Although the level of evidence reported in the case report is not high, its value is still very high, especially in exploring new treatment methods for diseases that currently do not have ideal treatment methods. This evidence is particularly valuable for hydrogen, a tool that is highly safe and easily accessible to humans. Regarding the treatment of ME/CFS, German scholars have reported very effective cases, and the case is the author himself, who is also a researcher at the Max Planck Institute in Germany. Later, more research was conducted by scholars who believed that hydrogen had no effect on such diseases. This has led to controversy over whether hydrogen has therapeutic effects. In this case, more research evidence is needed to truly determine whether it is truly effective and the magnitude of this possibility. Of course, the final determination still requires evidence from large-scale and rigorous controlled clinical studies. This case can provide new evidence support for further research.

The incidence of chronic fatigue syndrome is getting higher and higher. The symptoms of viral infection such as COVID-19, especially Changxinguan, are close to chronic fatigue syndrome from the perspective of symptoms. The effect of hydrogen on Changxin Corona has also been studied. So these studies can be put together for comprehensive analysis.

Japanese scholars have reported a case study of hydrogen inhalation therapy for this disease. The following is an introduction to the latest research paper, published in the journal Medical Gas Research. The authors are from Keio University and Miz Corporation in Japan. The hydrogen inhalation method used in this study is a hydrogen concentration of 6-7%, with a gas supply of 2000 milliliters per minute, for 3-6 hours per day, for more than 2 consecutive months.

Hirano, Shin ichi *; Ichikawa, Yusuke; Sato, Bunpei; Takefuji, Yoshiyasu; Satoh, Fumitake. Hydrogen successfully treated myalgic encephalomyelitis/chronic fatigue syndrome: a report of 4 cases Medical Gas Research 14 (2): p 84-86

The characteristic of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is unexplained fatigue and discomfort lasting for more than 6 months, accompanied by neurological and psychiatric symptoms, including mild fever, headache, weakness, cognitive impairment, and depression. The onset and severity of these symptoms vary, reducing the quality of life and social, occupational, and personal activity abilities of affected individuals, with some even bedridden. It is estimated that the number of ME/CFS patients in the United States is between 836000 and 2.5 million.

Although it is currently unclear whether there are objective and biological abnormalities in ME/CFS, recent neuroimaging, blood biomarker analysis, and energy metabolism and mitochondrial studies have shown that ME/CFS patients have these abnormalities. ME/CFS may be caused by the immune system activated inside and outside the brain, which triggers the release of inflammatory factors. ME/CFS is believed to cause abnormalities in the central nervous system and autonomic nervous system, as well as abnormalities in overall energy metabolism and immune system, and involve oxidative and nitrogen stress. The dysfunction of systemic energy metabolism may be related to the structural and functional abnormalities of mitochondria.

Hydrogen is a gaseous molecule that selectively removes reactive oxygen species and nitrogen species (i.e. hydroxyl radicals (· OH) and peroxynitrite) with strong oxidizing ability. Hydrogen gas easily penetrates the blood-brain barrier and biofilm, reaches mitochondria, and protects cells from · OH induced cell damage. A recent literature review revealed that hydrogen reduces acute or chronic fatigue in animals and healthy subjects. We have also reported that the anti fatigue effect of hydrogen involves protection of mitochondria, which may also improve the pathogenesis of ME/CFS. Therefore, we conducted this case study to test this hypothesis by examining the efficacy of inhaling hydrogen gas therapy in four ME/CFS patients.

Case 1

We introduce a 58 year old male ME/CFS patient who successfully responded to hydrogen gas inhalation therapy. The Canadian Consensus Criteria (CCC) are based on a score of 21 symptoms (asymptomatic: 0, mild: 1, moderate: 2, severe: 3), including typical symptoms of ME/CFS such as post exercise fatigue, sleep disorders, cognitive impairment, pain, autonomic nervous system disorders, and chemical allergies. The score for each symptom and the total score for 21 symptoms (with a maximum score of 63) are used to determine whether the symptoms have improved or worsened. To evaluate the efficacy of hydrogen gas inhalation therapy in this patient, we conducted bi weekly patient medical interviews and CCC records, as there is currently no accurate method to evaluate the material efficacy of ME/CFS except for the patient's subjective symptoms.

The patient experienced extreme fatigue, headache, and other symptoms in April 2012, as well as clear thinking and difficulty concentrating. He went to multiple hospitals in an attempt to diagnose and treat these symptoms, but was unsuccessful. He visited the National Center for Neurology and Psychiatry (NCNP) in 2019. Many tests have been conducted, and subjective symptoms meet CCC's ME/CFS standards. Various treatments have been carried out for about two years, but none have been successful.

The patient inhaled 6-7% hydrogen gas (2 L/min, MHG-2000 α, MiZ Co., Ltd., Kamakura, Japan) daily for 3-5 hours from June 2021 to November 2021. The severity scores before and after hydrogen gas treatment are shown in Table 1 and Figure 1.

Figure 1: Changes in overall severity score and cerebral fog in ME/CFS patients after inhaling hydrogen gas. Note: Patients inhale 6-7% hydrogen gas produced by water electrolysis every day for 3-5 hours. The severity score before and after each hydrogen gas treatment is based on CCC records, and the total score is calculated (the highest score is 63 points). He received the COVID-19 vaccine in weeks 8 and 11, but the vaccination worsened the symptoms of ME/CFS. However, after 14 weeks of inhaling hydrogen gas for treatment, symptoms returned to pre vaccination levels.

Table 1: 21 symptom severity scores of ME/CFS patients after inhaling hydrogen gas (hydrogen gas). The severity score before treatment was 29 points, which decreased to 23 points after 4 weeks of treatment, confirming a significant reduction in chronic severe fatigue and intense fatigue after vigorous exercise. The improvement of headache, muscle pain after exercise, joint pain, lack of concentration, and recurrent throat pain has also been noted. Further improvement was observed after 6 weeks. The severe fatigue, headache, and muscle pain after vigorous exercise are significantly relieved. Weight gain, increased foot blood flow, shortness of breath during exertion, and decreased sensitivity to sound have also been observed. Although not reflected in the severity score, "brain fog" decreased; The severity score dropped to 15 points after 6 weeks. The severity score after 8 weeks is 16 points, which is not significantly different from 6 weeks; However, the number of days without "brain fog" has increased.

The patient was vaccinated with COVID-19 vaccine at week 8 and week 11. 5 days after the first vaccination, the symptoms of ME/CFS temporarily worsened, but after 10 weeks of continuous hydrogen uptake (severity score of 16), the symptoms improved. 8 days after the second vaccination (12 weeks after hydrogen absorption), the symptoms of ME/CFS were more severe than after the first vaccination, with a severity score of 27. However, after continuous hydrogen uptake, the symptoms returned to pre vaccination levels after 14 weeks, and the severity score dropped to 15. Although COVID-19 vaccine aggravated the symptoms of ME/CFS, it was only temporary, and hydrogen absorption significantly alleviated these symptoms.

The severity score after 16 weeks is the same as after 14 weeks, but there is a significant improvement in daily activity levels. Therefore, the patient can undergo rehabilitation training and resume work. However, due to his unstable condition, the patient can only engage in activities equivalent to those of a healthy person every three days. Nevertheless, it was observed that his recovery was stable. Although fatigue may still occur after exercise, patients can recover by resting for a few hours and absorbing hydrogen. After 18 weeks, the severity score was the same as after 14 and 16 weeks; However, he can carry out activities of daily life, such as housework, light work and going out in the community. His physical symptoms have been completely eliminated after the vaccination of COVID-19 Vaccine. Due to the patient's increased range of activity after 20 weeks of treatment, he took a small trip. After returning home, he felt tired and easily fell asleep, but recovered after a few days, indicating the anti fatigue effect of hydrogen gas. In addition, the severity score for this week has dropped to 13.

Due to the therapeutic effect of hydrogen on ME/CFS in the first case, we conducted three more case studies on it. We provided the same hydrogen inhalers as in the first case for the three patients referred by NCNP. The efficacy of hydrogen was evaluated twice after 3 weeks and 8-9 weeks through interviews and recording of general symptoms, as patients were unable to self rate through CCC.

Case 2: A 43 year old woman was diagnosed with possible ME/CFS by NCNP in 2017. She had tried various treatment methods, but the results were not satisfactory. Prior to inhaling hydrogen, she was unable to maintain standing, upright, and sitting positions due to severe decline in upper, lower, and trunk function. Lying in bed for most of the day, indoor activities require a wheelchair. She also exhibits symptoms of systemic pain, weakness, discomfort, fatigue after fatigue, sleep disorders, as well as mild fever, bradycardia, and hypotension, which were diagnosed through testing at NCNP. This patient inhaled hydrogen gas for 6 hours per day from the end of August 2021 to early November 2021. After 3 weeks of inhalation, the frequency of sleep disorders and daily headaches and migraine attacks decreased. After 9 weeks, hydrogen inhalation continued to improve symptoms such as sleep disorders, headaches, and migraines.

Case 3: An 18-year-old woman was diagnosed with possible ME/CFS by NCNP in April 2020. She had tried various treatment methods, but the results were not satisfactory. She spends most of the day lying in bed. From the end of August 2021 to the end of October 2021, she began inhaling hydrogen gas for 5 hours every day. About 3 weeks after inhalation, she noticed a reduction in fatigue, improvement in bowel movements, and improvement in mood. After 8 weeks, her daytime sleep time decreased and she had more time for physical activity, but she still felt tired.

Case 4: An 18-year-old male was diagnosed by NCNP in August 2020 with possible ME/CFS and fibromyalgia. Various treatment methods were attempted, but the results were not satisfactory. Before inhaling hydrogen gas, patients exhibit symptoms such as fatigue, headache, muscle weakness, systemic pain, sleep disorders, slow thinking, lack of concentration, decreased memory, tinnitus, and cerebral fog. From the end of August 2021 to early November 2021, he began inhaling hydrogen gas for 6 hours every day. After approximately 3 weeks of treatment, headache and systemic pain were relieved. After 9 weeks, the improvement effect of hydrogen inhalation on these symptoms persisted, and the use of analgesics decreased. In addition, the symptoms of cerebral fog have also improved.

We are developing substances that can alleviate the pathogenesis of ME/CFS. Clinical studies investigated the therapeutic effects of antibody drugs rituximab, nicotinamide adenine dinucleotide hydride, coenzyme Q10, and acetyl-L-carnitine on ME/CFS, but found that they were ineffective or had limited efficacy. Therefore, it is necessary to develop therapeutic drugs that can cure symptoms of ME/CFS rather than just alleviate them.

In this case study, we observed the efficacy of hydrogen therapy in 4 ME/CFS patients. Case 1 is a patient diagnosed with ME/CFS 2 years ago, who did not respond to various therapies and received hydrogen inhalation therapy for 20 weeks. Hydrogen inhalation significantly alleviates post exercise fatigue, recovery time, shortness of breath during exercise, headache, sore throat, lack of concentration, abnormal body temperature, and sensitivity to sound. Cases 2-4 are also patients who have no response to various treatment methods. After 8-9 weeks of hydrogen inhalation treatment, all three patients showed improvement in symptoms such as headache, systemic pain, sleep disorders, intestinal peristalsis, decreased motivation, and cerebral fog. These four cases are the first to prove that hydrogen inhalation can alleviate these symptoms.

COVID-19 is caused by infection with severe acute respiratory syndrome coronavirus 2. Although acute symptoms disappear within 2-3 weeks, some patients still have "sequelae" within a few months after their initial infection. Many symptoms are referred to as "long-term COVID" or "post COVID", similar to ME/CFS. However, despite these similarities, it is still unclear whether COVID-19 infection is a triggering factor for the development of ME/CFS. Botek et al. [21] recently conducted a single blind randomized trial on 50 post COVID patients and reported that 14 days of hydrogen inhalation improved physical and respiratory function during the acute phase of infection. Although further large-scale research is needed, if we assume that the development mechanism of "long-term COVID" or "post COVID" is the same as that of ME/CFS, then our case study results are supported by the findings of Botek et al. [21].

In summary, as this is a case study based on self-assessment by a small number of patients, rather than a randomized controlled trial clinical study, there are some limitations to this study. However, the obtained results suggest the potential of hydrogen gas as a therapeutic gas for ME/CFS. Further large-scale clinical studies are needed to evaluate the efficacy and potential mechanisms of hydrogen gas as a therapeutic agent for ME/CFS.

References

1. Carruthers BM, van de Sande MI, De Meirleir KL, et al. Myalgic encephalomyelitis: International Consensus Criteria. J Intern Med. 2011;270:327-338.

2. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121:953-959.

3. Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Population; Institute of Medicine. The National Academy Collection: Reports funded by National Institutes of Health. Beyond Myalgic Encephalomyelitis/Chronic Fashion Syndrome: Redefining an Illness. Washington (DC): National Academy Press (US); two thousand and fifteen

4. Komaroff AL, Takahashi R, Yamamura T, Sawamura M. Neurologic abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome: a review. Brain Nerve. 2018;70:41-54.

5. Hornig M, Montoya JG, Klimas NG, et al. Distinct plasma immune signatures in ME/CFS are present early in the course of illness. Sci Adv 2015;1:e1400121.

6. Hornig M, Gottschalk G, Peterson DL, et al. Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome. Mol Psychiatry. 2016;21:261-269.

7. Lawson N, Hsieh CH, March D, Wang X. Elevated energy production in chronic fatigue syndrome patients. J Nat Sci. 2016;2:e221.

8. Boles RG, Zaki EA, Kerr JR, Das K, Biswas S, Gardner A. Increased prevalence of two mitochondrial DNA polymorphisms in functional disease: Are we describing different parts of an energy-depleted elephant? Mitochondrion. 2015;23:1-6.

9. Billing Ross P, Germain A, Ye K, Keinan A, Gu Z, Hanson MR. Mitochondrial DNA variants correlate with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome. J Transl Med. 2016;14:19.

10. Naviaux RK, Naviaux JC, Li K, et al. Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2016;113:E5472-5480.

11. Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007;13:688-694.

12. Hirano SI, Ichikawa Y, Kurokawa R, Takefuji Y, Satoh F

13. Hirano SI, Ichikawa Y, Sato B, Takefuji Y, Satoh F. Molecular hydrogen as a medical gas for the treatment of myalgic encephalomyelitis/chronic fatigue syndrome: possible efficacy based on a literature review. Front Neurol. 2022;13:841310.

14. Carruthers BM, Jain AK, De Meirleir KL, et al. Myalgic encephalomyelitis/chronic fatigue syndrome. J Chronic Fatigue Syndr. 2003;11:7-115.

15. Fluge Ø, Rekeland IG, Lien K, et al. B-Lymphocyte depletion in patients with myalgic encephalomyelitis/chronic fatigue syndrome: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2019;170:585-593.

16. Castro Marrero J, S á ez Franc à s N, Segundo MJ, et al. Effect of coenzyme Q10 plus nicotinamide adenine dinucleotide supplementation on maximum heart rate after exercise testing in chronic fatigue syndrome - A randomized, controlled, double-blind trial. Clin Nutr. 2016;35:826-834.

17. Castro Marrero J, Cordero MD, Segundo MJ, et al. Does oral coenzyme Q10 plus NADH supplementation improve fatigue and biochemical parameters in chronic fatigue syndrome? Antioxid Redox Signal. 2015;22:679-685.

18. Forsyth LM, Preuss HG, MacDowell AL, Chiazze L Jr., Birkmayer GD, Bellanti JA. Therapeutic effects of oral NADH on the symptoms of patients with chronic fatigue syndrome. Ann Allergy Asthma Immunol. 1999;82:185-191.

19. Poenaru S, Abdallah SJ, Corrales-Medina V, Cowan J. COVID-19 and post-infectious myalgic encephalomyelitis/chronic fatigue syndrome: a narrative review. Ther Adv Infect Dis. 2021;8:20499361211009385.

20. Nath A. Long Haul COVID Neurology. 2020;95:559-560.

21. Botek M, Krej čí J, Valenta M, et al. Molecular hydrogen positively affects physical and respiratory function in acute post-COVID-19 patients: a new perspective in rehabilitation. Int J Environ Res Public Health. 2022;19:1992.