRef]
  5. Tirelli, U.; Lleshi, A.; Berretta, M.; Spina, M.; Talamini, R.; Giacalone, A. Treatment of 741 Italian patients with chronic fatigue syndrome. Eur. Rev. Med. Pharmacol. Sci. 2013, 17, 2847–2852. [Google Scholar]
  6. Tirelli, U.; Cirrito, C.; Pavanello, M.; Del Pup, L.; Lleshi, A.; Berretta, M. Oxygen-ozone therapy as support and palliative therapy in 50 cancer patients with fatigue—A short report. Eur. Rev. Med. Pharmacol. Sci. 2018, 22, 8030–8033. [Google Scholar] [PubMed]
  7. Arpino, C.; Carrieri, M.P.; Valesini, G.; Pizzigallo, E.; Rovere, P.; Tirelli, U.; Conti, F.; Dialmi, P.; Barberio, A.; Rusconi, N.; et al. Idiopathic chronic fatigue and chronic fatigue syndrome: A comparison of two case-definitions. Ann. Dell’istituto Super. Di Sanità 1999, 35, 435–441. [Google Scholar]
  8. Tirelli, U.; Chierichetti, F.; Tavio, M.; Simonelli, C.; Bianchin, G.; Zanco, P.; Ferlin, G. Brain positron emission tomography (PET) in chronic fatigue syndrome: Preliminary data. Am. J. Med. 1998, 105, 54S–58S. [Google Scholar] [CrossRef]
  9. Montoya, J.G.; Holmes, T.H.; Anderson, J.N.; Maecker, H.T.; Rosenberg-Hasson, Y.; Valencia, I.J.; Chu, L.; Younger, J.W.; Tato, C.M.; Davis, M.M. Cytokine signature associated with disease severity in chronic fatigue syndrome patients. Proc. Natl. Acad. Sci. USA 2017, 114, E7150–E7158. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  10. Tirelli, U.; Marotta, G.; Improta, S.; Pinto, A. Immunological abnormalities in patients with chronic fatigue syndrome. Scand. J. Immunol. 1994, 40, 601–608. [Google Scholar] [CrossRef]
  11. Tirelli, V.; Pinto, A.; Marotta, G.; Crovato, M.; Quaia, M.; De Paoli, P.; Galligioni, E.; Santini, G. Clinical and immunologic study of 205 patients with chronic fatigue syndrome: A case series from Italy. Arch. Intern. Med. 1993, 153, 116–120. [Google Scholar] [CrossRef] [PubMed]
  12. Estévez-López, F.; Mudie, K.; Wang-Steverding, X.; Bakken, I.J.; Ivanovs, A.; Castro-Marrero, J.; Nacul, L.; Alegre, J.; Zalewski, P.; Słomko, J.; et al. Systematic Review of the Epidemiological Burden of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Across Europe: Current Evidence and EUROMENE Research Recommendations for Epidemiology. J. Clin. Med. 2020, 9, 1557. [Google Scholar] [CrossRef]
  13. Vincent, A.; Brimmer, D.J.; Whipple, M.O.; Jones, J.F.; Boneva, R.; Lahr, B.D.; Maloney, E.; St Sauver, J.L.; Reeves, W.C. Prevalence, incidence, and classification of chronic fatigue syndrome in Olmsted County, Minnesota, as estimated using the Rochester Epidemiology Project. Mayo Clin. Proc. 2012, 87, 1145–1152. [Google Scholar] [CrossRef]
  14. Lim, E.J.; Ahn, Y.C.; Jang, E.S.; Lee, S.W.; Lee, S.H.; Son, C.G. Systematic review and meta-analysis of the prevalence of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). J. Transl. Med. 2020, 18, 100. [Google Scholar] [CrossRef]
  15. Capelli, E.; Lorusso, L.; Ghitti, M.; Venturini, L.; Cusa, C.; Ricevuti, G. Chronic fatigue syndrome: Features of a population of patients from northern Italy. Int. J. Immunopathol. Pharmacol. 2015, 28, 53–59. [Google Scholar] [CrossRef]
  16. Spazzapan, S.; Bearz, A.; Tirelli, U. Fatigue in cancer patients receiving chemotherapy. Anal. Publ. Stud. Ann. Oncol. 2004, 15, 1576. [Google Scholar]
  17. Solomon, L.; Reeves, W.C. Factors influencing the diagnosis of chronic fatigue syndrome. Arch. Intern. Med. 2004, 164, 2241–2245. [Google Scholar] [CrossRef] [Green Version]
  18. Brenna, E.; Araja, D.; Pheby, D.F.H. Comparative Survey of People with ME/CFS in Italy, Latvia, and the UK: A Report on Behalf of the Socioeconomics Working Group of the European ME/CFS Research Network (EUROMENE). Medicina 2021, 57, 300. [Google Scholar] [CrossRef]
  19. Kennedy, G.; Abbot, N.C.; Spence, V.; Underwood, C.; Belch, J.J. The specificity of the CDC-1994 criteria for chronic fatigue syndrome: Comparison of health status in three groups of patients who fulfill the criteria. Ann. Epidemiol. 2004, 14, 95–100. [Google Scholar] [CrossRef] [PubMed]
  20. Kuratsune, H. Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Brain Nerve 2018, 70, 11–18. [Google Scholar] [PubMed]
  21. Carruthers, B.M.; van de Sande, M.I.; De Meirleir, K.L.; Klimas, N.G.; Broderick, G.; Mitchell, T.; Staines, D.; Powles, A.C.; Speight, N.; Vallings, R.; et al. Myalgic encephalomyelitis: International Consensus Criteria. J. Intern. Med. 2011, 270, 327–338. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Bruun Wyller, V.; Bjørneklett, A.; Brubakk, O.; Festvåg, L.; Follestad, I.; Malt, U.; Malterud, K.; Nyland, H.; Rambøl, H.; Stubhaug, B.; et al. Diagnosis and Treatment of Chronic Fatigue Syndrome/Myalgic Encephalopathy (CFS/ME) [Internet]; Report from Norwegian Knowledge Centre for the Health Services (NOKC) No. 09-2006; Knowledge Centre for the Health Services at The Norwegian Institute of Public Health (NIPH): Oslo, Norway, 2006. [Google Scholar]
  23. Chew-Graham, C.; Dowrick, C.; Wearden, A.; Richardson, V.; Peters, S. Making the diagnosis of Chronic Fatigue Syndrome/Myalgic Encephalitis in primary care: A qualitative study. BMC Fam. Pract. 2010, 11, 16. [Google Scholar] [CrossRef] [Green Version]
  24. Son, C.G. Differential diagnosis between “chronic fatigue” and “chronic fatigue syndrome”. Integr. Med. Res. 2019, 8, 89–91. [Google Scholar] [CrossRef]
  25. Nelsen, D.A., Jr. Differential diagnosis for chronic fatigue syndrome. Am. Fam. Physician 2003, 67, 252. [Google Scholar]
  26. Craig, T.; Kakumanu, S. Chronic fatigue syndrome: Evaluation and treatment. Am. Fam. Physician 2002, 65, 1083–1089. [Google Scholar]
  27. Tirelli, U.; Cirrito, C.; Pavanello, M. Ozone therapy is an effective therapy in chronic fatigue syndrome: Result of an Italian study in 65 patients. Ozon Ther. 2018, 3, 27–30. [Google Scholar] [CrossRef]
  28. Morelli, L.; Bramani, S.C.; Morelli, F.C. Oxygen-ozone therapy in meningoencephalitis and chronic fatigue syndrome. Treat. Field Compet. Sports Case Rep. Ozone Ther. 2019, 4, 20–23. [Google Scholar]
  29. Borrelli, E.; Bocci, V. A novel therapeutic option for Chronic Fatigue Syndrome and Fibromyalgia. Riv. Ital. Ossig.-Ozonoterap. 2002, 1, 149–153. [Google Scholar]
  30. Viebahn-Haensler, R.; León Fernández, O.S. Ozone in Medicine. The Low-Dose Ozone Concept and Its Basic Biochemical Mechanisms of Action in Chronic Inflammatory Diseases. Int. J. Mol. Sci. 2021, 22, 7890. [Google Scholar] [CrossRef]
  31. Bjørklund, G.; Dadar, M.; Pivina, L.; Doşa, M.D.; Semenova, Y.; Maes, M. Environmental, Neuro-immune, and Neuro-oxidative Stress Interactions in Chronic Fatigue Syndrome. Mol. Neurobiol. 2020, 57, 4598–4607. [Google Scholar] [CrossRef]
  32. Chirumbolo, S.; Valdenassi, L.; Simonetti, V.; Bertossi, D.; Ricevuti, G.; Franzini, M.; Pandolfi, S. Insights on the mechanisms of action of ozone in the medical therapy against COVID-19. Int. Immunopharmacol. 2021, 96, 107777. [Google Scholar] [CrossRef]
  33. Paul, B.D.; Lemle, M.D.; Komaroff, A.L.; Snyder, S.H. Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome. Proc. Natl. Acad. Sci. USA 2021, 118, e2024358118. [Google Scholar] [CrossRef] [PubMed]
  34. Baker, R.; Shaw, E.J. Diagnosis and management of chronic fatigue syndrome or myalgic encephalomyelitis (or encephalopathy): Summary of NICE guidance. BMJ 2007, 335, 446–448. [Google Scholar] [CrossRef] [Green Version]
  35. Neuberger, G.B. Measures of fatigue Arthritis and Rheumatisms. Arthritis Care Res. 2003, 48, S175–S183. [Google Scholar] [CrossRef]
  36. Tirelli, U.; Franzini, M.; Valdenassi, L.; Pisconti, S.; Taibi, R.; Torrisi, C.; Pandolfi, S.; Chirumbolo, S. Fatigue in post-acute sequelae of SARS-CoV2 (PASC) treated with oxygen-ozone autohemotherapy-preliminary results on 100 patients. Eur. Rev. Med. Pharmacol. Sci. 2021, 25, 5871–5875. [Google Scholar] [PubMed]
  37. lvis, A.M.; Ekta, J.S. Ozone therapy: A clinical review. J. Nat. Sci. Biol. Med. 2011, 2, 66–70. [Google Scholar]
  38. Anderson, G.; Maes, M. Mitochondria and immunity in chronic fatigue syndrome. Prog. Neuro.-Psychopharmacol. Biol. Psychiatry 2020, 103, 109976. [Google Scholar] [CrossRef]
  39. Maes, M.; Twisk, F.N.; Kubera, M.; Ringel, K. Evidence for inflammation and activation of cell-mediated immunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Increased interleukin-1, tumor necrosis factor-α, PMN-elastase, lysozyme and neopterin. J. Affect Disord. 2012, 136, 933–939. [Google Scholar] [CrossRef]
  40. Maes, M.; Twisk, F.N.; Ringel, K. Inflammatory and cell-mediated immune biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome and depression: Inflammatory markers are higher in myalgic encephalomyelitis/chronic fatigue syndrome than in depression. Psychother. Psychosom. 2012, 81, 286–295. [Google Scholar] [CrossRef] [PubMed]
  41. Brenu, E.W.; Huth, T.K.; Hardcastle, S.L.; Fuller, K.; Kaur, M.; Johnston, S.; Ramos, S.B.; Staines, D.R.; Marshall-Gradisnik, S.M. Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis. Int. Immunol. 2014, 26, 233–242. [Google Scholar] [CrossRef]
  42. Wei, M.; Tu, L.; Liang, Y.H.; Liu, J.; Gong, Y.J.; Zhang, J.H.; Zhang, Y.H. Effects of ozone exposure on percentage of CD4(+)CD25(high)Foxp(3+) regulatory T cells and mRNA expression of Foxp3 in asthmatic rats. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 2013, 31, 693–696. [Google Scholar]
  43. Broderick, G.; Fuite, J.; Kreitz, A.; Vernon, S.D.; Klimas, N.; Fletcher, M.A. A formal analysis of cytokine networks in chronic fatigue syndrome. Brain Behav. Immun. 2010, 24, 1209–1217. [Google Scholar] [CrossRef] [Green Version]
  44. Che, L.; Jin, Y.; Zhang, C.; Lai, T.; Zhou, H.; Xia, L.; Tian, B.; Zhao, Y.; Liu, J.; Wu, Y.; et al. Ozone-induced IL-17A and neutrophilic airway inflammation is orchestrated by the caspase-1-IL-1 cascade. Sci. Rep. 2016, 6, 18680. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Chen, Z.H.; Saito, Y.; Yoshida, Y.; Sekine, A.; Noguchi, N.; Niki, E. 4-Hydroxynonenal induces adaptive response and enhances PC12 cell tolerance primarily through induction of thioredoxin reductase 1 via activation of Nrf2. J. Biol. Chem. 2005, 280, 41921–41927. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Wang, X.; Dong, H.; Li, Q.; Li, Y.; Hong, A. Thioredoxin induces Tregs to generate an immunotolerant tumor microenvironment in metastatic melanoma. Oncoimmunology 2015, 4, e1027471. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Meeus, M.; Van Eupen, I.; Hondequin, J.; De Hauwere, L.; Kos, D.; Nijs, J. Nitric oxide concentrations are normal and unrelated to activity level in chronic fatigue syndrome: A case-control study. In Vivo 2010, 24, 865–869. [Google Scholar]
  48. Robinson, M.; Gray, S.R.; Watson, M.S.; Kennedy, G.; Hill, A.; Belch, J.J.; Nimmo, M.A. Plasma IL-6, its soluble receptors and F2-isoprostanes at rest and during exercise in chronic fatigue syndrome. Scand. J. Med. Sci. Sports 2010, 20, 282–290. [Google Scholar] [CrossRef]
  49. Milne, G.L.; Musiek, E.S.; Morrow, J.D. F2-isoprostanes as markers of oxidative stress in vivo: An overview. Biomarkers 2005, 10 (Suppl. S1), S10–S23. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Box plot representation of the impressive change in fatigue symptoms at 30 days after oxygen-ozone autohemotherapy in the 200 patients treated with O2-O3-AHT.
Figure 1. Box plot representation of the impressive change in fatigue symptoms at 30 days after oxygen-ozone autohemotherapy in the 200 patients treated with O2-O3-AHT.
Jcm 11 00029 g001
Table 1. Results of fatigue treatment in ME/CFS patients with O2-O3-AHT (mean ± SD).
Table 1. Results of fatigue treatment in ME/CFS patients with O2-O3-AHT (mean ± SD).
Before TreatmentAfter TreatmentKW Test
Delta %
All patients
6.825 ± 0.381 2.085 ± 1.503H = 293.6672
Δ% = 69.45
Male patients
6.725 ± 0.450 2.725 ± 1.781H = 54.4956
Δ% = 59.48
Female patients
6.878 ± 0.3291.748 ± 1.211H =195.388
Δ% = 74.58
Statistical and FFS score data
Mean age (all):
33.085 ± 13.503 SD
Mean age (males):
37.406 ± 13.958 SD
Mean age (females):
30.809 ± 12.730 SD
7 to 7 = 17 to 6 = 47 to 5 = 177 to 4 = 97 to 3 = 57 to 2 = 427 to 1 = 87
6 to 6 = 06 to 5 = 66 to 4 = 36 to 3 = 06 to 2 = 116 to 1 = 155 to 1 = 0
Sex distribution: Males = 69; Females = 131 Age distribution: <18 years old = 13; from 18 to 29 years old = 89; ≥30 years old = 98 Spearman Rank Correlation 0 p > 0.05 (n.s) p = 0.33356, rho = −0.0687, S = 1424930. 3283. KS test for ages p = 0.38765 (n.s.). Higher score delta 7 to 1 = 43.5%. Best performance: 77.5%; Excellence: 51%.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Tirelli, U.; Franzini, M.; Valdenassi, L.; Pandolfi, S.; Berretta, M.; Ricevuti, G.; Chirumbolo, S. Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Greatly Improved Fatigue Symptoms When Treated with Oxygen-Ozone Autohemotherapy. J. Clin. Med. 2022, 11, 29.

AMA Style

Tirelli U, Franzini M, Valdenassi L, Pandolfi S, Berretta M, Ricevuti G, Chirumbolo S. Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Greatly Improved Fatigue Symptoms When Treated with Oxygen-Ozone Autohemotherapy. Journal of Clinical Medicine. 2022; 11(1):29.

Chicago/Turabian Style

Tirelli, Umberto, Marianno Franzini, Luigi Valdenassi, Sergio Pandolfi, Massimiliano Berretta, Giovanni Ricevuti, and Salvatore Chirumbolo. 2022. "Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Greatly Improved Fatigue Symptoms When Treated with Oxygen-Ozone Autohemotherapy" Journal of Clinical Medicine 11, no. 1: 29.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop