The aim of this study is to evaluate the efficiency and safety of immunoadsorption forthe treatment of post-COVID syndrome (PCS).Efficacy will be measured (1) subjectively as an improvement of the score ofquestionnaires like the multidimensional fatigue inventory (MFI-20), Chalder fatiguescale, Bell-score, modified medical research council dyspnea scale (mMRC) and thePost-COVID functional scale (PCFS) and (2) objectively as an improvement inneurocognitive testing with the Montreal cognitive assessment (MoCA) and the improvementof the hand-grip strength.40 participants with symptoms of PCS and a PCFS score of at least 2 will be included ineach group (Addendum from February 2024: An additional 40 patients with the sameinclusion and exclusion criteria will be treated using the devices and materials ofanother manufacturer, following the same design, and the results will be evaluatedseparately.). After excluding other causes of the symptoms and evaluating the baselineburden of symptoms, each participant will undergo 5 sessions of immunoadsorption with animmunoglobulin-binding adsorber and 5 sham treatments, or vice versa. The order oftreatments (immunoadsorption first or sham first) will be randomized. Each participantwill be blinded to the type of treatment they receive. An 8-week therapy-free period willseparate the two treatment blocks. All examinations will be conducted before the firsttreatment, 2 weeks after the first treatment cycle, before the second treatment cycle,and 2 and 6 weeks after the second treatment cycle.The results of the study will inform future treatment strategies for PCS and willcontribute to a better understanding of the pathophysiological insights behind theongoing symptoms.
Post-COVID syndrome (PCS) refers to symptoms that develop 3 months from the onset of
COVID-19 with symptoms that last for at least 2 months and cannot be explained by an
alternative diagnosis (Soriano, Murthy et al. 2022). The nature of the symptoms has not
been a factor in the definition of PCS. The prevalence of PCS is estimated to be 43% of
all severe acute respiratory syndrom coronavirus 2 (SARS-COV-2)-infected patients, with
hospitalized patients more likely to suffer from persistent symptoms (54%) than
non-hospitalized patients (32%). Women are more likely to experience PCS than men
(incidence, 49% vs 32%, respectively) (Chen, Haupert et al. 2022). The most common
symptoms are fatigue (23%), memory impairment (14%), dyspnea (13%), sleep disturbances
(11%), and joint pain (10%) (Chen, Haupert et al. 2022). Headaches, myalgia, anxiety or
depression are also frequently reported.
In terms of the type, variety and duration of symptoms, PCS resembles a clinical picture
observed after various viral infections, such as Eppstein-Barr virus, herpes simplex
virus or influenza virus, namely myalgic encephalomyelitis and chronic fatigue syndrome
(ME/CFS). Here, too, patients mainly suffer from fatigue, impaired concentration and
memory, and non-restorative sleep. Some authors consider post-COVID as a form of ME/CFS
triggered by the SARS-CoV-2 infection or the immune response to the infection. The
underlying pathophysiology likely depends on the different viruses but is incompletely
understood. Similarly, the causes of PCS are unclear to date. Autoimmunity is suspected
to play a major role in all post-virus syndromes. It may be triggered by the defense
against infections and is probably maintained by similarity of endogenous proteins with
pathogen components (molecular mimicry). In the context of this autoimmunity, antibodies
against endogenous structures can also be formed, such as antinuclear antibodies, which
are directed against components of the cell nuclei. Antibodies against α- and
β-adrenergic receptors and muscarinic acetylcholine receptors, among others, have been
detected in patients suffering from ME/CFS as well as in patients with PCS.
Many patients are limited in their daily lives by the symptoms that develop or persist
after SARS-COV-2-infection and suffer from a diminished quality of life. To date, there
is little evidence on potential therapies for these complaints. Immunoadsorption (IA)
efficiently removes (auto-)antibodies from the circulation and has been proposed as a
potential therapy for PCS. The current trial will investigate the efficacy of IA for the
treatment of PCS.
40 participants with PCS and a PCFS-score of at least 2 will be included in each. Each
participant will undergo 5 sessions of IA with an immunoglobulin-binding adsorber and 5
sham treatments or vice versa. Sham treatment will be performed in the same ways as IA,
but the IA device will not be set up with an adsorber. The order of treatments
(immunoadsorption first or sham first) will be randomized. The participants are blinded
to the order of treatments. An intervention-free interval of 8 weeks will separate both
treatment blocks (Addendum from February 2024: 40 patients additional with the same
inclusion and exclusion criteria will be treated using the devices and materials of
another manufacturer, following the same design, and the results will be evaluated
separately.).
The primary outcome of the study is the efficacy of IA vs. sham, measured as changes in
the PCFS (0-4), Chalder-fatigue scale (0-33), MFI-20 (20-100), Bell score (0-100),
montreal cognitive assesment and the hand-grip strength before therapy compared to values
after immunoadsorption and after sham-treatment. Secondary outcomes are (1) the number
and severity of adverse events, (2) the prevalence of auto-antibodies like antinuclear
antibodies, antibodies against adrenoreceptors and antibodies against muscarinic
acetylcholine receptors in patients with PCS and (3) the change in concentration of the
auto-antibodies in context of therapy and sham-treatment. In addition, various
assessments (Complete blood count with differential, Antinuclear antibody
Thyroid-stimulating hormone, C-reactive protein, Vitamin B12, Vitamin D, 25-dihydroxy,
Ferritin, Urinalysis, ECG, spirometry, psychological questionaires) will be performed
during screening period to be able to exclude other diseases as the cause of the PCS
symptoms. In addition, safety-relevant parameters such as heart rate, blood pressure,
electrolyte concentra-tions, fibrinogen concentration and the concentration of the
immunoglobulin fractions are measured before and after each treatment.
The results of the study will inform future treatment strategies for PCS and will
contribute to a better understanding of the pathophysiological insights behind the
ongoing symptoms.
Device: Immunoadsorption
Immunoadsorption (IA) is a well-established extracorporeal therapy for several autoimmune
diseases such as systemic lupus. Its therapeutic effect is based on the removal of
antibodies (ABs) from the plasma including auto-ABs and it is used if an immediate
response to therapy is necessary. Side effects (SE) of the IA are rare, but
angiotensin-converting enzyme (ACE)-inhibitors are prohibited concomitant medication.
Notable SE may include increased susceptibility to infection, transient disorders of
blood coagulation, or allergic reactions to materials of the adsorber or tubing system.
To ensure an effective therapy, a blood flow of at least 45 ml/min is necessary. In some
patients, adequate blood flow can be achieved by cannulation of peripheral veins but in
most patients is the placement of a central venous catheter necessary. Central venous
catheter placement carries potential risks such as injury to the lung or mispuncture of
the carotid artery.
Device: Sham-apheresis
Sham-apheresis is a procedure without any known therapeutic effects. As there are no
known therapeutic effects there are also no known side effects excepted the risk of an
allergic reaction to materials of the tubing system or to citrate, which is necessary to
prevent clotting inside the extracorporeal system. To ensure a smooth operation a
blood-flow of at least 45ml/min is necessary. In some patients, adequate blood flow can
be achieved by cannulation of peripheral veins. However, in most patients, placement of a
Shaldon catheter into the internal jugular vein is necessary. Shaldon catheter placement
carries other potential risks such as injury to the lung resulting in pneumothorax or
mispuncture of the carotid artery. However, since the catheter placement is
sonography-guided, the risks for such adverse events are minimized.
Inclusion Criteria:
- Meeting the WHO diagnostic criteria for PCS
- Written informed consent to participate in the study
- Previous participation in the Gutenberg Post-Covid Study or previously conducted
comparable preliminary examinations
- Minimum age of 18 years
- Value on the Post-COVID functional scale of at least 2
Exclusion Criteria:
- Psychiatric diagnosis
- Allergy to adsorber materials, materials of the tubing systems or to the substances
used for immunoadsorption
- Pregnancy
- Medical contraindications to immunoadsorption such as severe blood clotting
disorders or immunodeficiency syndromes
- Existing antibody-mediated autoimmune disease
- Intake of ACE-inhibitors 7 days prior to the inclusion in to the study or during the
study period
UNIVERSITÄTSMEDIZIN der Johannes Gutenberg-Universität Mainz I. Medizinische Klinik und Poliklinik
Mainz, Rheinland-Pfalz, Germany
Not Provided