To date, there is only limited evidence for the clinical efficacy of immunoadsorption in the treatment of post-COVID syndrome. It is not among the treatments recommended by current German guidelines [37]. Nevertheless, the treatment is offered in some settings as a non-reimbursable individual health service (Individuelle Gesundheitsleistungen, IGeL), with total costs estimated to exceed 16,000 euros for a full treatment course [38]. However, due to the disease burden, which is substantial for many patients, there is often a high demand for therapeutic interventions that extend beyond symptomatic treatment. In light of the growing critical assessment of previous observational data and the new controlled evidence from the literature—which has so far failed to confirm clinically relevant efficacy—this prospective exploratory study investigates the effectiveness of immunoadsorption in post-COVID syndrome with regard to the reduction of autoantibodies as well as objective and subjective performance, contributing to the current evidence base.

Despite the approximately 400 patients seen annually in our post-COVID outpatient clinic, recruitment efforts had limited success. The main reason was that only a subset of patients received a confirmed diagnosis of post-COVID syndrome [2]. Furthermore, many patients did not meet inclusion criteria, primarily due to relevant comorbidities. Among the 133 screened patients, antibodies against β1/β2aR and M3/M4mAcR were not detectable in 29%. Additionally, several patients resigned at short notice for personal reasons, due to safety concerns, or because of spontaneous clinical improvement. As a result, only 18 instead of the planned 20 participants could be included in the study.

Our study population showed a representative distribution of demographic characteristics (Table 1). Consistent with the literature, the majority of our patients were women of middle age, with a symptom profile typical of post-COVID syndrome [5, 39]. The most commonly reported symptoms among our participants were four core symptoms: fatigue, cardiopulmonary complaints, cognitive impairments, and pain.

Adverse events (AEs) such as hypotension, access-related problems, paresthesia, and urticaria are reported in 8.4% of registered immunoadsorption procedures [40]. The risks observed in our study, such as arterial mispuncture during CVC placement and superficial thrombophlebitis after peripheral access, did not raise additional safety concerns.

Immunoadsorption rapidly and significantly reduced IgG and circulating antibodies against β1/β2aR and M3/M4mAcR in our patients. The subsequent increase in antibody concentrations to baseline levels during follow-up visits at 3 and 6 months (V12, V24) suggests that there was no sustained reduction in antibody titers, and therefore possibly no long-term clinical benefit is to be expected. The absence of correlations between changes in autoantibody titers and both objectively measured and subjectively reported outcomes supports the hypothesis that autoantibodies may not be the primary driver of symptoms in our patient cohort.

If autoantibodies are indeed disease drivers, a long-term therapeutic effect cannot be anticipated from immunoadsorption. While immunoadsorption effectively removes circulating antibodies, complement, and pro-inflammatory cytokines, it does not eliminate the antibody-producing B cells [41]. This aligns with clinical experience in other autoimmune diseases, such as multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis, where autoantibodies are rapidly cleared, leading to transient clinical improvement, until antibody levels rise again after some weeks [42]. In rheumatoid arthritis and multiple sclerosis, a clinical response has been observed in 48% and 88% of cases respectively within a follow-up period of up to 12 weeks after immunoadsorption [43]. In contrast, our data do not show such a pronounced clinical efficacy in post-COVID patients, despite the significant reduction in autoantibodies and immunoglobulins. This suggests that the observed symptom burden may be driven by mechanisms beyond circulating autoantibodies.

In our participants, no significant improvement in objectively measured physical performance was observed after immunoadsorption, including 6MWT distance, daily step count, handgrip strength, resting heart rate on ECG, and spirometry.

Since only a limited number of validated objective tests are currently available for assessing disease activity in post-COVID conditions, subjective assessments in terms of structured diaries were also incorporated into data collection. Diary analysis revealed a minor reduction in pain and overall symptom burden, along with a decrease in fatigue and increased perception of physical activity. These findings suggest a partial subjective improvement, which, however, did not correlate with objective performance gains. Furthermore, no significant association was found between changes in circulating autoantibody levels and subjectively reported symptoms in the correlation analysis. This suggests that the observed subjective changes may not be directly mediated by the reduction of autoantibodies. Interestingly, the home-based 6MWT showed increases in walking distance after immunoadsorption, whereas no corresponding improvement was observed in the setting of the standardized clinical consultation for any participant. This discrepancy between home- and clinic-based results highlights the methodological challenges in interpreting subjective self-reports compared to objective performance measurements.

To date, one randomized trial, several small-scale studies and case series have been published on immunoadsorption in post-COVID patients with elevated antibodies against β-adrenergic and/or muscarinic receptors. Similar to our study, these publications report that immunoadsorption can temporarily reduce autoantibodies and immunoglobulin G [26,27,28,29]. In all these investigations, including our own, five treatment sessions were performed within a period of less than 14 days. However, the studies show heterogeneous findings regarding clinical efficacy. Due to different questionnaires and inconsistent objective measured parameters, the results are not directly comparable. The questionnaires and scores used in these studies are summarized in Table 4.

The first randomized, patient-blinded, sham-controlled crossover trial investigating immunoadsorption in 40 post-COVID syndrome was recently published. Although immunoadsorption significantly reduced circulating autoantibodies against G-protein-coupled receptors as well as IgG levels, no clinically relevant improvements were observed compared with sham treatment regarding fatigue, functional status, cognitive performance, or handgrip strength. The authors therefore concluded that, despite successful autoantibody depletion, immunoadsorption did not provide a clinically meaningful benefit in post-COVID syndrome [30].

In another one study, 14 of 20 patients reported a clinically relevant improvement of at least 10 points in the SF-36 Physical Functioning Score after immunoadsorption [26]. Additionally, sustained improvements were observed in fatigue, post-exertional malaise and pain, as well as in cognitive, autonomic, and immunological clinical parameters. In another study [27], a transient improvement of symptoms was documented in one of two patients treated with immunoadsorption. One patient reported a clear improvement in physical and mental condition after the fifth treatment cycle. However, two months after treatment, symptom severity had returned to baseline levels. The other patient reported only a minor subjective improvement. In a further observational study [28], all 12 post-COVID patients showed neuropsychological improvements and slightly increased handgrip strength 30 days after immunoadsorption. However, subjective symptoms remained unchanged. In a case series of 10 patients with post-COVID syndrome, no clinically relevant changes in mental or physical health were observed following immunoadsorption [29].

Despite a significant reduction in autoantibodies observed in several studies – including the present study and the recently published, sham-controlled study [43] – no clinically relevant benefit of immunoadsorption has been demonstrated in the majority of studies.

In addition to immunoadsorption, therapeutic plasma exchange (TPE) has also been investigated in patients with post-COVID syndrome. In a randomised, double-blind, placebo-controlled Phase II trial involving 50 patients, TPE proved to be a safe procedure; however, compared with the placebo group, it did not lead to any significant improvements in functional capacity, symptoms, cognitive function or health-related quality of life [44]. These findings underscore the need to critically evaluate the clinical efficacy of using apheresis procedures to treat post-COVID syndrome, particularly as the reduction of autoantibodies alone is not sufficient to achieve sustained clinical improvement.

In our study, we used a smartwatch step counter to obtain an objective assessment of daily activity. A systematic review of 32 observational studies on daily activity showed that healthy young adults typically take approximately 7000–13,000 steps per day [45]. We hypothesized that a reduction in fatigue and pain would lead to an increase in daily activity resulting in increased step counts. Reduced pain and fatigue were reported by 50% of our participants, but this was not accompanied by an increase in daily steps. Notably, after immunoadsorption, nine participants reported pain scores above 5 on the numerical rating scale, indicating severe pain, yet still walked more than 10,000 steps per day.

Furthermore, our participants reported Bell Disability Scale scores of 39.8 (SD 15.3) points before immunoadsorption, corresponding to moderate functional impairment with only a few hours of light activity per day. Despite this, they achieved an average of 9029 steps (SD 3896) per day. After immunoadsorption, participants reported higher Bell scores (52.4, SD 20.0), indicating improved self-perceived function, although their daily step count did not increase.

This discrepancy between objectively measured activity, comparable to that of healthy adults, and subjectively reported severe symptoms such as pain and fatigue should be pursued in future studies.

In addition to subjective parameters, our study also collected objectively measurable outcomes, which should be considered in future studies. Precise methods such as cardiopulmonary exercise testing and lactate measurements during bicycle ergometry enable changes in physical capacity to be reliably assessed. Furthermore, modern wearables, such as wrist-worn devices, offer the opportunity to measure a wide range of physiological parameters, including step count and heart rate, as well as oxygen saturation, skin temperature, ECG, blood pressure and sleep patterns. These multimodal data not only provide insights into improvements in physical fitness but also offer a more comprehensive understanding of patients’ quality of life and daily routine.

Our study has several methodological limitations. As previously mentioned, only 18 participants were enrolled instead of the originally planned 20, which was due to some patients withdrawing prior to the start of this invasive procedure. A placebo-controlled design would have required CVC placement in patients with poor peripheral venous access, to simulate blood exchange without immunoadsorption. Moreover, due to the complexity in assessing therapeutic response and the subjective nature of widespread symptoms, a very large sample size would have been required to detect notable improvement in symptoms, making funding somewhat difficult. After careful considerations a placebo group could not be not established in our study for ethical and logistical reasons.

Although immunoadsorption has proven to be safe and effective in removing immunoglobulin G and specific autoantibodies in our and in other studies [26,27,28,29], we did not observe any objectively measurable, significant improvement in physical performance in patients with post-COVID syndrome. Nevertheless, some participants reported at least minor subjective improvements in their diaries, particularly regarding pain and fatigue.

From a clinical perspective, these results indicate that careful patient counseling is warranted regarding this experimental intervention, which is currently offered outside established, guideline-based medical care. Given the often high expectations of affected patients, transparent communication regarding the limited evidence base, potential risks, and frequently self-funded costs of this procedure is essential.