Studies indicate an overlap between post-COVID syndrome (PCS) and ME/CFS (Kedor et al.,
2022). Post-infectious ME/CFS (ICD-10 code G93.3) is a complex and severely disabling
disease with no approved treatment and thus, a very high medical need. Following an acute
infection, patients suffer from severe central and muscle fatigue, chronic pain,
cognitive impairment, and immune and autonomic dysfunction. The key symptom of ME/CFS is
exertion intolerance with minor exertion resulting in symptom aggravation, also called
post-exertional malaise (PEM), lasting until the next day up to weeks.

Various pathogens are known to induce post-infectious ME/CFS, including the Epstein-Barr
virus and SARS-CoV-2 (Sotzny, 2018). The investigators' ongoing Charité PA-COVID study
(Berlin prospective COVID-19 patient cohort) and other reports show that SARS-CoV-2
triggers ME/CFS in a subset of mostly younger patients without preexisting comorbidities
(Kedor et al., 2022). Due to the rapid increase of COVID-19 incidence worldwide, the
prevalence of post-COVID-19 ME/CFS will likely be a substantial problem for health care
and society.

The evidence for an autoimmune etiology in post-infectious ME/CFS is growing (reviewed in
Sotzny et al., 2018). Also, COVID-19 is a disease with a high risk for autoimmunity and
developing ME/CFS due to the infection of many different cell types and the severity of
immune activation. There is evidence from several studies from the investigators and
other groups that natural regulatory autoantibodies targeting G protein-coupled receptors
(GPCR) are involved in the pathogenesis of various autoimmune diseases. The investigators
and others described enhanced levels and dysfunction of ß2R autoantibodies in ME/CFS and
their correlation with the severity of key clinical symptoms (Freitag et al., 2021). The
investigators' working hypothesis is that GPCR-specific autoantibodies with altered
binding affinity or epitope specificity lead to immune dysregulation and autonomous
dysfunction, and play a significant role in the pathomechanism of ME/CFS (Wirth et al.,
2020). The investigators observed -- in a not yet published study -- a close correlation
of ß2R antibodies with symptom severity in ME/CFS after COVID, similar to ME/CFS after
other infections (Freitag et al., 2021). Two small proof-of-concept studies with
immunoadsorption (IA) in patients with ME/CFS after other infections have shown
improvements in symptoms in most patients (Scheibenbogen et al., 2018; Toelle et al.,
2020).

In this observational non-controlled trial, PCS ME/CFS patients who receive IA will be
evaluated for clinical efficacy, a decrease in autoantibodies, and a change of
biomarkers. IA with Miltenyi's TheraSorb® column will be performed in the approved use.
Patients who have symptom improvement after the 1st IA will receive two additional IAs at
3 and 6 months, which will also be documented. Symptom severity will be assessed by
online questionnaires and at repeated time points.

Patients will be recruited for IA from the investigators' ongoing observational study
with a follow-up of at least six months without disease improvement (Kedor et al., 2022).
Patients have received a comprehensive diagnostic assessment to exclude other diseases,
central nervous system, or organ comorbidity. ß2R autoantibodies in serum are determined
by ELISA (Celltrend). Within four weeks prior to IA, patients will be assessed for
eligibility for study participation by clinical investigation, laboratory analysis, and
symptom questionnaires. The first ten patients will be treated end of August - mid of
October and analyzed for efficacy until the beginning of December 2022 with a grant from
the Weidenhammer-Zoebele foundation. The subsequent ten patients will be treated and
analyzed with funding from the Federal Ministry of Education and Research(BMBF). These
ten patients will also receive vessel diagnostics before (within four weeks) and four
weeks after the first IA. In all 20 patients, blood will be collected the week before and
four weeks after the first IA. All visits and treatments will take place in outpatient
clinics.

Antibody depletion in PCS using IA has yet to be investigated in a clinical trial. The
results of this observational study will provide the basis for a RCT using IA and, in
responders, consecutive B-cell depleting therapy with an anti-CD20 monoclonal antibody
versus placebo.