Abstract
We read with attention the article by Ranque and Cogan (1) entitled "Internal medicine at the crossroads of Long COVID diagnosis and management." While the authors raise questions regarding the interplay between persistent symptoms, psychological factors, and illness perception in Long COVID (LC), key aspects of their interpretation overlook do not reflect substantial biomedical evidence, thereby affecting the conclusions drawn. In addition, insufficient little attention is paid to the epistemic and clinical implications of uncertainty, including the harm it has caused patients 1 .
This commentary offers a constructive critique and proposes a more comprehensive perspective of LC with direct impact on patient care. The authors adopt a narrative review approach rather than a systematic evaluation of evidence strength. In the absence of meta-analytic synthesis, risk-of-bias assessment, or standardized quality appraisal, causal inferences remain limited and prone to extrapolations (2,3).
The article relies on broad and heterogeneous definitions of LC, conflating self-reported prolonged symptoms with clinically confirmed cases, while not consistently applying discounting standardized criteria proposed by WHO, NASEM, or ISARIC (4,5). Such criteria are essential for conceptual coherence, etiological interpretations, and the avoidance of overgeneralization (6).
Similarly, their survey relies on a non-random, voluntary sample confined to a single national context, thereby limiting representativeness and introducing potential bias.The discussion emphasizes that psychological factors drive and perpetuate LC symptoms through the theoretical and clinically applied construct of "Functional Somatic Disorder (FSD)", promoted as a replacement for earlier notions such as somatoform disorders or medically unexplained symptoms (7,8).
However, the existing literature is limited by selection bias and reliance on self-report screening tools, risking conflating primary pathology with psychological symptoms and obscuring causality. It has also not yielded mechanistic insight or objective outcomes and lacks longitudinal follow-up. Moreover, FSD lacks has been criticized for its lack of conceptual and clinical robustness, with including poor differentiation between overlapping patient groups, blurred diagnostic boundaries, and overly inclusive criteria, raising the risk of it functioning as an unstable diagnostic 'container' thereby functioning as a broad residual category rather than a coherent clearly delineated disease entity (9)(10)(11)(12).
Without longitudinal or causal-modeling analyses, assigning primary etiological significance to psychological factors neglects likely overlooks reverse causality and overstates their role (13,14). Moreover In particular, citing a 'non-sequitur' is invoked when the failure of biomedical interventions in clinical trials is cited to support psychological explanations seems unwarranted, even though given that trial authors themselves acknowledged a lack of biomarkers as a key limitations (15).
By contrast, the oppositeno analogous conclusion is not drawn from the poor-quality limited evidence base for "cognitive behavioral therapy" and "gradual physical activity" (16,17).
Another limitation lies in Of further concern is the selective emphasis on functional or psychosomatic explanations at the expense of a substantial body of biomedical evidence supporting the multi-systemic nature of LC. , as reflected in three biomedical evidentiary gaps, constraining mechanistic interpretation and, in turn, the conclusions drawn:
(i) Immunological uncertainty Claims that there is no consensus on immunological mechanisms are not well supported when grounded in a restricted in selective citation base rather than in a comprehensive appraisal of the literature ( 18), a standard seemingly not applied consistently to other post-viral acute infection syndromes (PAIS) like such as Guillain-Barré (19).
The authors also faildo not to consider pre-pandemic evidence of linking human coronaviruses associated withto prolonged symptoms (20)(21)(22)(23)(24), as well asnor key post-pandemic research increasingly pointing to associations with consistently implicating viral persistence, immune dysregulation, neuroinflammation, endothelial/microvascular and skeletal muscle damage, mitochondrial dysfunction, blood-brain barrier disruption, autonomic impairment, post-exertional malaise and broader multisystem injury .
Emerging evidence of causal mechanisms further supports biologically grounded hypotheses and motivates mechanistic and interventional research (51). Advanced neuroimaging reveals has reported neural and metabolic alterations, interpreted as consistent withlinked to diffuse gliosis, distinct from primary psychiatric disease, and consistent aligned with LC patients' symptoms (52)(53)(54)(55). In addition, candidate biomarkers provide converging evidence support for the hypothesis of viral persistence and biological dysfunction, which has been replicated in across different cohorts (56)(57)(58).
These systematic omissions constrain mechanistic interpretation and the conclusions drawn. LC is a complex condition whose persistent uncertainty places patients in a position of heightened vulnerability and clinicians in an epistemic bind. Sociological research in healthcare shows that clinical uncertainty is not merely epistemic but also relational and emotional, with "not knowing" itself being burdensome (59,60). When clinicians fail to engage in reflexivity (ie.eg., acknowledging their own limitations, knowledge gaps, and the relational impact of uncertainty) and instead advance definitive judgments, or at least suggestive assertions, that frame illness primarily or disproportionately as psychosomatic/psychosocial, patients may further experience avoidable distress, self-doubt, diminished agency, isolation, and further psychological burden (60-64).
Conversely, reflexive practice enables clinicians to acknowledge patients' embodied uncertainty, support shared decision-making, and strengthen the therapeutic alliance. Paradoxically, such reflexive practice-presumably central to FSD-oriented care-is absent from frameworks often described as socalled "functional," "holistic," or "biopsychosocial" frameworks (65). As a result, FSD may engender stigma, adversely affecting patient well-being, healthcare experiences, and clinical outcomes (66), consistent with LC patients' testimonies, which highlight that limited clinical reflexivity and epistemic humility can turn uncertainty itself into a source of harm (67)(Figure 1).
LC is heterogeneous both clinically and biomedically, encompassing multiple symptom clusters, trajectories, and levels of impairment that likely reflect partially distinct underlying mechanisms and care needs, thereby underscoring the need for biomedical subclassification. Notably, LC is well-now widely documented described as a post-acute infection syndrome (PAIS) (68)(69)(70)(71)(72)(73), substantiated supported by comprehensive biomedical frameworks that integrate a vast array of replicated findings replicated across geographically distinct cohorts (74)(75)(76)(77)(78)(79)(80) and support by emerging interventions targeting underlying pathophysiological mechanisms (51,81).
In this regard, We we are concernedsuggest that the article overstates overemphasizes psychosomatic/psychosocial explanations by privileging drawing primarily on a narrow subset of the literature over the broader biomedical and medico-sociological record; evidence from chronic disease research indicates that psychological responses typically reflect the consequences of prolonged illness rather than its primary cause-a pattern also observed in LC (82)(83)(84)(85)(86).Moreover, this subset is then viewed through the lens of FSD.
As highlighted in 2.1, FSD's conceptual rationale as well as its application in clinical practice-both solely defined and applied at the symptom level-by design suffer from the limitation of vast heterogeneity, and by implication from a lack of representativeness, translational validity and causal attribution. Subsequently conceptual and practical critique to FSD and similar frameworks like the somatic symptom disorder (SSD) are frequently defended abated through what resembles a motte-and-bailey strategy pattern (87):, shifting from strong and 'new' claims of functional or psychological etiology to vaguebroader, more readily defensible "multifactorial," "biopsychosocial," or "stress-related" formulationsassertions when challenged (88,89),.
Thus, the limited biological components of these diagnoses are overemphasized, while insufficient consideration is given to their lack of specificity, predictive value, and underlying validity, instead centering on nonspecific symptoms such as "fatigue."overrepresenting their limited biological components.These concerns extend to everyday diagnostic and treatment practice, as illustrated by the diagnostic criteria for SSD (90).
While criterion A allows for virtually any biopsychosocial factor to account for symptom onset or persistence, the appropriate application of criterion B depends heavily on the clinician's knowledge, reflexivity, and epistemic humility. As a result, ostensibly patient-related observations, such as "excessive thoughts, feelings or behaviors" and "an ongoing high level of anxiety about health or symptoms," may instead reflect clinician bias or countertransference 2 .
Accordingly, the scientific and clinical use of FSD-like concepts may contribute to diagnostic creep, patient stigmatization, and psychological and physical harm. This need for humility also applies to integrative biopsychosocial or holistic models, which may have value in PAIS if their current scientific and clinical limitations beyond the symptom level are acknowledged and if they are held to the same standards of scrutiny as biomedical evidence, rather than being used as etiological or therapeutic shortcuts in the absence of biomarkers or effective treatments.
Acknowledging the vast and growing body of evidence for the biological underpinnings of LC and PAIS, together with their overlap with-and implications for-other diseasesAcknowledging the primary biological nature of LC (80,(91)(92)(93), does neither discount the relevance of psychological or social factors in symptom experience-as in any chronic illness-, nor diminish the need for psychological/social support as well as for long-term health outcome monitoring does neither discount the relevance of psychological factors in symptom experience-as in any chronic illness-, nor diminish the value of psychological support (69,94,95) .;
ratherRather, it reinforces the need for integrative, flexible, and relational care grounded in epistemic humility (67), while that acknowledges acknowledging the history and actuality of iatrogenesis in PAIS (65).A multifaceted, interdisciplinary clinical approach prioritizing targeted biomedical perspectives should include:
• partnership with expert patient experts living with emerging illnesses to enhance conceptual clarity,
• rigorous causal inference before mechanistic attribution,
• integration of biomedical data, conceptualizing subclassification and targeted therapies,
• cultivation of reflexivity and epistemic humility (e.g., explicit uncertainty communication, shared decision-making, and iterative reassessment)
We hope this commentary contributes to a balanced and evidence-based interpretation and management of LC, helping bridge translational gaps, and highlighting the importance need of biomedical priorities in the sustained collaboration among between biomedical researchers, clinicians, and patients to advance understanding, diagnosis, and treatment of this evolving condition and other PAIS (96).
is the section "Arguments for a functional disorder" —
