Following mild to moderate COVID infection, around 10% of individuals develop post-COVID
syndrome (PCS) characterized by symptoms like fatigue, exercise intolerance, cognitive
impairment, headaches, and muscle pain (Kedor et al., 2022). Some PCS patients may later
be diagnosed with ME/CFS, a severe and chronic disease triggered by infections
(Renz-Polster & Scheibenbogen, 2022). ME/CFS presents symptoms such as debilitating
fatigue, exercise intolerance, post-exertional malaise (PEM), headaches, muscle pain,
cognitive impairment ("brain fog"), orthostatic intolerance, autonomic dysfunction, sleep
disturbances, and a general feeling of illness. Currently, no curative therapy for ME/CFS
exists. Therapeutic procedures for ME/CFS mainly focus on symptom management, but
evidence-based and standardized treatments are urgently needed due to the high number of
patients and the impact on healthcare (Renz-Polster & Scheibenbogen, 2022). Off-label
drug and non-drug approaches are used, but their effectiveness lacks sufficient evidence
from controlled trials.

ME/CFS and PCS may have different underlying pathomechanisms, with some patients showing
endothelial dysfunction and reduced blood flow (Haffke et al., 2022). Enhancing blood
flow and promoting the formation of new capillaries is a potential therapeutic approach
due to the presumed role of reduced blood flow. In this regard, Hyperbaric Oxygen Therapy
(HBOT) is under investigation as a treatment for ME/CFS and PCS, showing promising
results in trials (e.g., Zilberman-Itskovich et al., 2022; Robbins et al., 2021;
Kjiellberg et al., 2022; Akarsu et al., 2013). This non-interventional observational
study aims to document symptom progression in 60 patients with ME/CFS who underwent HBOT
following COVID or other infections. The study does not focus on evaluating the efficacy
of HBOT itself.

ME/CFS patients currently participating in the Chronic Fatigue Syndrome CARE (CFS_CARE)
study at Klinik Bavaria in Kreischa will have the opportunity to receive HBOT treatment
as a supplementary offer from the clinic upon completion of the CFS_CARE study.
Additionally, these patients will be invited to participate in this observational study
during the final CFS_CARE presentation at the 12-month mark. HBOT is performed as part of
the Conformité Européenne (CE) certificate, as an outpatient procedure within standard
clinical practice, and independent of the study focus. Throughout the HBOT treatment,
patients will undergo health assessments and symptom evaluations four weeks after
treatment initiation and four weeks after completing the HBOT sessions. To facilitate
this, patients will receive a link to a RedCap file containing questionnaires, including
those previously utilized in the CFS_CARE study (36-Item Short Form Health Survey
(SF-36), Munich Berlin Symptom Questionnaire (MBSQ), Chalder Fatigue Questionnaire, Bell
Score). Completing the questionnaires typically requires approximately 45 minutes. The
questionnaires will be collected every two months over 12 months, resulting in a total
follow-up period of 10 months. A follow-up visit at the outpatient clinic is scheduled
for four weeks after HBOT is completed.

The study's primary endpoint is to identify improvements in physical function following
HBOT. This will be achieved by utilizing the SF-36 Physical Function (PF) questionnaire,
which commonly serves as the primary endpoint in clinical trials focused on ME/CFS. It
has been shown that an increase of at least 10 points in the SF-36 PF (range 0 - 100 =
healthy) defines clinically relevant improvement ("a little better"), and an increase of
20 points defines greater clinical improvement ("much better") (Brigden 2018). Therefore,
an increase of at least 10 points 4 weeks after HBOT is defined as a response and
assessed as the primary endpoint.

The study-related measures do not pose significant risks or additional burdens to
participants aside from the time required to complete the questionnaires. However, it has
the potential to generate valuable knowledge regarding HBOT as a potential treatment for
ME/CFS. To date, there has been no documentation of the efficacy of HBOT in ME/CFS
through a clinical trial employing objective methods. The results of this observational
study are expected to serve as the foundation for a potential interventional randomized
controlled trial (RCT).