The scale of the problem justifies the effort. The most recent estimates cited by the authors suggest that roughly six percent of United States adults and half a percent of children and adolescents are still living with new or persistently worsened symptoms that began shortly after an acute SARS-CoV-2 infection. For clinical purposes, the authors define Long COVID as new or worsened symptoms developing after confirmed or suspected infection and persisting for more than three months, a deliberately broad formulation that sidesteps the stricter laboratory-confirmation requirements of research definitions. The dominant symptoms cluster around fatigue, post-exertional malaise, cognitive impairment often called brain fog, and orthostatic intolerance, the lightheadedness and palpitations that appear or worsen when a patient stands upright.

What makes the review distinctive is its use of clinical vignettes that mirror how patients actually describe their lives. In one case, a 32-year-old woman with a history of anxiety reports four months of fatigue that is qualitatively different from anything she has felt before. After minimal activity, she describes crashing, as though wearing a lead coat, with profound exhaustion and difficulty thinking that can persist for hours to days. Even preparing meals or answering emails has become a hurdle, and she has cut back her work hours. Her symptoms began about a month after a mild COVID-19 infection, a temporal link that might easily be missed if a clinician never asks about preceding illness.

A second vignette captures the dysautonomia pattern: a previously athletic 19-year-old develops palpitations, lightheadedness, and near-fainting on standing, symptoms that improve when she lies down. She recalls an upper respiratory illness two weeks before onset, and although she never tested herself, multiple family members had confirmed COVID-19 at the time. A third describes a 45-year-old aerospace engineer whose forgetfulness, word-finding difficulty, and slowed processing speed have cost him deadlines at work, all despite a normal basic laboratory evaluation. Together, the cases illustrate the review’s central message: Long COVID frequently announces itself through recognizable symptom clusters, and related conditions such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome often ride alongside it.

Beneath the clinical patterns, the authors propose a three-part conceptual framework for what SARS-CoV-2 actually leaves behind. The first category is a hit-and-run phenomenon, in which acute infection causes direct end-organ tissue injury with lasting consequences, such as pulmonary fibrosis or vascular events. The second is a stressor effect, in which the infection reduces physiological reserve and unmasks or accelerates chronic diseases like diabetes, hypertension, or rheumatoid arthritis in the following weeks and months. The third and most scientifically contested category is ongoing biological dysregulation, encompassing persistent viral reservoirs, immune dysregulation, gut dysbiosis, mitochondrial dysfunction, and microvascular clotting, processes repeatedly identified in basic science studies but largely invisible to current clinical diagnostic tools. Management of the first two categories follows standard practice, the authors note, while the third currently rests on rehabilitation and supportive care.

Diagnostically, the review resists exotic testing. Because no clinically available biomarker can confirm or exclude Long COVID, and severe symptoms can coexist with entirely normal conventional results, the workup serves mainly to rule out competing diagnoses and addressable sequelae. The authors recommend a focused physical examination guided by the patient’s symptoms, with particular attention to orthostatic vital signs, which are often skipped and frequently abnormal in this population. Targeted laboratory and imaging studies, including complete blood count, metabolic panel, thyroid function, and inflammatory markers, follow the same logic a primary care clinician would apply to any undifferentiated complaint. A validated ten-item questionnaire for post-exertional malaise, the DSQ-PEM, can help document a symptom that patients often struggle to articulate.

On treatment, the message is sobering but constructive: there is no cure, and no FDA-approved medication, yet validation and education alone can meaningfully improve quality of life. The authors emphasize that mental health conditions are not the cause of Long COVID, but the illness frequently produces new or worsened depression and anxiety, partly because patients do not feel believed by clinicians or loved ones. Nonpharmacologic strategies form the backbone of care. Activity pacing, energy conservation, and task modification, such as spreading grocery shopping and meal preparation across separate days or using a scooter and a seated chopping station, help patients live within their energy envelope. Referral to therapists experienced with chronic fatiguing illnesses, typically in neurorehabilitation rather than orthopedic settings, can be transformative: physical therapy for fatigue and activity intolerance, occupational therapy for self-care and job demands, and speech therapy for attention, memory, and breathing discomfort despite normal pulmonary tests.

One warning stands out with unusual force. While some patients tolerate gradual, supervised exercise progression, graded exertion must be approached with extreme caution in patients with post-exertional malaise. The authors cite evidence that even seemingly minor overexertion can trigger delayed symptom flares and has been associated with amyloid deposition, reduced mitochondrial enzyme activity, and signs of severe skeletal muscle damage in affected patients. For those with orthostatic intolerance, simpler measures carry real benefit: increasing daily fluid intake to 2.5 to 3.5 liters and sodium to 2.8 to 4 grams, equivalent to 7 to 10 grams of salt, alongside compression garments such as waist-high stockings or an abdominal binder, provided no contraindications exist.

Pharmacologic management remains symptom-based, borrowing indications from other contexts: beta blockers or ivabradine for POTS, stimulants for attention-dominant brain fog, gabapentinoids for neuropathic pain, and SSRIs for new or worsened mood symptoms. Two off-label options receive special mention. Low-dose naltrexone, an opioid receptor blocker, has been associated in some patients with improved pain, fatigue, and cognition, and a 2026 systematic review and meta-analysis examined the evidence base. Patients with suspected mast cell activation syndrome triggered by Long COVID sometimes report relief from combined H1 and H2 antihistamines. The authors also address the longer arc of illness: symptoms persist beyond one year in roughly a quarter of patients and beyond two years in about ten percent, making documentation of functional impact, workplace accommodation letters, and disability paperwork an essential, billable-worthy part of primary care.

Perhaps the most practical contribution is a set of principles for delivering all of this within a standard visit. The authors advise screening for preceding illness and symptom duration in the history, asking which symptom is most bothersome right now, and tackling only one or two symptoms per visit while leveraging longitudinal follow-up. Medication trials should be stepwise, one intervention at a time, starting low and titrating slowly, with de-prescribing of drugs that may worsen fatigue or cognition. Written after-visit summaries matter disproportionately for patients with cognitive symptoms, and telehealth or first-appointment scheduling can spare fatigued patients the exertion of a waiting room. On prevention, the review is equally concrete: vaccination shows a dose-dependent reduction in Long COVID risk, early outpatient antivirals offer modest protection, with nirmatrelvir/ritonavir associated with a 26 percent relative risk reduction, molnupiravir 14 percent, and ensitrelvir 45 percent, while metformin was linked to a 41 percent reduction in incidence in a randomized trial. Indoor air filtration, N95 or KN95 masking, and isolation during infectivity round out the defensive toolkit. Until reliable biomarkers and curative therapies arrive, the authors argue, the frontline of Long COVID medicine will remain the primary care office, and clinicians equipped with a structured approach can already change what the illness means for the patients living with it.

Subject of Research: Clinical evaluation and management of Long COVID in primary care

Article Title: Long COVID in Primary Care: A Practical Approach to Evaluation and Management

Article References: Chopra, A., Bonilla, H. F., & Cheng, A. L. (2026). Long COVID in Primary Care: A Practical Approach to Evaluation and Management. Journal of General Internal Medicine. https://doi.org/10.1007/s11606-026-10901-w

Image Credits: AI Generated

DOI: 10.1007/s11606-026-10901-w

Keywords: Long COVID, primary care, SARS-CoV-2, post-exertional malaise, dysautonomia, POTS, brain fog, ME/CFS, diagnosis, rehabilitation, antivirals, prevention

The clinical picture the review describes is dominated by a symptom that has no equivalent in most other diseases: post-exertional malaise, or PEM. Patients with ME/CFS experience a worsening of fatigue, pain, cognitive dysfunction, and other symptoms after physical or mental exertion, and the deterioration is disproportionate and delayed, often appearing a day or more after the triggering activity. The authors identify PEM as the cardinal feature of the disease, the hallmark that most reliably distinguishes it from ordinary fatigue or depression. Alongside PEM, the core clinical characteristics include persistent, unexplained fatigue that does not resolve with rest, unrefreshing sleep, and cognitive impairment that patients frequently describe as brain fog. Multisystem involvement means that cardiovascular, gastrointestinal, neurological, and immunological symptoms can all coexist in the same patient, making the presentation bewilderingly heterogeneous.

That heterogeneity has been one of the greatest obstacles to scientific progress. The review traces the history of diagnostic criteria for ME/CFS and finds a succession of definitions that varied widely in their requirements, producing patient populations that were not comparable across studies. Some earlier criteria emphasized fatigue alone, a choice that allowed conditions such as major depressive disorder to be folded into the diagnosis and reinforced the historical linkage of ME/CFS to psychiatry. The authors are blunt about the consequences: inconsistent diagnostics, the absence of any validated biomarker, and decades of psychological framing delayed recognition of the disease and marginalized the patients living with it. Diagnosis today remains clinical, resting on symptom patterns and the exclusion of other conditions, which means that underdiagnosis is widespread and prevalence estimates vary considerably across countries and study designs.

One of the most consequential shifts documented in the review concerns treatment. For years, graded exercise therapy was offered to ME/CFS patients on the theory that deconditioning perpetuated their symptoms and that carefully escalated activity would restore function. The review notes that this approach has now been formally withdrawn from treatment guidelines, with evidence of harm: for a disease in which exertion itself triggers pathological worsening, pushing patients to exercise can precipitate severe and prolonged relapses. The withdrawal represents an acknowledgment that a treatment paradigm built on the wrong model of the disease caused real damage. Pacing, the strategy of carefully balancing activity and rest to stay within an individual’s energy envelope, remains a pragmatic management approach, but the review is clear that no disease-modifying treatment currently exists.

The pathophysiological section of the review is where the technical story becomes most compelling. Multiple independent lines of evidence now point to mitochondrial dysfunction as a central abnormality. Mitochondria are the cellular power plants that convert nutrients into adenosine triphosphate, the molecular currency of energy, and studies in ME/CFS patients have found impaired energy production and abnormal metabolic profiles consistent with cells that cannot generate ATP efficiently. Metabolomic assays, which survey hundreds of small molecules in blood or urine, have detected reproducible disturbances in energy metabolism pathways, and some researchers have proposed these metabolic signatures as candidate diagnostic biomarkers. Electrophysiological assays, which measure the electrical activity of cells, offer another emerging tool for objectifying a disease that has long lacked laboratory confirmation.

Immune dysregulation forms a second pillar of the pathophysiological evidence. The review describes abnormalities in immune cell function and inflammatory signaling that suggest the immune system in ME/CFS is chronically activated yet ineffective, a state that could explain both the flu-like symptoms many patients report and their vulnerability to symptom flares. Autonomic imbalance is a third strand: dysregulation of the autonomic nervous system, which controls heart rate, blood pressure, and other involuntary functions, manifests as orthostatic intolerance and other cardiovascular symptoms that worsen when patients stand upright. Neuroinflammation, inflammation within the central nervous system, provides a plausible mechanism for the cognitive impairment that so many patients experience. Finally, alterations in the gut microbiome, the community of microorganisms inhabiting the intestine, have been documented in ME/CFS and may contribute to systemic inflammation through the gut-immune axis.

On the therapeutic frontier, the review highlights several strategies under investigation. Among the most intriguing are mTOR inhibitors, drugs that modulate the mechanistic target of rapamycin pathway, a central cellular signaling hub that regulates metabolism, growth, and autophagy. Given the metabolic disturbances observed in patients, pathway modulation represents a rational therapeutic hypothesis, though the authors present it as exploratory rather than established. The review also emphasizes methodological innovation: decentralised clinical trial designs, which recruit and follow participants remotely rather than requiring frequent visits to academic centers, could overcome one of the practical barriers that has hampered ME/CFS research, namely that the disease itself often prevents patients from traveling to study sites.

The intersection with Long COVID receives particular emphasis as a scientific accelerant. A substantial fraction of people infected with SARS-CoV-2 develop a chronic post-infectious syndrome whose symptoms overlap strikingly with ME/CFS, including PEM, cognitive dysfunction, and unrefreshing sleep. The review frames this convergence as a chance to rapidly advance the study of post-infectious chronic diseases more broadly, because Long COVID has attracted funding, patient cohorts, and scientific talent on a scale ME/CFS never achieved. Insights from one condition are likely to inform the other, and the enlarged research community now working on post-acute infection syndromes may finally supply the mechanistic answers that decades of ME/CFS research struggled to reach in isolation.

To convert this momentum into durable progress, the authors argue for stringent subtyping of patients, uniform data collection across studies, and ongoing patient participation in research design. Subtyping acknowledges that ME/CFS may encompass several distinct biological subgroups with different triggers and mechanisms, and that pooling them has obscured signals in past studies. Standardized data collection would make findings comparable across laboratories and countries, while involving patients, who possess detailed experiential knowledge of symptom patterns and treatment harms, would help ensure that research questions and outcome measures are clinically meaningful. The review closes with a call for equitable research funding, contending that biomarker discovery and the development of disease-modifying treatments will remain out of reach until investment matches the disease burden. Caring for people with ME/CFS, the authors conclude, is not only a clinical obligation but a public health one, a statement that would have been difficult to publish in a major translational medicine journal a generation ago.

Subject of Research: Pathophysiology, diagnosis, and treatment of myalgic encephalomyelitis/chronic fatigue syndrome

Article Title: Comprehensive review of myalgic encephalomyelitis/chronic fatigue syndrome

Article References: Jeyaraman, M., Jeyaraman, N., Ramasubramanian, S., Schäfer, L., Migliorini, F., & Balaji, S. (2026). Comprehensive review of myalgic encephalomyelitis/chronic fatigue syndrome. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08833-4

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08833-4

Keywords: ME/CFS, chronic fatigue syndrome, post-exertional malaise, mitochondrial dysfunction, neuroinflammation, immune dysregulation, autonomic dysfunction, gut microbiome, Long COVID, graded exercise therapy, diagnostic criteria, biomarkers

The analytical strategy was deliberately layered. First, the researchers used multivariable logistic regression to ask which of 14 symptom domains independently predicted the presence of muscle problems. In the full model, three symptoms emerged as significant independent predictors: breathing problems carried an odds ratio of 2.49 (95 percent confidence interval 1.42 to 4.38, p = 0.001), flu-like symptoms an odds ratio of 1.97 (1.14 to 3.42, p = 0.015), and temperature-regulation disorders an odds ratio of 1.97 (1.10 to 3.51, p = 0.021). When the model was restricted to a reduced set of physiological symptoms, cardiovascular symptoms additionally reached significance with an odds ratio of 1.87 (1.09 to 3.24, p = 0.024). These odds ratios indicate that patients reporting each of these symptoms had roughly double the odds of also reporting muscle problems compared with patients who did not, after accounting for the other symptoms in the model.

Correlation analysis reinforced the impression that muscle symptoms travel with a distinct physiological cluster. Tetrachoric correlations, which estimate the latent association between binary symptom variables, showed substantial relationships between muscle problems and breathing difficulties (rho = 0.52), cardiovascular symptoms (rho = 0.49), and temperature-regulation disorders (rho = 0.49), with somewhat weaker but still notable links to visual disturbances (rho = 0.39) and flu-like symptoms (rho = 0.39). Values in this range suggest that the co-occurrence of these symptoms is far from random and points toward a common underlying driver rather than a coincidental clustering of unrelated complaints.

The centerpiece of the study, however, was its latent-variable modeling. Using exploratory factor analysis followed by structural equation modeling (SEM), the authors tested whether the physiological symptoms could be explained by a single latent factor, an unobserved variable hypothesized to generate the observed symptom pattern. The model fit was strong by conventional standards: the root mean square error of approximation (RMSEA) was 0.046, well below the 0.06 threshold typically considered acceptable; the comparative fit index (CFI) was 0.971 and the Tucker-Lewis index (TLI) was 0.952, both close to the 0.95 benchmark; and the standardized root mean square residual (SRMR) was 0.026, far under the 0.08 cutoff. Together these indices indicate that a single latent physiological dysregulation factor provides a parsimonious and statistically credible account of how these symptoms co-occur in the sample.

Not every symptom behaved identically within this structure. Gastrointestinal complaints loaded substantially on the latent factor even though they showed no independent association with muscle problems in the multivariable regression, suggesting they belong to the broader physiological pattern but are not tightly coupled to the muscle-specific manifestation. Urogenital symptoms also displayed a smaller but significant loading on the factor alongside substantial item-specific variance, indicating that they are partly woven into the shared dysregulation and partly driven by their own distinct processes. This kind of decomposition, separating shared from symptom-specific variance, is precisely what latent-variable approaches are designed to deliver, and it hints that ME/CFS pathology may involve both a common multisystem thread and parallel, partially independent symptom channels.

The sex-stratified analyses produced a striking descriptive asymmetry. In women, all five physiological symptoms, breathing, cardiovascular, thermoregulatory, visual, and flu-like, independently predicted muscle problems. In men, only breathing problems and temperature-regulation disorders remained significant. Yet when the authors formally tested the overall symptom-by-sex interaction, the result did not reach statistical significance, meaning the data do not establish that the symptom associations genuinely differ between the sexes. One exception appeared at the individual symptom level: the association between breathing-related symptoms and muscle problems showed a statistically significant interaction with sex, hinting that this particular link may be stronger in one sex than the other. The authors urge caution here, noting that the overall interaction test was non-significant and the confidence interval for the interaction estimate was wide, leaving the finding exploratory at best.

Menopausal status, approximated by age-defined proxy groups, added another descriptive layer. Women classified as premenopausal by this proxy showed significant associations between muscle problems and cardiovascular symptoms, visual disturbances, and temperature-regulation disorders, whereas women classified as postmenopausal showed significant associations with breathing difficulties and flu-like symptoms. Flu-like symptoms were independently associated with muscle problems in the postmenopausal subgroup but not in the premenopausal one. Once again, however, the formal test told a more conservative story: the overall menopausal-by-symptom interaction was not statistically significant (Wald chi-square of 5.96 on 5 degrees of freedom, p = 0.310). The authors therefore frame these subgroup contrasts as exploratory differences in association rather than evidence of a menopause-specific effect, a distinction that matters enormously for how the findings should be cited and built upon.

Stability across disease duration offered further reassurance about the latent factor’s measurement properties. The specified physiological factor showed statistical comparability across cross-sectional disease-duration groups, meaning there was no overall evidence that the factor means something different in patients early versus late in their illness. This kind of measurement invariance is a prerequisite for meaningful comparison across patient subgroups and lends weight to the idea that the dysregulation factor is a stable feature of the disease rather than an artifact of illness stage, survivorship bias, or shifting symptom reporting over time.

What could the latent factor represent biologically? The authors are careful not to overclaim, but they note that the findings are compatible with the hypothesis that the symptom-dysregulation factor reflects a chronic post-exertional malaise-associated multisystem response. The symptom cluster it captures, spanning respiratory, cardiovascular, thermoregulatory, visual, and flu-like domains, overlaps substantially with the territory of autonomic dysfunction, vascular dysregulation, immune activation, and metabolic disturbance, all of which have been implicated in ME/CFS by prior physiological studies. Whether the latent factor corresponds to genuinely interacting mechanisms across these systems is a question the present cross-sectional design cannot answer, and the authors explicitly call for longitudinal and biomarker-based studies to test it.

The practical implications could be considerable. If muscle symptoms indeed serve as a candidate integrative symptom within a measurable latent dysregulation factor, then symptom-based phenotyping may help stratify patients for clinical trials, a persistent challenge in a disease as heterogeneous as ME/CFS. Better stratification could, in turn, accelerate the development of mechanism-based therapeutic approaches by ensuring that patients sharing a common physiological signature are studied together. The study was conducted in 2022 under Declaration of Helsinki protocols approved by the Ethics Committee of Furtwangen University, Germany, and was partially funded by the Ministry of Social Affairs, Health and Integration using state funds approved by the Baden-Württemberg State Parliament, with the subsequent analyses unfunded. As an exploratory, cross-sectional analysis of registry data, it cannot establish causality or direction, and its subgroup findings demand replication. But by quantifying how tightly muscle symptoms are woven into a broader physiological web, and by providing a statistically well-fitting latent structure that future biomarker studies can interrogate, the work offers ME/CFS researchers a concrete, testable framework for one of medicine’s most perplexing chronic illnesses.

Subject of Research: Latent physiological symptom-dysregulation and muscle symptoms in ME/CFS analyzed by sex and menopausal-status proxy group

Article Title: Muscle symptoms and a latent physiological symptom-dysregulation factor in ME/CFS: exploratory analyses by sex and age-defined menopausal-status proxy group

Article References: Habermann-Horstmeier, L., & Horstmeier, L. M. (2026). Muscle symptoms and a latent physiological symptom-dysregulation factor in ME/CFS: exploratory analyses by sex and age-defined menopausal-status proxy group. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-09018-9

Image Credits: AI Generated

DOI: 10.1186/s12967-026-09018-9

Keywords: ME/CFS, chronic fatigue syndrome, muscle symptoms, physiological dysregulation, post-exertional malaise, structural equation modeling, factor analysis, sex differences, menopausal status, autonomic dysfunction, symptom phenotyping, Journal of Translational Medicine

The commentary, authored by Lotte Habermann-Horstmeier of the Villingen Institute of Public Health in Germany, does not present new experimental data. Instead, it offers something arguably more valuable at this stage of the field: a structured, testable framework. Drawing on a targeted synthesis of literature from PubMed and Web of Science, the author sorts evidence into three categories—direct SLE findings, findings from ME/CFS research, and cross-condition mechanistic inference—and insists that these be kept rigorously separate. The result is a hypothesis-generating proposal for an SLE–ME/CFS research phenotype, a defined subgroup of lupus patients whose symptoms persist for at least six months, worsen after exertion, and include unrefreshing sleep, cognitive symptoms, or orthostatic intolerance, once alternative explanations and comorbidities have been systematically excluded.

The clinical rationale for such a phenotype rests on a well-documented gap between conventional disease measures and patient experience. In lupus, indices of inflammatory activity often normalize under treatment, yet patient-reported outcomes tell a different story. Fatigue ranks among the most prevalent and disabling complaints across the disease course, and studies of patients in remission have repeatedly documented impaired physical function, reduced exercise capacity, sleep disturbance, and neurocognitive symptoms that conventional lupus metrics fail to capture. This discordance has practical consequences: patients whose laboratory values look reassuring may nonetheless be functionally limited, and clinicians lack a framework for understanding—or investigating—why.

What makes the proposed phenotype more than a descriptive label is the mechanistic scaffolding beneath it. The commentary assembles direct evidence from lupus research pointing to several interacting biological systems. Residual immune activation persists in many patients despite apparent disease control, with ongoing immune cell activation and inflammatory signaling detectable below the threshold captured by clinical indices. Oxidative stress, an imbalance between reactive oxygen species and antioxidant defenses, has been documented in SLE and can damage cellular components ranging from lipids to DNA. Mitochondrial alterations—the dysfunction of the organelles that generate cellular energy—have likewise been reported, offering a plausible route from biochemical injury to the fatigue and exercise intolerance patients describe.

Vascular and autonomic mechanisms form a second pillar of the framework. Endothelial dysfunction, a impairment of the blood vessels’ inner lining that precedes atherosclerosis, is well established in lupus and contributes to the disease’s elevated cardiovascular risk, but it may also compromise tissue perfusion during exertion and in the brain. Dysautonomia—disordered regulation by the autonomic nervous system—has been described in SLE patients and can produce orthostatic intolerance, the lightheadedness, palpitations, and cognitive dulling that occur when standing disrupts cerebral blood flow. These findings matter because they map directly onto symptoms that dominate the lived experience of the proposed subgroup: exercise that triggers a disproportionate crash, sleep that does not restore, and thinking that falters when upright.

It is here that the commentary’s most provocative move occurs: importing carefully flagged mechanistic insights from ME/CFS research. That field, long marginalized but increasingly rigorous, has accumulated human evidence of impaired cellular energetics, with studies suggesting that energy metabolism in patient cells behaves abnormally under stress; of autonomic dysfunction measurable in the clinic; of altered cerebral perfusion on neuroimaging; and of neuroimmune dysregulation involving inflammatory signaling that reaches the central nervous system. Post-exertional symptom exacerbation—the hallmark worsening of symptoms hours to days after physical or cognitive effort—serves as the condition’s defining feature and a key anchor for the proposed lupus phenotype. The author is explicit that these ME/CFS findings are hypotheses for lupus, not established facts: they converge plausibly with direct SLE evidence, but they require direct validation in lupus cohorts before any conclusion can be drawn.

The framework’s deliberate non-linearity is one of its distinguishing technical features. Rather than proposing a single causal chain—molecule X causes symptom Y—the author describes interacting immune, metabolic, vascular, autonomic, and neurocognitive mechanisms that may reinforce one another dynamically over time. Mitochondrial dysfunction, for instance, could amplify oxidative stress, which in turn could worsen endothelial function and autonomic regulation, while neuroimmune signaling could sensitize the brain’s fatigue and cognitive circuits. Such feedback structures resist the one-biomarker-one-diagnosis model and instead call for multidimensional phenotyping: simultaneous measurement of immune markers, redox balance, vascular function, autonomic testing, exercise physiology, and neurocognitive performance in the same patients, tracked longitudinally.

Methodological caution runs throughout the proposal. The commentary is explicitly a theoretical, non-systematic synthesis, prioritizing human studies, systematic reviews, meta-analyses, and translational work, and it stops short of defining a new diagnostic entity or a fixed disease trajectory. The proposed phenotype is framed as a research construct—a way to stratify patients for prospective longitudinal studies—rather than a clinical diagnosis. This distinction is important for lupus care, where symptoms such as fatigue and cognitive difficulty can also arise from hypothyroidism, anemia, sleep apnea, depression, medication side effects, or active disease that standard measures miss. The framework therefore requires structured exclusion or assessment of alternative explanations before a patient is classified within the subgroup, mirroring the case-definition discipline developed in ME/CFS research.

If the hypothesis survives prospective testing, the implications could be substantial. A validated SLE–ME/CFS research phenotype would give investigators a stratification tool for clinical trials, separating patients whose persistent symptoms arise from ongoing inflammatory activity from those whose illness follows a different biological path. It could sharpen biomarker discovery by directing attention toward autonomic, endothelial, mitochondrial, and neuroimmune measures rather than conventional serology alone. And it could reshape supportive care, since interventions developed for ME/CFS—pacing strategies to avoid post-exertional crashes, graded approaches to rehabilitation, orthostatic management—might be adapted and formally tested in the lupus subgroup, rather than applied indiscriminately to all patients.

The proposal also carries a message about how medicine handles diseases that fall between specialties. Lupus is the rheumatologist’s territory; ME/CFS remains contested and under-resourced; and patients whose illness straddles the two risk falling into the gap. By articulating a phenotype that borrows mechanistic rigor from one condition to explain unresolved symptoms in the other, the commentary offers a template for hypothesis-driven bridge-building across diagnostic boundaries. The author is careful to frame the work as hypothesis-generating, and the next step—longitudinal, multidimensional studies of lupus patients with persistent symptoms—will determine whether the SLE–ME/CFS research phenotype describes a real biological subgroup or merely a useful way of organizing uncertainty. Either outcome would advance a conversation that many patients, whose suffering persists long after their inflammation has quieted, have been waiting for the field to have.

Subject of Research: Persistent fatigue and related symptoms in long-standing systemic lupus erythematosus and their proposed mechanistic overlap with ME/CFS

Article Title: Persistent symptom burden in long-standing systemic lupus erythematosus: a subgroup-focused hypothesis for an SLE–ME/CFS research phenotype

Article References: Habermann-Horstmeier, L. (2026). Persistent symptom burden in long-standing systemic lupus erythematosus: a subgroup-focused hypothesis for an SLE–ME/CFS research phenotype. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08867-8

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08867-8

Keywords: systemic lupus erythematosus, ME/CFS, chronic fatigue, post-exertional malaise, dysautonomia, endothelial dysfunction, mitochondrial dysfunction, oxidative stress, neuroimmune dysregulation, orthostatic intolerance, disease phenotype, Journal of Translational Medicine

The research team, led by investigators at the Pain & Fatigue Study Center in the Department of Neurology, drew participants from an NIH-funded parent study designed to examine the relationship between cardiopulmonary exercise testing and post-exertional malaise, the hallmark symptom of ME/CFS. Between August 2021 and July 2025, forty-nine adults aged 25 to 60 years who met the 1994 Fukuda case definition completed both assessments. To ensure a substantial current symptom burden, participants were required to report moderate-to-severe ratings on post-exertional malaise and on at least three of seven additional symptoms, including sore throat, headache, myalgia, and unrefreshing sleep. Individuals with medical conditions that could explain the fatigue, including anemia identified by routine laboratory testing, were excluded, as were those taking medications that blunt cardiovascular responses and those with certain psychiatric diagnoses.

The orthostatic assessment relied on the 10-minute lean test, a protocol originally developed by NASA to detect orthostatic intolerance in astronauts returning from spaceflight. After at least ten minutes of supine rest, baseline blood pressure, heart rate, respiratory rate, and end-tidal carbon dioxide were recorded in triplicate at one-minute intervals using a portable capnograph and pulse oximeter. Participants then stood with feet together roughly six to eight inches from a wall and leaned against it without moving for ten minutes, while the same parameters were captured every minute. This test captures several distinct physiological abnormalities: postural orthostatic tachycardia syndrome, defined as a heart rate rise of at least 30 beats per minute or an absolute heart rate of at least 120 beats per minute; supine hypocapnia, defined as any baseline end-tidal carbon dioxide below 34 mmHg; and the postural orthostatic syndrome of hypocapnia, in which carbon dioxide falls below that threshold only upon standing.

Blood volume was measured with the semiautomated Daxor BVA-100 system, a technique regarded as a reference standard for quantitative intravascular volume assessment. After a baseline blood sample was drawn, human serum albumin labeled with iodine-131 was injected intravenously and allowed to equilibrate. Five additional samples were collected at 15, 21, 27, 33, and 39 minutes to correct for the gradual leakage of albumin out of the vasculature, and plasma volume at time zero was extrapolated from at least three samples with a coefficient of variation of no more than 3.9 percent. Total blood volume was calculated as the sum of plasma volume and red blood cell volume, and all values were normalized to each participant’s ideal body size. Total blood volume was then categorized as hypovolemic if it deviated more than 8 percent below the predicted value, normovolemic within 8 percent, and hypervolemic above 8 percent, thresholds consistent with prior ME/CFS blood volume research.

The results painted a picture of remarkable physiological heterogeneity. Seventeen participants, or 35 percent, were classified as hypovolemic, twenty-one as normovolemic, and eleven as hypervolemic. Red blood cell volume told a similar story: nearly half of the cohort, twenty-four participants, had a red cell volume deficit more than 10 percent below ideal, a phenotype that, when routine hemoglobin and hematocrit values are normal, can be considered an occult red cell mass deficit rather than conventional anemia. Yet when the researchers cross-tabulated these volume categories against lean-test outcomes, no significant associations emerged. Fifty-five percent of participants exhibited at least one orthostatic abnormality, with hypocapnic responses proving at least as common as tachycardia: twenty participants showed the postural orthostatic syndrome of hypocapnia, six showed supine hypocapnia, six met criteria for POTS, and four had both POSH and POTS. The distribution of these abnormalities, however, was statistically indistinguishable across hypovolemic, normovolemic, and hypervolemic groups, and the same held true for red blood cell volume categories.

These findings directly confront a body of earlier work. Multiple previous studies have reported reduced total or compartmental blood volumes, smaller cardiac chambers, and diminished stroke volume in subsets of ME/CFS patients, and one pilot study using a dual-isotope technique found lower blood volumes among patients whose day-to-day symptoms suggested orthostatic intolerance. That earlier study, however, relied on clinical history rather than contemporaneous physiological testing, leaving open the possibility that subjective symptom reports and objective orthostatic physiology diverge. By combining quantitative blood volume analysis with a standardized lean test incorporating capnography, the Mount Sinai team demonstrated that even objectively confirmed orthostatic abnormalities do not track with measured volume status. In other words, a patient can be quantitatively hypovolemic yet pass the lean test, or have entirely normal blood volume yet exhibit marked hypocapnia or tachycardia upon standing.

The null result does not mean blood volume is clinically irrelevant. Identifying hypovolemia in an individual patient may still matter, because volume expansion remains a logical therapeutic target for that subgroup. But the new data help explain why pharmacological volume expansion has disappointed in controlled trials: randomized studies of fludrocortisone, a mineralocorticoid that promotes sodium and water retention, showed limited benefit in ME/CFS, implying that correcting hypovolemia alone is often insufficient. The authors argue that orthostatic intolerance in this illness likely arises from multiple converging mechanisms that static volume measurements cannot capture. Among the candidates are impaired venous constriction and excessive venous capacitance, which promote gravitational pooling of blood in the legs; autonomic dysregulation, evidenced by reduced vagal modulation and altered heart rate variability at rest, during sleep, and during orthostatic challenge; and abnormalities of neurohumoral control, including the renin-aldosterone paradox described in POTS and small-fiber neuropathy identified in subsets of patients.

Cerebral perfusion adds another critical dimension. Previous controlled work has shown that upright posture can substantially reduce cerebral blood flow in ME/CFS patients even when heart rate and blood pressure remain within conventional limits, and that this cerebral blood flow reduction during tilt testing is independent of deconditioning as defined by exercise testing. Deconditioning itself, which can reduce plasma volume and ventricular mass over weeks of bed rest, is unlikely to account for the high prevalence of orthostatic intolerance in this population, since patients show greater cerebral blood flow reductions than healthy, sedentary controls. Taken together, these observations support a model in which orthostatic pathology in ME/CFS reflects dynamic failures of autonomic, vascular, respiratory, and cerebral hemodynamic regulation rather than a simple deficit in the amount of blood in the circulation.

The study has limitations that the authors acknowledge candidly. The sample of forty-nine participants, recruited from a single tertiary care center and limited to patients well enough to undergo testing, constrains statistical power and may underrepresent the most severely affected patients. The eight-day interval between the lean test and the blood volume assessment, together with the lack of standardization of acute hydration and salt intake, may have introduced temporal variability in both volume and hemodynamic measures. Anxiety-related hyperventilation and other breathing-pattern abnormalities could not be excluded as contributors to the hypocapnic findings, because state anxiety and tidal volume were not assessed. The 10-minute lean test also imposes milder orthostatic stress than head-up tilt, so hypovolemia-driven instability might conceivably emerge only under more prolonged or severe challenge. The absence of a healthy control group further precluded direct comparison of volume patterns between patients and volunteers.

Even with those caveats, the message for the field is clear and consequential. Orthostatic intolerance was highly prevalent in this cohort, yet neither total blood volume nor red blood cell volume category predicted who would exhibit supine hypocapnia, POSH, or POTS on standardized testing. The authors call for multicenter studies that incorporate dynamic measurements of cerebral blood flow, respiratory pattern, and carbon dioxide regulation during graded orthostatic stress, integrated with blood volume status, to build comprehensive pathophysiological models of the illness. Such phenotype-directed approaches, they argue, will be essential for developing rational therapies that address the actual mechanisms driving orthostatic symptoms, rather than assuming that a single measurable deficit, however intuitively appealing, holds the key to one of ME/CFS’s most disabling features.

Subject of Research: The relationship between measured blood volume, red blood cell volume, and orthostatic intolerance in adults with myalgic encephalomyelitis/chronic fatigue syndrome

Article Title: Total blood volume and red blood cell volume are not associated with orthostatic intolerance in adults with myalgic encephalomyelitis/chronic fatigue syndrome

Article References: Total blood volume and red blood cell volume are not associated with orthostatic intolerance in adults with myalgic encephalomyelitis/chronic fatigue syndrome. (n.d.). https://doi.org/10.14814/phy2.71087

Image Credits: AI Generated

DOI: 10.14814/phy2.71087

Keywords: ME/CFS, orthostatic intolerance, blood volume, red blood cell volume, POTS, hypocapnia, lean test, capnography, autonomic dysfunction, cerebral blood flow, hypovolemia, Physiological Reports