Statement on Chapter 91 “Chronic Fatigue Syndrome” in the Newly Published 10th Edition of
Dear members of the responsible editorial team at Springer Nature,
Dear Professor Linden,
Dear Professor Hautzinger,
Dear Dr. Kupferschmitt,
Dear Professor Köllner,
We are a group of more than 140 physicians, psychotherapists, pharmacists, and veterinarians who are themselves affected by Post-COVID and ME/CFS of various causes. Our group includes specialists from almost all somatic medical disciplines, as well as numerous psychiatrists, psychosomatic medicine specialists, and medical and psychological psychotherapists. As healthcare professionals with, in some cases, extensive professional experience and substantial practical knowledge, complemented by expertise gained from lived experience, we feel compelled to comment on the chapter “Chronic Fatigue Syndrome” by Dr. Kupferschmitt and Professor Köllner, as it contains significant methodological and substantive errors.
Given the large number of points requiring criticism, we will list them below in bullet-point form. In addition, we have compiled a number of studies on the somatic pathogenesis of the disease, which we strongly encourage our colleagues to consider.
1. Disease terminology and classification
1.1.
The title itself refers exclusively to “CFS” rather than “ME/CFS”, and the text likewise predominantly uses “CFS” alone, which is highly problematic. The term “CFS” was used in the 1980s and 1990s to psychologize the disease that had been recognized by the WHO as Myalgic Encephalomyelitis (ME) in 1969. For this reason, focusing on this terminology is rejected by experts and patient organizations. The scientifically established terminology is ME/CFS, which also clearly distinguishes the disease linguistically from fatigue states associated with other underlying conditions, which differ substantially both etiologically and in terms of therapeutic implications.
1.2.
The neurological classification of ME/CFS and the corresponding correct ICD-10 coding (G93.3x) are omitted. Instead, Myalgic Encephalomyelitis is equated with psychiatric and psychosomatic disorders such as neurasthenia (F48.0) and somatoform disorders (F45.x), or with other conditions such as fibromyalgia (M79.7) and other fatigue states. However, these must not be used synonymously, as they are entirely different diseases with different treatment approaches. The ICD-10 explicitly excludes a diagnosis of neurasthenia (F48.0) when G93.3x is present, and also in the case of R53.0/1. The term “fatigue syndrome” (“Müdigkeitssyndrom”) listed in the text has likewise long since been removed from the ICD-10 as an incorrect term.
1.3.
Post-COVID syndrome (PCS) as an umbrella term and ME/CFS as a specific disease are not sufficiently differentiated throughout the text. In addition, both are conflated with nonspecific fatigue (e.g. the statement that “post-viral fatigue” has long been known independently of COVID).
1.4.
Conclusions derived from studies of PCS cohorts are repeatedly transferred to ME/CFS, even though it was not established whether the individuals studied actually fulfilled the diagnostic criteria for ME/CFS (see also point 10).
2. Diagnostic criteria and the cardinal symptom PEM/PENE
2.1.
The Canadian Consensus Criteria (CCC; Carruthers et al., 2003) are mentioned but are not adequately or accurately explained. ME/CFS can be diagnosed using these clinical criteria, as well as the International Consensus Criteria (ICC; Carruthers et al., 2011), particularly with consideration of Post-Exertional Malaise (PEM)/Post-Exertional Neuroimmune Exhaustion (PENE) and the exclusion of relevant differential diagnoses.
2.2.
The statement that there are “no reliable clinical symptoms” or no reliable diagnostic criteria contradicts the simultaneous mention of established clinical criteria. Symptoms are also described that do not, in fact, correspond to the disease, such as “chronic, non-restorative fatigue.”
2.3.
In particular, the nature and significance of PEM/PENE should be presented centrally and unambiguously.
2.4.
Autonomic dysfunction (dysautonomia) can occur as a manifestation of ME/CFS. Orthostatic intolerance (OI) and postural orthostatic tachycardia syndrome (POTS, G90.80) are common comorbidities, but they are by no means obligatory components of ME/CFS.
3. Publications on the somatic pathogenesis of ME/CFS
Contrary to the statement in the text that “there is currently no empirical evidence for the etiological concepts associated with ME/CFS,” numerous empirical findings supporting a somatic pathogenesis of ME/CFS already exist. We will cite only a few examples here so as not to exceed the scope of this statement.
The studies have identified, among other findings, endothelial dysfunction (Scherbakov et al., 2020), reduced cerebral blood flow (van Campen et al., 2020), and altered red blood cell deformability (Saha et al., 2019). In addition, impaired adrenergic signaling (Hartwig et al., 2020) and autoantibodies against G-protein-coupled receptors (Freitag et al., 2021) have been identified.
Other studies demonstrate cerebral neuroinflammation and disruption of the glymphatic system (Yu et al., 2026; Thapaliya et al., 2026). Furthermore, disturbances in energy metabolism (Lien et al., 2019; Tomaskovic et al., 2026), alterations in plasma proteomics with maladaptive regulation following exertion (Germain et al., 2025), and pathological muscle changes have been described, providing a basis for hypotheses regarding the pathophysiology of PEM/PENE (Appelman et al., 2024; Charlton et al., 2026; Davenport et al., 2025; Davenport et al., 2026; Scheibenbogen and Wirth, 2025; Westermeier et al., 2026). It has also already been demonstrated that pathological metabolic changes in muscle cells can be induced by exposure to serum from ME/CFS patients (Mughal et al., 2025).
4. Differentiation from psychiatric and psychosomatic disorders
4.1.
Although the stated purpose should be to differentiate ME/CFS from primarily psychogenic disorders, the authors’ presentation effectively promotes a psychosomatic and even psychogenic explanation of ME/CFS. This begins with the synonymous linking of ME/CFS to neurasthenia and somatoform disorders, which are even explicitly provided in the text with diagnostic codes, while any correct somatic coding is omitted. It continues throughout the chapter in the form of erroneous assumptions about the disease and its possible management.
4.2.
Patient behavior is pathologized without any supporting evidence. The text states, for example:
“A striking characteristic of some patients with fatigue is […] dysfunctional illness behavior involving self-harming protective and avoidance behavior, increased self-monitoring, and involvement of the social environment,”
which allegedly “fulfills the criteria for a hypochondriacal disorder” (section 91.1, p. 568).
Here, pacing, which is essential activity management in the presence of PEM/PENE, is labeled as dysfunctional and the disease itself is placed in close proximity to hypochondria. This is not only unsupported by evidence but also stigmatizing.
4.3.
Social isolation may likewise constitute a reasonable protective mechanism in ME/CFS in view of PEM/PENE and should not be prematurely interpreted as pathological behavior. Fear of PEM/PENE can be an understandable and adaptive response to repeatedly experiencing deterioration following overexertion.
4.4.
Psychiatric and psychosomatic diagnoses should not be used as fallback diagnoses for medically insufficiently researched diseases or unexplained symptoms (Schomerus et al., 2026).
5. Stigmatization of patients
5.1.
The assertion that a “striking characteristic of some patients with fatigue” is “a combative, reproachful attitude toward healthcare providers who do not share their diagnostic assumptions” is scientifically unsupported, inappropriately judgmental, and ultimately harmful to people with ME/CFS. The same applies to the label “aggressive patients” and the alleged “defensive attitude” and “sense of grievance.”
5.2.
Self-help and patient empowerment in the field of ME/CFS have emerged in response to decades of inadequate healthcare provision. Compared with other diseases, ME/CFS remains severely underserved. Even in 2026, the disease is not included in any standard medical school curriculum, and irreversible harm resulting from inappropriate treatment remains common. Pathologizing efforts to change these conditions encourages biased or inadequate treatment and makes scientifically informed care more difficult.
5.3.
When patients reject psychosomatic concepts because these concepts overemphasize the role of the psyche or the possibility of activation and pathologize appropriate behavior, this constitutes a necessary form of protection against the resulting inappropriate treatment.
5.4.
The authors likewise present incorrect diagnostic classifications and disease concepts. Problems within our healthcare professions are externalized and inappropriately shifted onto patients.
5.5.
It is neither plausible nor supported by evidence that a hypochondriacal presentation is a characteristic feature of patients with ME/CFS. No data or conceptual model is presented to explain why this particular disease should differ from other severe diseases in the prevalence of anxious or hypochondriacal comorbidities. Since, unlike people with depression, patients with ME/CFS do not generally have a primary impairment of drive or motivation, and often have to learn to monitor themselves precisely because their functional limits become apparent only with a delay, this attribution may even be dangerous. Accurate differential diagnosis is only possible if healthcare professionals understand the underlying somatic disease.
5.6.
The same applies to other psychiatric comorbidities and behavioral problems.
5.7.
The authors’ overall model is also stigmatizing, as it overlooks the broad middle ground of healthy coping between avoidance and endurance, as well as the component of resource assessment. In effect, 100% of patients are labeled as dysfunctional.
5.8.
It is an ethical professional obligation not to cause additional harm to seriously ill patients. Stigmatization of people with ME/CFS may, in addition to the risk of harmful overactivation and iatrogenic psychological harm—including suicidal thoughts (König et al., 2024)—perpetuate deficiencies in care. These may include denial of recognition within the social-medical system, more difficult access to assistive devices, nursing care and other support services, withholding of symptom-oriented treatment, or inappropriate referral to primarily psychotherapeutic care instead of needs-based multidisciplinary treatment.
5.9.
The text also implies that affected individuals “attribute” their symptoms to the disease because it has been “present in the media after the coronavirus pandemic,” rather than acknowledging high infection rates with a novel, highly pathogenic virus as a cause of the increasing number of cases.
6. Information on psychiatric comorbidities and their treatment
6.1.
The claimed prevalence of psychiatric comorbidities of up to 70% appears dramatically inflated and should be supported by clearly identifiable sources. We also question what the exclamation mark in this context is intended to emphasize, and what such an exclamation mark is doing in a scientific publication.
6.2.
It should be explicitly acknowledged that inappropriate screening instruments can lead to an overestimation of psychiatric comorbidities. In particular, the PHQ-9 and GAD-7 are not suitable for people with ME/CFS to distinguish depressive or anxiety symptoms from symptoms caused by the disease itself (Schomerus et al., 2026).
6.3.
When discussing depression and anxiety disorders, a distinction should also be made between primary psychiatric comorbidity and psychological consequences of a chronic, severely burdensome somatic illness.
6.4.
Psychological distress without psychopathological significance, such as appropriate grief over often profound losses, as well as realistic fear, should be clearly distinguished from mental disorders. Accordingly, fear of PEM/PENE should not be equated with an anxiety disorder.
6.5.
The authors identify depression and anxiety disorders as common comorbidities and state that their treatment should be integrated into the treatment plan in accordance with the respective clinical guidelines. In the presence of PEM/PENE, however, many elements of guideline-based psychotherapy involve substantial physical and/or emotional activation and are therefore contraindicated in ME/CFS. Treatment must accordingly always be adapted to PEM in order to prevent iatrogenic harm (see also Grande et al., 2023), and emotional activation should likewise be kept as low as possible as an integral part of psychotherapy.
6.6.
Somatopsychic and neuropsychiatric aspects are not discussed, even though neuroinflammation and emotional fatigue may mimic depressive phenomena, while postural tachycardia and orthostatic intolerance can be mistaken for panic attacks or anxiety attacks. Careful differential diagnosis in this regard is essential and should not be omitted from any such publication.
7. Pacing and activation
7.1.
The authors use the concept of pacing incorrectly. Pacing is not “slow activation” and should therefore not be described as such. Nor is it a psychotherapeutic procedure. Rather, the goal of pacing is to make the best possible use of the energy resources available within an individual’s personal limits while avoiding PEM/PENE.
7.2.
Accordingly, activation is contraindicated in ME/CFS. ME/CFS is precisely not a disease characterized by pathological avoidance. Rather, patients must restrict their activity despite their healthy drive to remain active in order to prevent progression.
7.3.
The recommendation of gradual increases in activity is not only professionally incorrect and grossly negligent in severe ME/CFS and pronounced PEM/PENE. Even milder forms of the disease can deteriorate as a result of overexertion. An increase in activity is only possible once sustained physical stability has been achieved. Externally imposed activation, however, puts this stability at risk.
7.4.
It is inherent to PEM/PENE that overexertion may only become apparent days later and, in the case of cumulative micro-overexertion, even weeks later. People with ME/CFS may be able to exceed their limits for a period of time, but they may subsequently experience delayed and not infrequently permanent deterioration as a consequence.
7.5.
The primary objective in ME/CFS, in addition to improving quality of life, is particularly to stabilize and preserve the remaining level of functioning and to provide symptomatic treatment. Treatment success should therefore not be assessed on the basis of a short-term or subjectively measured expansion of activity levels, but rather in terms of long-term functional capacity.
7.6.
There is also evidence that inactivity does not cause a “myalgic fatigue syndrome.” This is not an established technical term. Moreover, it has now been demonstrated that the muscles of patients with ME/CFS behave differently under inactivity than the muscles of healthy individuals (Charlton et al., 2026).
7.7.
The risk of nocebo effects is overemphasized in comparison with the widespread and considerably more serious risk of permanent harm resulting from activity escalation. Lack of knowledge among healthcare professionals or minimization of PEM/PENE continue to prevent appropriate patient education in the early stages of the disease. Appropriate education, however, can be decisive for prognosis: early pacing may contribute to recovery, while timely use of assistive devices, reduction of demands, and establishment of nursing and other support can limit exacerbation. Conversely, inappropriate concepts may promote overexertion.
7.8.
There are still no established safe rehabilitation concepts, as demonstrated by the study of a rehabilitation program specifically adapted to ME/CFS conducted by Charité Berlin in cooperation with the Kreischa Rehabilitation Clinic (Kedor et al., 2026, preprint). Despite optimal conditions, almost 45% of participants experienced deterioration. Contrary to the presentation in the text, harm resulting from rehabilitation interventions is therefore by no means merely a phenomenon of the past.