Knowledge base

Long COVID, ME/CFS, PEM & POTS — verständlich erklärt

Long COVID, ME/CFS, PEM & POTS — explained clearly

Carefully researched and sourced: from the basics through pacing to medication, diagnostics and care in Germany.

mypacing is not a medical device and does not replace medical diagnosis or treatment. This knowledge base informs you — every treatment decision belongs in the hands of a doctor. Last updated: 23 July 2026.

Why this knowledge base exists — and where it really works inside mypacing

We are Sarah and Siegfried. We didn't put this together to sound clever. We put it together because we would have needed it ourselves — for months. Back when no one could explain to us what a "crash" actually is. Why "more exercise" makes everything worse instead of better. Why Sarah's body didn't come back for two whole days after a single flight of stairs.

We were often told it "wasn't that bad", maybe it was in our heads. Today it is there in black and white that it is real. This knowledge would have spared us so much fear and so many setbacks back then. That is exactly why it is here now — open, honest, with sources. Without any promise of a cure, because there isn't one (yet). But with the thing that really helps: understanding.

And in mypacing this knowledge doesn't just sit there as text. It works in exactly the places where it counts for you.

  • In your doctor's report. We attach the studies you find here to your report — so your doctor sees the scientific background at a glance and doesn't start from zero. No more explaining why PEM is real. It's right there, with a source.
  • In the early warning — the "MIE" (mypacing Intelligence Engine). What research knows as typical triggers for a crash — overexertion, too little sleep, heat, long periods of standing — flows in exactly that way into your mindfulness signal and your action tips. And because many affected people contribute their anonymous daily values, this knowledge keeps getting sharper: if your group reacts particularly sensitively to warmth, mypacing weights exactly that more strongly for you. So what you are advised — what you'd better do today and what you'd better leave alone — shifts with what science and the community show together.
  • In the medication knowledge base. What each active substance does in the nervous system, which symptoms it has been observed to act on, and how well that is evidenced — honestly sorted by strength of evidence. Knowledge for the conversation with your doctor, not a recommendation.
  • In the insights. What many people show together, what a single person alone could never see — always anonymous, never individually traceable.

That is what makes mypacing different for us. No marketing, no selling, no company behind it. Just checked knowledge, gathered by someone affected and her husband, free and independent — and built into the places where it truly helps you in everyday life.

Stay in your own pace.
— Sarah & Siegfried

Introduction & Summary

This knowledge base pulls together the current, evidence-based state of knowledge on Long COVID / post-COVID, ME/CFS, post-exertional malaise (PEM) and POTS/dysautonomia in plain language. It is aimed at affected people, their relatives and interested professionals who use the mypacing platform — a tool to support energy management (pacing). Important up front: mypacing is not a medical device and replaces neither medical diagnosis nor treatment. These texts inform you; every treatment decision belongs in the hands of a doctor.

The common thread is the interplay of four conditions that overlap strongly in the clinic. Chapters 1–3 lead from the virological basics of SARS-CoV-2 through the definitions of Long COVID (WHO: post-COVID-19 condition; NICE cut-off from week 4 or 12) to the pathophysiology hypotheses discussed today, which probably reinforce one another (viral persistence, immune dysregulation, autoimmunity, endothelial and mitochondrial disturbances). Chapters 4–7 cover ME/CFS with its core symptom PEM, the POTS spectrum of orthostatic intolerance, as well as brain fog and further accompanying symptoms, ordered by pragmatic — not formally validated — subtypes.

The connecting hallmark symptom is PEM: an often time-delayed, disproportionate worsening after physical, mental or emotional exertion, with a prolonged recovery time. It is the central reason why pacing is at the heart of everything. Chapter 8 translates this into non-drug practice (crash triggers, pacing strategies). Chapters 9–10 place the medication options in context — all of them symptom-oriented, mostly off-label and with no curative claim. Chapter 11 makes clear that diagnoses are so far made clinically: there is no routinely available, validated biomarker. Chapter 12 points to guidelines and care structures in Germany and the EU.

Two messages run through all the chapters. First: none of these conditions can be cured at the root; the focus is on avoiding overexertion. Second: the state of knowledge is incomplete and in active development. This knowledge base therefore strives to be honest about what is established, what is plausible and what remains open — and so provides the basis for using mypacing in an informed and realistic way.

What this means for pacing & mypacing

One clear practical consequence follows from the whole state of knowledge: the most effective known way of dealing with PEM is to avoid it. Pacing means dosing activity so that your individual exertion limit is, as far as possible, not exceeded — not slowly "training yourself up". mypacing supports exactly this energy management, but it does not replace medical care and is not a medical device.

Heart rate as a guide. Many affected people use an individual upper heart-rate limit as a workable approximation, to stay in the "aerobic" range and prevent crashes. Such limits (often derived from simple rules of thumb) are aids to orientation, not validated medical thresholds. They do not replace listening to early warning signs and should ideally be accompanied by a doctor — especially because in POTS/dysautonomia heart rate alone (e.g. the orthostatic rise) can give a distorted picture.

Recognising and respecting PEM. Because the worsening often only sets in after 24–48 hours and can last for days to weeks, the link between activity and crash is not always immediately visible. Symptom and activity logs help you to find your own limit ("energy budget") and to stay below it.

Keeping triggers and environment in mind. Crashes do not arise only from physical effort. Cognitive load (screen time, conversations), emotional stress, orthostasis (long standing), lack of sleep, infections, pain, as well as sensory stimuli (light, noise) count as possible, partly modifiable PEM triggers. In POTS, simple measures can make everyday life easier: enough fluids and salt (after discussing with a doctor), compression, standing up slowly, avoiding heat. These ease circulatory symptoms but do not replace pacing.

What pacing is not. Pacing is not a cure and not a guarantee against crashes — it lowers their frequency and severity and protects against worsening from overexertion. Medications (chapters 9–10) act symptomatically, mostly off-label, and do not replace energy management.

Basic stance. mypacing provides structure, data and reminders for self-management. Decisions about limits, medication and exertion are made by the affected person together with their treatment team — not by the app.

Limits & open questions

This knowledge base describes a field in active development, and being honest about uncertainties is part of what it stands for.

Causes unclear. For Long COVID, ME/CFS and POTS there is no single, proven cause. The mechanisms discussed (viral persistence, immune dysregulation, autoimmunity, endothelial/mitochondrial disturbances) are plausible and in part well evidenced, but none is established as the sole explanation.

No biomarkers, clinical diagnosis. There is no routinely available, validated diagnostic test. Diagnoses rest on symptom criteria plus exclusion of other causes — which carries the risk of wrong and late diagnoses and makes it harder to tell overlapping pictures apart.

Thin medication evidence. The available studies, especially for POTS, are mostly small (often 11–54 people), short, cross-over in design and rarely carried out specifically in people with Long COVID or ME/CFS. No substance is approved for POTS in Germany; use is off-label. Supplements too lack proof of efficacy; none of it is curative.

Explicit warning about GET. Activating, escalating exercise therapy (graded exercise therapy, GET) is explicitly not recommended as a cure by the NICE guideline NG206 and can lead to worsening in PEM. "Push through" approaches are risky.

Be wary of promises of a cure. There is currently no cure. Offers that promise quick or complete recovery, "reprogramming" of the nervous system or expensive miracle cures should be judged critically — especially when they present pacing as unnecessary or push towards increasing exertion.

Open research questions. Subtyping, reliable exertion limits (including for heart-rate-based pacing), long-term courses, prognosis and causal therapies all remain unresolved. Recommendations may change with new evidence. This knowledge base is a snapshot and does not replace individual medical advice.

The chapters in detail

1. COVID-19 — basics

COVID-19 (Coronavirus Disease 2019) is the illness caused by the virus SARS-CoV-2. This section summarises virology, course, acute complications, risk groups, the current variant situation and vaccination in an evidence-based way, and places their relevance for Long COVID in context.

What is SARS-CoV-2?

SARS-CoV-2 belongs to the Coronaviridae family, genus Betacoronavirus (subgenus Sarbecovirus). It is an enveloped virus with a single-stranded positive-sense RNA of around 30,000 bases – one of the largest known RNA virus genomes [3]. Four structural proteins make up the virus particle: spike (S), envelope (E), membrane (M) and nucleocapsid (N) [3].

The way it enters cells explains the multi-organ character of the illness: the receptor-binding domain (RBD) of the spike protein's S1 subunit binds to angiotensin-converting enzyme 2 (ACE2) as its cell receptor. The serine protease TMPRSS2 and furin (at the S1/S2 cleavage site) "prime" the spike and enable membrane fusion [2]. Because ACE2 and TMPRSS2 are present in the epithelium of the airways, heart, kidney and gut (and in part in the vascular endothelium), the virus can affect several organ systems [2].

Symptoms and course

Typical acute leading symptoms are fever, dry cough, sore throat, fatigue/exhaustion, muscle pain (myalgia), headache, shortness of breath (dyspnoea) and nausea/diarrhoea. The variant-dependent loss of smell and taste (anosmia/ageusia) occurred above all in the pre-Omicron period [1]. The incubation period is a median of about 5 days, and for Omicron more like 3–4 days [1].

The following severity classification per NIH/WHO is a clinical grading tool (not intended for self-diagnosis or self-treatment) [1]: - asymptomatic: infection without symptoms - mild: symptoms without shortness of breath or abnormal imaging - moderate: lower airways affected, oxygen saturation (SpO2) ≥94 % on room air - severe: SpO2 <94 %, respiratory rate >30/min, PaO2/FiO2 <300 mmHg or lung infiltrates >50 % - critical: respiratory failure, septic shock, multi-organ dysfunction

Warning: In the event of shortness of breath, persistently low oxygen saturation, chest pain, confusion or a bluish-grey discolouration of the lips/skin, seek medical or emergency help (emergency call) immediately. The limits given do not replace a doctor's assessment.

Mortality depends strongly on age. The infection fatality rate (IFR) values given here come from a meta-analysis from the early pandemic phase (Levin et al. 2020, before broad immunity from vaccination/infection and before Omicron) [4]: roughly ~0.01 % at age 25, ~0.4 % at 55, ~1.4 % at 65, ~4.6 % at 75 and ~15 % at 85 – the IFR rises approximately log-linearly (doubling roughly every 5–8 years of life). Around 90 % of the geographic IFR differences were explained in this analysis by age structure alone [4]. Important: these historical IFR values cannot be carried over to today's situation; because of vaccination, past infections and less virulent Omicron sublineages, the current IFR is considerably lower. The age dependence as such, however, remains.

Acute complications

  • Lungs: viral pneumonia and acute respiratory distress syndrome (ARDS) are the main reason for intensive care; imaging shows bilateral, peripheral ground-glass opacities. Severe courses require oxygen up to invasive ventilation [1].
  • Heart: myocardial damage (raised troponin) is found in about 20–25 % of all hospitalised patients, and higher in severe courses; cardiac arrhythmias (above all atrial fibrillation) in up to ~10 %, acute myocarditis rarely (on the order of a few per 1,000 hospitalisations). These frequencies vary considerably depending on study, population and time of assessment. Myocardial damage is associated with markedly increased in-hospital mortality [5].
  • Clotting: the COVID-associated coagulopathy (raised D-dimer) favours venous thromboembolism (deep vein thrombosis, pulmonary embolism), especially in intensive care. This is why standard thrombosis prophylaxis is given to hospitalised patients (medically indicated and monitored — not self-medication) [7].
  • Kidney: acute kidney injury (AKI) affects roughly ~10 % on a normal ward up to 30–45 % of intensive-care patients; some become dialysis-dependent. AKI is strongly associated with increased mortality and longer length of stay [6].

Risk groups

The strongest risk factor for a severe course is higher age, followed by male sex, obesity, diabetes mellitus, arterial hypertension/cardiovascular pre-existing conditions, chronic lung (COPD) and kidney diseases, immunosuppression and pregnancy [1][4].

Variants (as of 2026)

Note on timeliness: virus variants and their WHO classification change continuously. The following details are time-sensitive and should, before use, be checked against the current lists from WHO, ECDC and RKI.

As of this section there are no more official Variants of Concern (VOC). Only Omicron sublineages are circulating; among the Variants of Interest or Variants under Monitoring were, among others, the BA.2.86 lineage, XFG, NB.1.8.1 and BA.3.2 — each without solid evidence of increased disease severity [8][9]. (The exact classification — VOI vs. VUM — and which lineage currently dominates must be checked against up-to-date sources.) Earlier main lineages were Alpha, Beta, Gamma, Delta and the earlier Omicron waves (BA.1/BA.2/BA.5, later JN.1).

Vaccination

The vaccines of the 2025/2026 season adapted to JN.1/LP.8.1 reduced emergency-department visits by ~50 % and hospitalisations by ~55 % in CDC studies (in those aged ≥65, ~48 % and ~53 % respectively) [10][11]; European VEBIS data showed ~59 % protection against medically attended illness (95 % CI 14–83 %), with protection waning over time [10]. The German STIKO recommends an ongoing booster, adapted each year to the circulating variant, above all for risk groups: those aged ≥60, chronically ill/immunocompromised people, nursing-home residents, medical staff and close contacts of the immunocompromised [10]. Safety note: vaccines are approved medicines; individual indication, benefit and possible side effects should be discussed with a doctor. The efficacy figures given are observational data (not randomised trials) with in part wide confidence intervals and apply to the respective period/population studied.

Relevance for Long COVID / ME-CFS

Especially important for this platform: post-COVID states including post-exertional malaise (PEM) and an ME/CFS phenotype can occur even after a mild acute course. The risk tends to be higher with a severe course, but is not limited to it [12][13]. If PEM is present as a core symptom, pacing/energy management is indicated; forced activation or a graded exercise therapy (GET) oriented towards increasing performance can be harmful in PEM and is not recommended as standard therapy for those with PEM in current guidelines (e.g. NICE 2021) [12][13].

This text serves as information, does not replace medical advice and contains no individual healing or treatment instruction. It makes no promise of a cure. Where uncertainties exist (e.g. wide confidence intervals, population-dependent frequencies, historical or time-critical data), they are flagged. The source references [1]–[13] named in the text have not yet been built out into their own clickable reference list for this chapter (unlike, for example, chapter 12), and could not be looked up individually within this review. For questions about specific figures: hallo@mypacing.app.

2. Long COVID / post-COVID — definition, epidemiology, symptom clusters

What do "Long COVID" and "post-COVID" mean?

The terms describe health problems that persist, newly appear or recur after an acute SARS-CoV-2 infection and cannot be explained by another diagnosis. In practice two time-based cut-offs are used: according to the English NICE guideline one speaks of "ongoing symptomatic COVID-19" for symptoms between weeks 4 and 12, and of "post-COVID syndrome" for symptoms lasting longer than 12 weeks [2]. The World Health Organization (WHO) defines the "post-COVID-19 condition" more narrowly by consensus: symptoms that are usually present three months after the onset of infection, last at least two months and cannot otherwise be explained [1]. "Long COVID" is often used as an umbrella term for all longer-lasting courses and is a term coined by affected people. Important: this is not a single, uniform disease but a collective term for very different symptom patterns, presumably with several, partly overlapping disease mechanisms; the underlying mechanisms (e.g. immune dysregulation, autoimmunity, endothelial/clotting changes, viral persistence, reactivation of other viruses) are the subject of research and have so far not been conclusively clarified [4]. The German-language care guidelines (AWMF S1 guideline) follow these definitions and stress the exclusion of other causes [3].

Epidemiology — how common is Long COVID?

Reliable frequency figures are difficult because studies use different definitions, follow-up periods, control groups and survey methods. The estimates for prevalence after a past infection therefore range from a few percent to over 10 % and depend strongly on study design [4]. Controlled studies that also record symptoms in non-infected comparison groups usually give lower values, because many symptoms (e.g. tiredness) are common in the general population anyway [5]. This methodological uncertainty should be kept in mind with all figures; individual percentage values should therefore be interpreted with caution.

Relatively consistent risk factors are: female sex, higher age, a severe acute course (especially hospital/intensive-care treatment), a high number of acute symptoms and certain pre-existing conditions [4]. (Note: Long COVID can also occur after a mild or outpatient-treated infection; a severe acute course is not a precondition.) Full vaccination before the infection is associated in several studies with a lower risk, and infections with later virus variants (Omicron) seem to lead to Long COVID less often than early variants — but both observations are not conclusively established [4]. Children and adolescents are, by current data, overall affected less often and mostly more mildly than adults, though the evidence here is limited [4]. A significant proportion of those affected improve over months, while in a minority the symptoms persist long-term [4].

Symptom clusters

Long COVID can affect several organ systems; the literature describes a very large number of different symptoms (over 200 in extensive surveys) [4]. In practice, frequently recurring clusters can be recognised:

  • Fatigue and exertion intolerance: pronounced exhaustion that is not sufficiently relieved by sleep. Central to it is post-exertional malaise (PEM) — a worsening after physical or mental effort, often time-delayed (hours to days later). This pattern overlaps with chronic fatigue syndrome (ME/CFS) and has immediate consequences for activity management [4].
  • Neurocognitive complaints: difficulties with concentration and memory ("brain fog"), word-finding problems, headaches, sleep disturbances [4].
  • Autonomic dysregulation: racing heart, dizziness and complaints on standing up, in part in the sense of a postural tachycardia syndrome (POTS) [4].
  • Cardiopulmonary symptoms: shortness of breath, chest pain, exertional dyspnoea, palpitations [4].
  • Others: muscle and joint pain, smell/taste disturbances, gastrointestinal complaints, skin changes and mood changes [4].

These clusters can occur singly or in combination and can change over time.

Warning signs — have them checked by a doctor: symptoms such as new or severe chest pain, acute/increasing shortness of breath, fainting or near-fainting, racing heart at rest, neurological deficits (e.g. paralysis, speech or vision disturbances), signs of a thrombosis (one-sided swollen, painful leg) or pronounced mental crises/suicidal thoughts are not "typical Long COVID complaints that you can wait out", but require prompt — and for acute complaints emergency — medical assessment. Cardiac and pulmonary causes must be ruled out.

Note on therapy and medications

For Long COVID there is so far no approved, causal drug therapy. Care is symptom-oriented and relies above all on activity and energy management ("pacing"), especially where PEM has been shown, as well as on treating individual complaints [2][3].

Important safety note on activity: where PEM is present, a forced, stepwise escalating training programme ("graded exercise therapy", GET) can worsen the symptoms; "pushing through" or "training against the exhaustion" is not recommended in PEM. The aim of pacing is to stay within the individual exertion limit and to avoid overexertion (crashes). Increases in activity should be made only cautiously, in a symptom-oriented way and ideally with medical/therapeutic guidance.

Substances under discussion — for example low-dose naltrexone (LDN, presumed mechanism via immune modulation/microglia) — are used exclusively off-label and within studies; the evidence is limited to small, in part uncontrolled investigations and is low or insufficient for a general recommendation [4]. Many over-the-counter (OTC) food supplements also lack solid proof of efficacy. Every drug measure can have side effects and interactions and belongs in a doctor's hands — this text does not replace individual advice and deliberately contains no dosing instruction and no promise of a cure. Central to it all remains the careful exclusion of treatable differential diagnoses [3].

Note: the references [1]–[5] point to established reference types (WHO, NICE, AWMF guideline as well as review/controlled studies). Their content was checked for plausibility, but within this check they could not be read against in full text; the specific figures and association statements should be understood as orientation and checked against the primary sources before further use (e.g. in a conversation with your doctor).

3. Long COVID — pathophysiology hypotheses

Long COVID (WHO: post-COVID-19 condition) is a multisystem condition without a single, proven cause. According to the WHO case definition, the symptoms usually appear from three months after a probable or confirmed SARS-CoV-2 infection, last at least two months and cannot be explained otherwise [17]. In Germany, the AWMF S1 guideline "Long/Post-COVID" (living guideline, reg. 020-027) and RKI information resources provide recommendations and orientation on diagnostics and care; it is a consensus-based S1 (not evidence-graded S3) guideline [15][16]. Research in 2023–2025 is converging on several mechanisms that probably reinforce one another. Important for affected people and those treating them: none of the following hypotheses is established as the sole cause, and none alone explains all cases. Long COVID is heterogeneous and presumably to be divided into subphenotypes; the major reviews stress that the mechanisms probably do not compete but are interconnected [1][2].

Viral persistence (reservoir hypothesis)

SARS-CoV-2 RNA, viral antigens and spike protein have been detected in tissues months after the infection – among others in the gut, lymphatic tissue and blood plasma [3][4]. Findings on accumulation along the skull-meninges-brain axis so far come mostly from animal models and post-mortem studies and are not yet established for living Long COVID patients [uncertain]. Persisting viral antigen is regarded as a plausible but unproven ongoing trigger of chronic inflammation and is the target of antiviral studies (e.g. nirmatrelvir/ritonavir [Paxlovid], monoclonal antibodies). These substances are approved for acute therapy; their use in Long COVID is experimental/off-label. The randomised trials published so far (among others with prolonged nirmatrelvir/ritonavir dosing) mostly showed no convincing benefit; a treatment effect is currently not proven and should be assumed only within controlled studies [3]. Safety note: no unsupervised or prolonged intake of antiviral medicines outside medical care – nirmatrelvir/ritonavir has clinically relevant drug interactions.

Immune dysregulation and complement activation

Cervia-Hasler et al. (Science 2024) showed, in active Long COVID, a persisting complement dysregulation with an elevated terminal complement complex and signs of thromboinflammation; in those who recovered the markers largely normalised – a promising candidate biomarker that, however, has not yet been broadly replicated independently and is not clinically validated [5]. Linked to this, an ongoing systemic inflammation is being discussed.

Autoantibodies and autoimmunity

Functional autoantibodies against G-protein-coupled receptors (adrenergic β1/β2, muscarinic M2/M3, angiotensin AT1/ETA receptors) have been repeatedly described. These have been linked to autonomic dysfunction and disturbed vascular regulation; molecular mimicry and IgG transfer models (transfer of patient IgG into mice) support a possible causal contribution [6][7]. Assessment: the evidence is heterogeneous – some well-controlled studies found no consistent elevation of these autoantibodies, and a causal contribution in humans is not conclusively proven [uncertain].

Reactivation of latent herpesviruses

A reactivation of latent viruses, above all the Epstein-Barr virus (EBV), has been observed in a proportion of Long COVID sufferers and described in cohort studies as a prognostic factor; HHV-6 and CMV are also being discussed [8]. Whether this is a cause, a cofactor or an accompanying phenomenon is open.

Microclots and endothelial dysfunction

Pretorius/Kell describe fibrinaloid, amyloid-containing microclots in platelet-poor plasma that may be resistant to fibrinolysis and could impair oxygen transport in capillaries [9][10]. These findings have so far not been independently replicated in a standardised way and are methodologically disputed and are therefore to be regarded as a hypothesis. In parallel there are signs of persisting endothelial damage (raised von Willebrand factor, soluble thrombomodulin) that could link microclot, complement and hypoperfusion findings. Safety note: anticoagulant treatment or a so-called "triple anticoagulation" (dual antiplatelet therapy plus anticoagulation) based solely on microclot tests is not evidence-based, carries substantial bleeding risks and is explicitly not recommended outside of studies. The same applies to blood-washing/apheresis offers against "microclots", whose benefit is not proven.

Autonomic dysfunction (POTS/orthostatic intolerance)

Orthostatic intolerance and postural tachycardia syndrome (POTS) occur more frequently in strongly symptomatic patients [11]. Discussed mechanisms are autoantibodies against adrenergic/muscarinic receptors, small-fibre neuropathy, hypovolaemia and deconditioning. Diagnostics and therapy (e.g. standing/tilt-table assessment, non-drug measures) should be carried out with medical guidance.

Mitochondrial/metabolic muscle dysfunction and PEM

A muscle biopsy study (Appelman et al., Nat Commun 2024; n=25 Long COVID vs. 21 controls) showed reduced oxidative phosphorylation and altered succinate dehydrogenase activity, amyloid-containing (extracellular) deposits and, after maximal exertion, focal necrosis – large necrotic fibre areas occurred in around 36 % of the Long COVID patients [12]. This is discussed as an objective correlate of post-exertional malaise (PEM) and, pathophysiologically, supports the pacing principle (exertion within one's individual energy limit) over a rigidly graded increase in activity (graded exercise therapy, GET). Safety note: in pronounced PEM, GET can worsen symptoms; current guidelines (among them NICE) recommend pacing and advise against forced increases in activity.

Gut-serotonin axis and neuroinflammation

Wong/Levy et al. (Cell 2023) postulate a cascade: viral persistence in the gut → interferon response → reduced tryptophan uptake → serotonin deficiency → disturbed vagal signalling → cognitive symptoms; in the animal model, serotonin precursors or an SSRI reversed symptoms [13]. This is a still largely preclinical hypothesis – a conclusion that SSRIs are a Long COVID therapy in humans cannot be derived from it. SSRIs are approved (for other indications); their use against core Long COVID symptoms would be off-label and unproven in efficacy; stopping or starting them on one's own should not happen without medical consultation. In cognitive impairment, signs of a disturbed blood-brain barrier and ongoing systemic inflammation have also been reported [14]; PET studies on microglial activation are contradictory, so that "brain fog" is regarded as multifactorial.

Overlap with ME/CFS and assessment

A relevant proportion of those affected meet, from about six months onwards, the diagnostic criteria for ME/CFS with the hallmark symptom PEM; several of the mechanisms named overlap, which suggests a (partly) shared pathophysiology [1]. Overall, a working model of an interconnected process emerges (persistence → immune/complement activation → endotheliitis/microclots → hypoperfusion/mitochondrial dysfunction); this causal chain is plausible, but its linkage is not yet proven. For targeted therapies, biomarker-based subphenotypes and controlled studies are needed [1][2].

Note: all the mechanisms named above are hypotheses or association findings of varying maturity, not established causes. No concrete self-treatment can be derived from any section. This text serves to convey knowledge, is not a promise of a cure and does not replace medical diagnosis or treatment.

4. ME/CFS — criteria, epidemiology, severity levels, overlap

Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a severe, chronic multisystem disease which the WHO classifies as a neurological disorder (ICD-10 G93.3; ICD-11 8E49). It is accompanied by signs of neurological, immunological, autonomic and energy-metabolic disturbances; the underlying pathophysiology, however, is not yet conclusively clarified and is the subject of active research (the formerly common labelling as a purely "neuroimmunological" disease pre-empts the still-open question of mechanism). Its core symptom is post-exertional malaise (PEM) — a disproportionate worsening of symptoms after physical, mental or emotional effort that was previously managed without problems. Characteristic is the often delayed onset, typically around 12–48 hours (sometimes up to 72 hours) after the exertion, and a duration of days to weeks (a so-called "crash") [1][12]. PEM distinguishes ME/CFS from ordinary exhaustion and is the diagnostically decisive feature.

Diagnostic criteria

Several sets of criteria exist, some of them differing in strictness:

  • IOM/NAM criteria 2015 (clinical, adopted in the USA by the CDC): for the diagnosis, all three core symptoms must be present — (1) a substantial reduction of activity over at least 6 months with profound fatigue not relieved by rest, (2) PEM and (3) unrefreshing sleep — plus at least one of two additional criteria: cognitive impairment or orthostatic intolerance [1][2]. Important is the threshold qualifier: the symptoms must be present at least half of the time at moderate, substantial or severe intensity [1].
  • Canadian Consensus Criteria (CCC 2003): stricter and closer to research use. PEM with prolonged recovery (typically ≥24 h) is mandatory; in addition, sleep disturbances, pain, ≥2 neurological/cognitive manifestations and symptoms from autonomic, neuroendocrine and immunological categories are required. The required symptom duration in adults is ≥6 months (the statement of a shortened duration of ≥3 months in children is widespread, but partly goes back to supplementary paediatric criteria and should not be attributed unchecked to the CCC itself). The CCC select a smaller, on average more severely affected patient group [4].
  • International Consensus Criteria (ICC 2011): use exclusively the term "myalgic encephalomyelitis". The mandatory criterion is post-exertional neuroimmune exhaustion (PENE); there is no 6-month waiting period, which is intended to enable an earlier diagnosis [5].
  • NICE guideline NG206 (2021, UK): requires four mandatory symptoms — fatigue, PEM, unrefreshing/disturbed sleep and cognitive difficulties ("brain fog"). The diagnosis should be made in adults as well as in children and adolescents only when the symptoms persist for at least 3 months. The frequently cited period of 4 weeks refers exclusively to the earlier suspicion of ME/CFS in children and adolescents (with then earlier referral to a specialist unit) — not to making the diagnosis [3].

Severity levels

The NICE guideline defines four severity levels [3]:

  • Mild: largely self-caring, light housework possible, usually still (reduced) in work; leisure activities have been given up.
  • Moderate: restricted mobility, mostly no longer in work, regular rest periods needed.
  • Severe: barely any self-care, often wheelchair-dependent, pronounced cognitive and sensory impairment.
  • Very severe: bedridden all day, care-dependent, needing help with personal hygiene and eating, extreme sensitivity to light, noise and touch.

According to frequently cited estimates, roughly a quarter (~25 %) of all those affected are house- or bedbound, many of them fully in need of care; this order of magnitude, however, rests on a limited data basis and should be understood as a rough estimate [9].

Epidemiology

In the USA, the CDC/NCHS Data Brief no. 488 (NHIS 2021–2022) reports a prevalence of 1.3 % of adults — women 1.7 %, men 0.9 %, with a peak at 60–69 years (2.1 %) and higher values with low income and in rural regions [6]. Worldwide, a pre-pandemic estimate was around 0.89 % (~65–71 million people) [11]. In Germany the number of those affected — mostly on the basis of extrapolations — is put at a rise, driven by Long COVID, from about 400,000 to over 600,000 (figures for 2024 in part up to ~650,000), including estimates of about 80,000 children and adolescents; a substantial share (by some accounts around two thirds) is regarded as unable to work [9][10]. These German figures come mostly from professional-society and association estimates and carry marked uncertainty. Historically, 80–90 % of cases are considered undiagnosed [11].

Overlap with Long COVID

PEM is the shared diagnostic link between Long COVID and ME/CFS. A meta-analysis (Dehlia & Guthridge, Journal of Infection 2024) found that, pooled, 51 % of Long COVID patients meet the ME/CFS criteria (95 % CI 42–60 %; 13 studies, n=1,973) [7]. The large RECOVER adult cohort (published in the Journal of General Internal Medicine, 2025) showed that 4.5 % of those infected with SARS-CoV-2 met the ME/CFS criteria after ≥6 months compared with 0.6 % of the non-infected; the adjusted hazard ratio was 4.93 (95 % CI 3.62–6.71), i.e. an approximately fivefold increased risk (the "eightfold" increase named in press releases refers to the crude prevalence ratio, not to the adjusted analysis). PEM was the most common symptom [8]. A frequent co-condition is orthostatic intolerance or postural tachycardia syndrome (POTS), which is at the same time part of the orthostatic IOM additional criterion [1].

Assessment and uncertainties

The various sets of criteria identify patient groups of different sizes and different severity, which makes prevalence figures and comparisons between studies harder. The German case numbers rest partly on extrapolations and carry uncertainty.

On therapy, medications and supplements the following should be noted:

  • There is so far no causal, approved therapy for ME/CFS. Treatments target individual symptoms (e.g. orthostatic intolerance, sleep, pain) and are largely off-label on a limited evidence base. Drug treatments should only be prescribed and monitored by a doctor; this text deliberately gives no dosages or intake recommendations.
  • Safety note (important): unlike in many other states of exhaustion, escalating/graded physical training programmes (graded exercise therapy, GET) are not recommended for ME/CFS. The NICE guideline NG206 (2021) explicitly advises against GET, because fixed escalation schemes can trigger PEM and worsen the condition [3]. Likewise, cognitive behavioural therapy should be understood not as curative but at most as a supportive measure.
  • A central component of management is pacing (activity management within one's individual exertion limit) in order to avoid PEM [12].

This text serves solely as information, does not replace medical advice or diagnosis and contains no individual treatment or healing instruction. In the event of worsening, very severe illness (e.g. being bedridden, swallowing/nutrition problems) or crises, medical or emergency help must be sought.

5. PEM — post-exertional malaise

Post-exertional malaise (PEM) is the characteristic core symptom of ME/CFS and a central feature of Long COVID. What is meant is a disproportionate, often time-delayed worsening of symptoms and functioning after an exertion that was tolerated without problems before the illness began. The Bateman Horne Center describes PEM as the defining hallmark symptom that helps to distinguish ME/CFS from other states of exhaustion [2]. (A note on precision: the term "pathognomonic", sometimes used, is strictly speaking too strong. PEM is the most strongly distinguishing feature, but it does not occur in absolutely all those affected and is not in every case exclusive to ME/CFS. As "highly specific/leading" the statement holds; as "proving in the narrow sense" it does not.) According to the NICE guideline NG206 (2021), PEM is defined by three features: the onset is often delayed by hours or days, the reaction is disproportionate to the activity, and recovery is prolonged — hours, days, weeks or longer. There PEM is one of four core symptoms required for the diagnosis (alongside disabling fatigue, unrefreshing sleep and cognitive disturbances) [1].

Triggers and course

PEM can be triggered by very different stimuli. Besides physical exertion (even sitting, brushing teeth, showering, cooking, walking), this includes cognitive demands (reading, writing, screen use, concentration), emotional stress (excitement, anger, grief), orthostatic load (long standing, upright posture, heat) and sensory stimuli (noise, bright light, strong smells) [2]. Characteristic is the delayed latency: the worsening often does not set in immediately but typically with a delay of hours to 1–2 days (often in the range of 12–48 hours); its peak may only be reached after about 24–72 hours — unlike normal tiredness, which sets in immediately and subsides quickly with rest [3][4]. The duration ranges from hours through days and weeks to months in severely affected people, with the severity often out of all proportion to the trigger [1][4]. The symptom spectrum includes flu-like complaints (sore throat, swollen lymph nodes, feeling feverish), increased fatigue, cognitive dysfunction ("brain fog"), muscle and joint pain, headaches, unrefreshing sleep, sensory hypersensitivity and orthostatic intolerance [4]. The Open Medicine Foundation describes PEM fatigue as fundamentally different from normal tiredness — "as if every muscle were leaden". Affected people report PEM markedly more often than people without ME/CFS — this clear difference is one of the reasons PEM is regarded as a core diagnostic criterion (see NICE NG206 above) [1][4].

Push-crash cycle and pacing

A common pattern is the push-crash cycle: on "good days" people overactivate to catch up, which triggers a delayed relapse ("crash"). Prevention is through pacing — deliberately budgeting one's strength and staying within one's individual "energy envelope", i.e. below the personal exertion limit at which no worsening occurs [3]. Pacing is not a cure but a strategy for symptom control and for avoiding worsening.

Important safety note: a graded physical activation increased according to a fixed plan (graded exercise therapy, GET) is not to be equated with pacing in ME/CFS. The NICE guideline NG206 (2021) explicitly no longer recommends rigid GET escalation programmes, because they can trigger PEM and worsen the condition [1]. Activity should therefore remain adapted to exertion and symptom-guided, not following a prescribed escalation scheme.

Making it objective: 2-day CPET

One approach to making the abnormal exertion intolerance measurable is the 2-day CPET: two maximal cardiopulmonary exercise tests 24 hours apart. People with ME/CFS typically show reduced performance on day 2, while healthy people remain largely stable — discussed by the National Academy of Medicine (2015, IOM report) as a possible objective expression of PEM [8]. A study in the Journal of Translational Medicine (2024, n=55) found on day 2 a drop in VO2peak of about 6 % (p≤0.01) and in VO2 at the ventilatory threshold (VT1/VAT) of about 6.7 % (p≤0.05), while controls stayed unchanged [5]. Historically the reported values range more widely — VO2peak drop roughly between −5 % and −22 %, at the ventilatory threshold roughly −6 % to −27 % [6]. The VT1 (aerobic/ventilatory threshold, depending on fitness roughly in the range of 40–75 % of VO2max, determined e.g. by the V-slope method) is discussed as a particularly disease-relevant finding and serves in some pacing concepts as an individual heart-rate limit [6]. (Assessment: the exact percentage values and the label as the "most disease-specific finding" come from individual studies and reviews; they are not to be read as normative values established across all cohorts.)

Important is the uncertainty of the data: not all studies reproduce the drop. A study in Frontiers in Physiology (given as: 2026) found no significant change in VO2peak (22.3 vs. 22.5 mL/kg/min) or peak power (127 W on both days) and questioned the suitability of the method for defining PEM — the subjectively perceived exertion, however, was increased [7]. (Verified: Frontiers in Physiology, 2026 — full text; the year and figures match the primary source.) The 2-day CPET remains scientifically disputed and, because of the real risk of triggering a severe, sometimes long-lasting PEM crash in the process, is clinically not routinely recommended; it should at most be considered in specialised settings after careful weighing of benefit and risk.

Capturing it in everyday life: DSQ-PEM

More practical and low-risk is the DSQ-PEM (DePaul Symptom Questionnaire, PEM short form) with five core items — for example a "dead, heavy feeling after starting to exert oneself", "physical exhaustion after minimal exertion" or "mental exhaustion after the slightest effort" — each rated by frequency and severity on a scale of 0–4 [12]. In common evaluations, PEM-positive means that frequency AND severity each reach ≥2; in validation data a very high proportion of ME/CFS patients (reported: ~97 %) affirmed at least one item at least moderately for at least half the time (internal consistency Cronbach's alpha ~0.84). In addition, the questionnaire captures symptom delay, PEM duration, possible triggers and the effectiveness of pacing [12][13]. (Verified against the original study: Cotler, Holtzman, Dudun & Jason, 2018, Diagnostics (MDPI) — full text; the 97 % figure and Cronbach's alpha of 0.84 match the primary source. A figure of "14" triggers asked about, named in the source text, could not be confirmed there and has been removed.)

Note

For PEM there is no approved causal medication and no proven cure. Symptom-oriented measures (e.g. against pain or orthostatic intolerance) are used individually and often off-label; their evidence is limited, and their use and dosing belong in a doctor's hands (possible side effects and interactions). The most important evidence-supported strategy remains avoiding overexertion through pacing; rigid increases in activity (GET) are not recommended [1][3]. In case of persistent or increasing worsening, new or alarming symptoms, medical assessment should be sought. This text serves as information, does not replace medical advice and is not a promise of a cure.

More on this in our blog: More on post-exertional malaise (PEM) and early crash detection

6. POTS / dysautonomia / orthostatic intolerance

Postural orthostatic tachycardia syndrome (POTS) belongs to the disorders of the autonomic (vegetative) nervous system (dysautonomias) and is part of the group of orthostatic intolerance – that is, symptoms that are triggered by standing upright and improve when lying down. On standing up, those affected experience a pronounced rise in heart rate, often accompanied by palpitations, light-headedness, presyncope (near-fainting), exhaustion, exertion intolerance and difficulty concentrating ("brain fog") [1][4]. Note: recurrent true fainting attacks (syncope) are atypical for POTS; they, as well as new chest pain, racing heart at rest or breathlessness, should be assessed by a doctor to rule out other (among them cardiac) causes.

Definition and diagnostic criteria

POTS is defined by a sustained rise in heart rate of ≥30 beats/minute within the first 10 minutes after standing up, or in the tilt-table test (head-up tilt) – in adults [1][6]. In adolescents (up to ~19 years) a higher threshold of ≥40 beats/minute applies, because young people physiologically respond more strongly with heart rate [4]. Decisive is the distinction from orthostatic hypotension (OH): OH is present with a drop in blood pressure of ≥20 mmHg systolic or ≥10 mmHg diastolic within 3 minutes. POTS is by definition without such a sustained drop in blood pressure – such a drop is an exclusion criterion [1][6]. The symptoms must be chronic: the international expert consensus statement (2015) typically requires a duration of ≥6 months; some (especially older or paediatric) definitions use ≥3 months [4].

Diagnostics

For everyday practice, the active stand test or the 10-minute NASA lean test is well suited: after 5–10 minutes of rest lying on the back (stable baseline values with two consistent measurements), the person stands with their shoulder blades against the wall, heels about 15 cm (6 inches) from the wall; pulse and blood pressure are measured every minute over 10 minutes [2][3]. The tilt table (monitored) is often used as a reference method for complex or delayed cases, while the low-threshold active stand test is suited to primary care and to strongly symptomatic patients [2]. Note: whether the tilt table counts as a "gold standard" is professionally disputed – the active stand test reproduces the everyday situation and is often equivalent or sufficient.

Subtypes

POTS is not a uniform disease; four widely accepted, partly overlapping primary subtypes are distinguished – the figures vary from study to study and should not be understood as fixed quantities [1]: - Neuropathic: length-dependent autonomic neuropathy with sympathetic denervation of the legs and venous pooling; a relevant proportion (in some series around ~50 %) shows a peripheral sudomotor (sweat-gland) denervation. - Hyperadrenergic: raised plasma noradrenaline when standing (guide value ≥600 pg/mL), often with tremor, palpitations and in part orthostatic hypertension (proportions in the literature about 30–60 %). - Hypovolaemic: reduced blood and plasma volume, in part with paradoxically low renin/aldosterone. - Autoimmune: often post-viral, female-dominant; autoantibody/ANA findings variable. Deconditioning (among other things reduced left ventricular mass) is, by contrast, not counted as its own primary subtype, but is discussed as a secondary, reinforcing factor that can add to any of the four subtypes and worsen symptoms – not as their cause.

Connection with hypermobility (EDS/HSD) and mast cells

POTS, joint-related hypermobility (hypermobility spectrum, HSD for short, or the more narrowly defined hypermobile Ehlers-Danlos syndrome, hEDS) and mast cell activation syndrome (MCAS) are noticeably often seen together in practice – sometimes called a "triad" in patient and clinical circles. An analysis of 100 young people with POTS (Frontiers in Neurology, 2025) found, depending on the criteria used, 13–34% with joint hypermobility and 2–87% with MCAS – the wide range shows how strongly such figures depend on the case definition used, and they should therefore not be misread as a fixed frequency. A possible mechanism discussed is that mast-cell elastases damage connective tissue in joints/ligaments (a possible contributing cause of hypermobility) while also damaging the gut lining, which via disrupted vagus-nerve function could favour dysautonomia – a plausible but not yet conclusively proven hypothesis. mypacing records hypermobility/EDS as its own entry in the health profile; a diagnosis, however, is always made by medical or specialist staff.

Frequency

The prevalence is roughly estimated at about 0.2 % of the population (on the order of ~0.5–3 million affected people in the USA – the estimates are uncertain); onset is mostly between 15 and 50 years, the ratio of women to men about 4–5:1 [4][6]. Newer, patient-led surveys, however, report a markedly higher female proportion of over 80 %; a possible reason discussed is that POTS is on average diagnosed later, or less often, in men. The true magnitude of the gender ratio therefore remains uncertain.

Basic therapy (non-drug)

The basis of treatment is non-drug measures [1][5]. The following amounts are orientation values and should be adjusted individually and by a doctor: - Fluids: often 2–3 litres/day to increase blood volume [1]; Dysautonomia International names a practical ~2–2.5 L [5]. A very high fluid intake without sufficient sodium intake is not sensible and is potentially harmful in heart/kidney disease. - Salt/sodium: increased intake is recommended – individually and under medical supervision, since contraindications such as heart or kidney disease and high blood pressure may exist [1][5]. Attention, units: sources do not always cleanly distinguish between table salt (NaCl) and sodium (≈10 g salt corresponds to ~4 g sodium); the figures in circulation (e.g. up to ~10 g salt/day or several grams of sodium/day) are therefore not directly comparable and should be checked against the original source. - Compression: compression garments (guide value ~30 mmHg ankle pressure, in part up to 40 mmHg), ideally waist-high (including the abdominal region), reduce venous pooling [5]. - Counter-manoeuvres (crossing the legs, tensing the muscles), raising the head of the bed and reclined/lying training (swimming, rowing, recumbent bike), which should be increased slowly and under guidance [5].

Medications – note

If basic therapy is not enough, different medications are used depending on the subtype (e.g. beta-blockers, ivabradine, fludrocortisone, midodrine, pyridostigmine). Important: most of these substances are not officially approved for POTS and are used off-label; the evidence rests mostly on small studies and expert consensus. Mechanism of action, benefit, side effects and contraindications must be weighed individually by a doctor. This text does not replace medical advice and deliberately gives no dosing recommendations; every drug therapy belongs in specialist hands.

Connection with Long COVID

POTS is described as one possible manifestation of Long COVID. In a highly symptomatic, non-hospitalised cohort, a substantial proportion (in one study ~31 %) were formally diagnosed with POTS [7][10]; in strongly selected groups, according to reports, up to ~79 % of highly symptomatic Long COVID patients met the POTS criteria, and the literature reports autonomic dysfunction in ~30–60 % [8]. One analysis described an approximately 5-fold increased POTS risk after COVID-19 infection compared with after vaccination [9] – with POTS also being rare after vaccination, and markedly rarer than after infection; this is not an argument against vaccination.

Placing the uncertainties: the prevalence, subtype and Long COVID figures vary considerably depending on cohort and investigation method; the Long COVID values named come from strongly selected, highly symptomatic groups and cannot be transferred to all those affected or to the general population. Several individual figures in this section (exact percentages, cohort sizes, quantities) should be verified against the original sources [1]–[10] before being passed on. Diagnosis and therapy should always be carried out individually and with medical guidance.

More on this in our blog: More on autonomic dysregulation in Long COVID and ME/CFS

7. Brain fog & further accompanying symptoms / subtypes

Many people affected by Long COVID, ME/CFS and POTS suffer not only from fatigue and post-exertional malaise (PEM) but from a whole cluster of accompanying symptoms. These often occur together and can be grouped into overlapping subtypes (neuro-cognitive, autonomic/cardiovascular, immune-inflammatory, pain-dominant, gastrointestinal). The subtype grouping is a pragmatic ordering scheme, not an established, validated classification. The connecting hallmark symptom remains PEM; several of the phenomena described here are at the same time considered possible modifiable PEM triggers and are thus relevant for pacing.

Important note: this section serves as information and does not replace medical advice, diagnosis or treatment. All medications and therapies named are to be used only with medical guidance. No dosages are deliberately given and no promises of a cure are made.

Brain fog (cognitive dysfunction)

"Brain fog" refers to problems with memory, attention, word-finding and executive function. The largest study so far (Hampshire et al., NEJM 2024, around 113,000 participants with online cognition tests) made measurable differences visible: those who recovered with early-resolving symptoms showed an equivalent of about −3 IQ points, people with persisting symptoms (Long COVID, over 12 weeks) about −6, and intensive-care courses about −9 points [1][2]. Assessment: these are small group-average effects, not an individual diagnosis or a measure of personal intelligence. The study was cross-sectional; people whose symptoms had already resolved had smaller losses. A true time course ("normalisation") cannot be directly proven from this – but the data suggest that brain fog in many affected people recedes as symptoms improve and is not necessarily permanent. As possible mechanisms, neuroinflammation with activation of microglia/glial cells, viral persistence, disturbances of the endothelium and blood-brain barrier, and – much more disputed – fibrin microclots ("microclots") are discussed; the microclot hypothesis has so far not been independently confirmed and is judged controversially. Imaging and spectroscopic methods (among them PET-MRI, 7-tesla MR spectroscopy) investigate these processes; peripheral blood inflammatory markers do not reliably reflect what happens in the brain [18][19]. These findings are promising, but are not to be regarded as causally established.

Mast cell activation (MCAS)

In a proportion of those affected, symptoms compatible with mast cell activation are found (flushing, itching, hives, gastrointestinal and circulatory complaints, food/stimulus intolerances). In a case-control study (Weinstock et al. 2021, n=136 Long COVID, mostly women) such symptoms were significantly increased after SARS-CoV-2 infection and resembled those of untreated MCAS patients; before infection, those affected and controls barely differed [3]. Important: the study recorded symptom questionnaires, not a laboratory-confirmed MCAS diagnosis – whether this is a true MCAS in the sense of the diagnostic criteria is open. Reviews discuss activated mast cells with increased mediator/cytokine release [4]. Therapy (doctor only): as symptomatic options, H1/H2 antihistamines and mast-cell stabilisers are discussed; the principle is blocking or stabilising mast-cell-mediated reactions. H1/H2 blockers are in part available over the counter (OTC); their use against Long COVID-associated mast-cell symptoms, however, is off-label and rests on small, uncontrolled studies (weak evidence). Medical assessment is required before any use (also to distinguish other causes and because of possible side effects/interactions). This is expressly not a dosing, self-treatment or healing instruction.

Small-fibre neuropathy (SFN)

Damage to thin nerve fibres can cause burning pain, abnormal sensations and autonomic disturbances. A skin-biopsy-based case-control study (published 2024) describes newly occurring SFN after COVID; a large part of those affected reported PEM. Patients treated with intravenous immunoglobulins (IVIG) responded more often in this small series (reported as 9/9 vs. 3/7, p=0.02) [5][6][7]. IVIG is an immunomodulating therapy; its use in post-COVID SFN is off-label, cost-intensive, associated with relevant side-effect potential and, given the very small case numbers (low evidence level, ~Class III), only preliminarily supported. It belongs exclusively in specialised medical hands. The widespread claim that up to ~50 % of chronic pain/fibromyalgia cases are based on an SFN comes from the fibromyalgia field; the transfer to Long COVID is an extrapolation and not reliably quantified.

Autonomic dysfunction, POTS and HRV

Orthostatic intolerance and POTS occur frequently together with mast-cell symptoms and SFN (described in the literature as the "POTS-MCAS-SFN triad"), with autonomic small-fibre damage as a hypothetical common denominator – a plausible but unproven construct. One possible measurement parameter is heart rate variability (HRV): studies show reduced nocturnal parasympathetic (vagal) activity and relative sympathetic dominance (e.g. Sci Rep 2023, n=103) [13][14]. Wearable-based HRV monitoring is being trialled to estimate individual exertion/PEM thresholds in pacing; this is so far experimental and not clinically validated [15].

Unrefreshing sleep

Despite sufficient sleep duration, those affected wake up unrefreshed. This "unrefreshing sleep" is a core criterion of ME/CFS diagnostics (IOM 2015 / SEID) [9] and very common in Long COVID; EEG studies point to an altered sleep microstructure and links to a disturbed circadian rhythm [10].

Hormonal / HPA-axis changes

In Long COVID, some studies show a flattened salivary/serum cortisol daily rhythm or a lowered morning cortisol value (in one cohort n≈96 the morning median was markedly lower than in controls) – a pattern that has also long been described in ME/CFS [16]. The figures named are study-specific and are not to be understood as a generally valid reference. Important: a cortisol substitution cannot be derived from this; the findings are at most markers, not a treatment indication. Taking cortisone/cortisol on one's own can be harmful.

Sensory overload

Hypersensitivity to light, noise and smells forms, in a factor analysis (Front Neurol 2025, n≈2,313 ME/CFS + ~299 PASC), its own sensory-perceptual factor (high factor loadings for light, noise and smell) [17]. Sensory overload can favour PEM and should be taken into account in pacing.

Gastrointestinal complaints

Nausea, diarrhoea, abdominal pain and irritable-bowel-like complaints persist in a substantial proportion. As possible mechanisms, viral persistence in the gut, dysbiosis/microbiome changes and chronic mucosal inflammation are discussed [11][12]; causal evidence is still lacking.

Overlap and assessment

Long COVID, ME/CFS, fibromyalgia and irritable bowel syndrome overlap strongly (pain, fatigue, unrefreshing sleep, cognitive disturbance, stimulus hypersensitivity) and presumably share mechanisms such as central sensitisation and autonomic/small-fibre dysfunction; the diagnostic distinction remains difficult [8]. Evidence note: many of the subtype findings named here come from small to medium-sized, in part uncontrolled studies (mostly low evidence level, ~Class III). Large controlled cohorts and uniform case definitions are still missing – the results are promising but preliminary and must be assessed by a doctor in the individual case.

8. Crash triggers & pacing (non-drug)

What is a crash (PEM)?

The core phenomenon behind every "crash" is post-exertional malaise (PEM) – a delayed, disproportionate worsening after exertion. PEM is the cardinal symptom of ME/CFS and is also frequently observed in Long COVID [1][7]. In POTS, PEM is not a defining feature, but it can occur, especially when ME/CFS or Long COVID are present as a comorbidity. According to the NICE guideline NG206, PEM is characterised by three features: the worsening of symptoms (1) often sets in delayed by hours to days, (2) is disproportionate to the triggering activity and (3) has a prolonged recovery time [1]. An NIH study describes a typical onset 24–48 hours after exertion, a duration of 24 hours up to several weeks, and core symptoms such as exhaustion, brain fog, neuromuscular complaints, head/throat pain, pain, nausea and sensitivity to light and noise [5][11].

Recognising triggers

Crashes do not arise only from exercise. Triggers are varied [7][11]:

  • Physical: also everyday activities (showering, cooking, shopping)
  • Cognitive: reading, conversations, screen work
  • Emotional: stress – including positive emotions
  • Orthostatic: prolonged sitting or standing [15]
  • Sensory: light, noise
  • Others: infections, heat, hormonal fluctuations/menstruation, travel, vaccine reactions

A symptom and activity diary over 1–2 weeks helps to determine individual triggers and one's personal exertion limit [4][8].

Important safety note: not every worsening is automatically a PEM crash. New, sudden or unusually severe symptoms – e.g. chest pain, shortness of breath, fainting/syncope, neurological deficits, persistent fever – should not be hastily dismissed as PEM but assessed by a doctor, so that other treatable causes are not overlooked.

Pacing: the central strategy

Pacing means staying within one's individual exertion limit ("energy envelope") – through conscious activity and energy management [6][10]. Important: pacing is expressly not an increase in activity but symptom-contingent – activity is adapted to current capacity, with the aim of avoiding a crash [1][6]. As a rule of thumb, it is widely recommended to do only about 50 % of what you feel capable of [6]. Established helper models are the spoon theory (dividing the limited daily energy into "spoons") and the 3-P rule (prioritise, plan, pace) [10]. Early warning signs such as increased brain fog, head/throat pain or a weak voice can signal an approaching crash and are a reason for an immediate break [11].

Heart-rate-based pacing

One possible objective anchor is heart rate. The Workwell Foundation uses, as a conservative estimate of the ventilatory/anaerobic threshold, resting heart rate + 15 bpm (example: resting rate 60 → threshold 75 bpm) [2]. Practical rules [2]:

  • Measure the resting heart rate over several (e.g. 7) days in the morning before getting up and average it; a morning deviation of about +10 bpm can indicate overexertion.
  • Exceed the estimated threshold only briefly if at all (on the order of a few minutes).
  • Use a heart-rate monitor with an alarm; on the alarm, stop and rest until the heart rate returns close to the resting rate.

The threshold formula is a rough, individual estimate and does not replace a spirometrically determined (CPET) threshold. According to the Workwell Foundation, more than 85 % of those affected show a blunted heart-rate response to exertion (chronotropic incompetence); age-based maximum heart-rate formulas (220 minus age) are therefore not suitable [2].

Why not GET?

Graded exercise increase (graded exercise therapy, GET) is explicitly no longer recommended by NICE NG206 – no programmes based on fixed, stepwise increases in physical activity [1]. Reasoning: GET increases the load in a fixed/time-based way regardless of symptoms and can in doing so exceed the (in ME/CFS low) anaerobic threshold, which can trigger PEM and cause harm [3]. Objectively, the two-day CPET supports a bioenergetic disturbance: unlike healthy people, many of those affected cannot reproduce their performance on the second day – the VO2 at the ventilatory threshold fell in studies by about −10.8 % (Snell 2013) or −15.8 % (Keller 2014), and the wattage at the threshold by about −11 % (Snell 2013) to −21 % (Keller 2014) [9][12]. These findings come from small samples; the effect sizes vary between studies. According to reports, continued exceeding of the exertion limit (contrary to pacing) increases the duration and severity of crashes [6].

Additional non-drug measures

  • Radical/aggressive rest: consistent, proactive resting – also before and after exertion, in a dark, low-stimulus environment. According to an NIH survey, complete rest is the most frequently named recovery method and is used preventively, not only after exhaustion has set in [5].
  • Orthostatic intolerance/POTS (often comorbid): compression garments, avoid long standing and heat, and if needed lying/sitting rather than upright activities [15]. Increased fluid and salt intake is often recommended in POTS, but is only sensible after consulting a doctor and is contraindicated in high blood pressure, heart or kidney disease. Important distinction: the warning against GET above applies specifically to ME/CFS, i.e. to exertion involving PEM. In POTS without PEM, a slowly and guidedly increased exercise programme started reclined/lying down – such as the Dallas or Levine protocol – is an established and explicitly recommended part of treatment [5]. When ME/CFS or Long COVID with PEM is also present, PEM caution takes priority; individual exercise progression then belongs in medically/therapeutically guided hands.
  • Breathing/ANS techniques: slow breathing (about 6 breaths/minute) and HRV biofeedback can favourably influence heart rate variability and vagal activity. The evidence so far comes from pilot/feasibility studies in Long COVID (e.g. HEARTLOC) and is not yet secured by large RCTs – so this is a plausible hypothesis, not an established benefit [13][14]. In ME/CFS it should also be noted that even seemingly light "exercises" can be a strain.
  • Sleep: characteristically unrefreshing in ME/CFS; sleep hygiene is recommended but does not cure the disease [1].
  • Nutrition: no specific diet is evidence-based curative; recommended are sufficient hydration, if needed more salt in POTS (see contraindications above) and a balanced diet against accompanying symptoms [15].

Note on medications/supplements: this section deliberately deals with non-drug strategies. For all substances (e.g. salt tablets in POTS): clarify mechanism of action, strength of evidence and off-label/OTC status individually with the treating doctor. No promise of a cure – the measures named aim at symptom and exertion management, not at cure. This does not replace individual medical advice.

Leading guidelines and institutions (NICE NG206, CDC as well as relevant AWMF guidelines – in the German context above all the guidelines on Long/Post-COVID or "fatigue"; a standalone AWMF ME/CFS guideline does not currently exist) agree at their core: actively recognise PEM, use pacing as the core strategy, log exertion and avoid the push-crash (boom-bust) cycle [1][4][8].

More on this in our blog: Learn more about pacing and energy envelopes

9. Medication I — autonomic / cardiovascular

This section describes medications and basic measures used in a disorder of circulatory regulation (dysautonomia) — in particular in postural tachycardia syndrome (POTS), which frequently occurs in the context of Long COVID and ME/CFS. Important up front: the available studies are almost all small (11–54 people), mostly designed as short-term cross-over investigations and carried out predominantly in "classic" POTS, not specifically in people with Long COVID or ME/CFS [5][10]. None of the substances named is approved in Germany for treating POTS — all are used off-label [10][11]. The therapy is fundamentally symptom-oriented and individual; in ME/CFS with exertion intolerance (PEM) these agents only ease circulatory symptoms and do not replace pacing [10].

Safety frame (applies to all the following substances): choice, dosing, tapering in and out and monitoring belong strictly in a doctor's hands. Agents affecting heart rate and blood pressure generally require baseline diagnostics (among them ECG, blood-pressure/pulse course) and follow-up checks. Do not stop or up-dose beta-blockers, ivabradine and pyridostigmine on your own. Interactions (e.g. further heart-rate-lowering agents, CYP3A4 interactions) and individual contraindications are to be checked by a doctor beforehand. This text is not an instruction for self-medication and promises no cure.

Basic therapy: salt and fluids

Best evidenced is volume/salt loading. In a controlled cross-over diet study (n=14 women with POTS) a high-salt diet (300 mmol ≈ 6.9 g sodium/day, corresponding to ≈ 17.5 g table salt) increased blood volume, lowered the standing heart rate and the noradrenaline raised on standing [7]. This study dose is considerably higher than the usual intake and was given under study conditions — such a high salt intake should not happen on one's own but only with medical guidance. Professional societies (Heart Rhythm Society) recommend, as a guide, about 10–12 g table salt (≈ 3–4 g sodium) and 2–3 litres of fluid daily [7]. Buffered electrolyte mixtures are gentler on the stomach than pure table salt. Contraindications/caution: heart failure, kidney disease, arterial hypertension; in these constellations an increased salt/fluid intake is potentially dangerous and defensible only after consulting a doctor. Acute i.v. saline infusions (1–2 l) improve symptoms in the short term (hours to days) but, because of infection and thrombosis risk (especially with an indwelling catheter), are explicitly not recommended as a long-term therapy [7].

Lowering the heart rate

Propranolol (low dose). Non-selective beta-blocker, CNS-penetrating, lowers the heart rate; by blocking β2-mediated vasodilation, peripheral vascular resistance can rise. In a randomised cross-over study (n=54) a low dose (20 mg) lowered the standing heart rate from 108 to 86/min and improved symptoms; a higher dose (80 mg) lowered the pulse more but did not improve symptoms further and in part worsened them (light-headedness, "brain fog", shortness of breath) — hence the principle "less is more" [2]. A small RCT (n=11) reported an acutely improved maximal oxygen uptake [3] (small sample, single finding — of limited reliability). Safety: off-label (approved among others for hypertension, angina); caution with low baseline blood pressure; in asthma/COPD non-selective beta-blockers are generally contraindicated because of bronchoconstriction, or defensible only in exceptional cases. Fatigue/tiredness is a generally known side effect documented for beta-blockers as a drug class – not an ME/CFS-specific effect. It carries more weight in ME/CFS and Long COVID, however, because fatigue is already pronounced there [2][5]. Do not stop abruptly (rebound tachycardia/blood-pressure rise possible); watch for bradycardia and AV conduction disturbances. Cardioselective beta-blockers (metoprolol, bisoprolol, nebivolol) have a much weaker, mostly retrospective evidence base (class IIb recommendation) [5].

Ivabradine. Selective inhibitor of the I_f channel in the sinus node; lowers the heart rate in a purely sinus-node-specific way without a drop in blood pressure, without a negative effect on heart contractility and without bronchoconstriction — an advantage over beta-blockers [1][8]. The best evidence comes from a randomised, double-blind, placebo-controlled cross-over study in hyperadrenergic POTS (n=22): the standing heart rate fell from 94 to 78/min, physical and social function improved, without relevant hypotension [1]. Safety: in the EU/Germany, ivabradine is approved only for symptomatic chronic heart failure and stable angina pectoris (coronary heart disease); use in inappropriate sinus tachycardia and in POTS is off-label (corrected: inappropriate sinus tachycardia is not an approved indication but a guideline-supported off-label use) [8]. Side effects: flashes of light/phosphenes (~3 % in the SHIFT study), bradycardia, increased atrial-fibrillation risk; contraindicated in pregnancy (teratogenic in animal studies), reliable contraception needed. Relevant interactions with strong CYP3A4 inhibitors and with verapamil/diltiazem (contraindicated or to be avoided) [1][8]. For Long COVID, the protocol of the randomised COVIVA study (ivabradine in post-COVID POTS/inappropriate sinus tachycardia; 2:1 active:placebo, ~40 evaluable people) was published in 2025; efficacy results are still pending. In addition, the larger platform study RECOVER-AUTONOMIC is studying POTS in Long COVID [9].

Pyridostigmine (Mestinon). Acetylcholinesterase inhibitor, strengthens the vagal "brake" on the heart and thereby lowers the heart rate without a rise in blood pressure. In a randomised cross-over study (n=17) 30 mg lowered the standing heart rate after 2 h from 111 to 100/min and improved the symptom score [4]; a retrospective case series (n=203) reported improvement in ~50 % [5] (retrospective, without a control group — only of limited reliability). Safety: off-label (approved for myasthenia gravis); typical side effects are abdominal cramps, nausea, diarrhoea, increased salivation/sweating — favourable with accompanying gastroparesis/constipation, unfavourable with diarrhoea [4][5]. Caution/contraindication with mechanical gastrointestinal or urinary-tract obstruction and with asthma (cholinergic bronchoconstriction/bradycardia possible).

Stabilising blood pressure and volume

Midodrine. A prodrug; its metabolite is a peripheral alpha-1 agonist that constricts vessels and veins, increases venous return and reduces venous "pooling". The approval rests on orthostatic hypotension (RCT n=171) [6]; in POTS there is cross-over evidence for less pooling [5]. Short duration of action (~4 h). Safety: off-label in POTS; characteristic are goose bumps, scalp tingling, urinary retention and above all a rise in blood pressure when lying down (supine hypertension) — the last dose should be several hours before lying down. Contraindications include severe organic heart disease, acute kidney disease, urinary retention, phaeochromocytoma, thyrotoxicosis; blood-pressure checks (also when lying down) are recommended [6].

Fludrocortisone. Synthetic mineralocorticoid; increases sodium/water retention and plasma volume. The evidence is weak and inconsistent — a placebo-controlled study in neurally mediated hypotension/chronic fatigue showed no advantage over placebo (class IIb recommendation) [5]. Safety: off-label; potassium loss (regular potassium checks recommended), oedema, high blood pressure, headache; blood-pressure checks and caution with longer use (mineralo-/glucocorticoid effects). Only sensible with sufficient salt and fluid intake [5].

Assessment

Overall, the evidence is limited and comes from small short-term studies; the most reliable are low-dose propranolol, ivabradine (hyperadrenergic POTS), pyridostigmine and salt/volume loading [1][2][4][7]. All statements concern the short-term symptom relief of circulatory complaints; proof of a lasting or disease-modifying benefit in Long COVID/ME/CFS is lacking, and none of the substances cures the underlying disease. The German AWMF S1 guideline Long/Post-COVID explicitly names POTS/dysautonomia and points to a symptom-oriented, individual therapy; the BfArM maintains an expert group on off-label use [10][11]. All statements do not replace medical advice; choice, dosing and monitoring belong in a doctor's hands.

10. Medication II — immunomodulatory / antiviral / symptomatic / supplements

For Long COVID, ME/CFS and POTS there is so far no approved, causally effective medication. Almost all the options described here are used either off-label (outside the approval) or as an over-the-counter OTC product, mostly on a low evidence level. The overarching principle of all guidelines remains PEM-avoiding pacing/energy management — the NICE guideline NG206 places recognising post-exertional malaise and energy management at the centre and explicitly advises against activating exercise therapy (GET) as a cure; no food supplement counts as curative [17]. Medications do not replace this approach.

General note: this section is an information overview, not a treatment recommendation. All the substances named are prescription-only or at least require advice and may only be taken after medical assessment, taking pre-existing conditions and one's individual medication into account. Dosages are orders of magnitude from the literature, not an intake instruction.

Immunomodulatory

Low-dose naltrexone (LDN). At a low dose (a fraction of the 50 mg standard dose approved for addiction treatment), naltrexone acts via a brief opioid-receptor blockade with reactive endorphin up-regulation and via a TLR4 antagonism at microglia — from which an anti-inflammatory, immunomodulatory effect is inferred; this mechanism is hypothetical and unproven in Long COVID [1][3]. The evidence comes from small, mostly uncontrolled studies; a 2025 systematic review could meta-analyse only two studies with around 95 patients, and the GRADE quality is very low [1][2]. Signals of improvement in fatigue, brain fog, headache and sleep are reported — on this data basis these are preliminary indications, not proof of efficacy [3]. LDN is off-label and is prescribed as a compounded formulation/capsule. Side effects are mostly mild (headache, vivid dreams/sleep disturbances, dizziness, gastrointestinal complaints). Safety: contraindicated during ongoing opioid therapy (triggering withdrawal, loss of analgesia) — pause under medical guidance before planned operations/opioid analgesia; caution in liver disease; use in pregnancy/breastfeeding not sufficiently studied [1][3]. Randomised studies are ongoing and are urgently called for.

Antihistamines in suspected MCAS. In assumed mast cell activation syndrome, H1 blockers (second generation, mildly sedating, e.g. cetirizine — can cause slight drowsiness —, loratadine, fexofenadine; sedating e.g. ketotifen) are combined with an H2 blocker (famotidine) to dampen histamine-mediated symptoms [4][5]. The evidence rests on case series and observational data with reported improvement; large RCTs are lacking, and the MCAS diagnosis in Long COVID remains professionally disputed (consensus criteria are often not met) [4]. Status: off-label or OTC (H2 blockers/H1 blockers partly available without prescription). Safety: ranitidine was withdrawn from the market because of NDMA contamination — use famotidine instead; watch for interactions and QT-relevant combinations [5].

Antiviral / metabolic

Metformin (prevention in the acute phase). The antidiabetic metformin inhibits, among other things, viral translation (mTOR-dependent) and acts anti-inflammatorily (mechanistically plausible, not proven). In the COVID-OUT RCT (1,126 included in the Long COVID analysis), a 14-day early dose during the acute infection lowered the Long COVID incidence over 10 months to 6.3 % compared with 10.4 % under placebo (relative reduction ~41 %, absolute ~4.1 percentage points); when started within the first few days after symptom onset, the relative reduction in the subgroup was larger (up to ~63 %) [6][7]. Important: this effect is preventive in the acute phase. A benefit as a fatigue therapy in already established Long COVID is not proven — in the 2026 adaptive RCT (Annals of Internal Medicine; see fluvoxamine below), which tested metformin and fluvoxamine against fatigue in established Long COVID, metformin brought no improvement in fatigue over placebo [8]. Off-label in this context. Safety: gastrointestinal side effects; contraindicated in relevant renal insufficiency and in situations with hypoxia/dehydration (rare but dangerous lactic acidosis); attention to contrast-agent administration and alcohol.

SSRI/SNRI (fluvoxamine). Sigma-1 receptor agonism and anti-inflammatory effects are discussed (hypothesis). A 2026 adaptive RCT (n=399, exclusively at 22 centres in Brazil — generalisability thereby limited) showed, after 60 days of fluvoxamine, a moderate improvement in fatigue that faded after stopping (after 30 days ~50 % more often low fatigue [score ≤3], after 60 days ~0.5 points lower, after 90 days — 30 days after stopping — only ~19 % advantage) [8]. Observational data point to a lower Long COVID risk with SSRI use in depressive patients — an association, not proof of causation [9]. Off-label for Long COVID; robustly evidence-based is its use in comorbid depression/anxiety. Safety: discontinuation syndrome (do not stop abruptly), serotonin syndrome with serotonergic combinations, initial activation/nausea; fluvoxamine is a strong CYP1A2 inhibitor with clinically relevant drug interactions (among them caffeine, theophylline, clozapine, tizanidine, some anticoagulants) — have combinations checked by a doctor [9].

What is advised against: the unlicensed "microclot" triple therapy (two platelet aggregation inhibitors plus a DOAC) is supported by no RCT; experts explicitly advise against it because of substantial bleeding risk and a thin causal basis [10][11]. Do not use on your own.

Symptomatic (POTS) and supplements

Salt and fluid intake (POTS). Increased table salt (in guidelines often up to ~8–10 g NaCl/day) and fluid intake (~2–3 l/day) are non-pharmacological first-line measures to increase blood volume [18]. Contraindicated, or only under medical guidance, in hypertension, heart or kidney failure — the amount should be set individually by a doctor, not applied across the board.

The following OTC supplements all have low evidence and are mainly useful in a proven deficiency. None is proven effective for Long COVID/ME/CFS:

  • CoQ10 (mitochondrial antioxidant): a small RCT (CoQ10+NADH) with signs of improvement in fatigue/heart-rate parameters after exertion; mostly well tolerated, possible interaction with warfarin (can weaken its effect) and antihypertensives [12][13].
  • D-ribose (ATP substrate): only uncontrolled pilot studies, high susceptibility to placebo; can lower blood sugar (caution with diabetes/tendency to hypoglycaemia) [14].
  • Magnesium: useful in deficiency; high doses → diarrhoea; caution/risk of accumulation in renal insufficiency.
  • B vitamins/B12: subjective benefit reported, no robust RCTs; B12 very safe, but long-term high B6 doses → sensory neuropathy (observe dose limits) [15].
  • Omega-3 (EPA/DHA): anti-inflammatory plausible, evidence mixed/negative; possibly additive bleeding risk with anticoagulants.
  • Vitamin D: correcting a deficiency is useful; no Long COVID therapy evidence; overdose → hypercalcaemia.
  • NAC: antioxidant/mucolytic, only preliminary PASC signals (e.g. dyspnoea); available in Germany over the counter as a mucolytic, in rare cases bronchospasm — caution in asthma [16].

Conclusion: all the substances named are off-label or OTC, are not proven curative for Long COVID/ME/CFS and should be used individually, with medical guidance and after weighing benefit and risk (including checking interactions) — and do not replace pacing [17].

11. Diagnostics, biomarkers & differentiation

ME/CFS, Long COVID and POTS are to this day diagnosed clinically on the basis of defined symptom criteria. There is no routinely available, validated diagnostic blood test or other biomarker [1][11]. The diagnosis is thus a combination of a positive diagnosis (typical symptom pattern) and an exclusion diagnosis (other treatable causes have been worked up). Laboratory and instrument-based investigations serve above all to exclude – not to prove – the disease.

Diagnostic criteria for ME/CFS

The widely used IOM/NAM criteria (2015) obligatorily require: (1) a substantial, newly appeared reduction in activity with fatigue over more than 6 months that is not substantially relieved by rest, (2) post-exertional malaise (PEM) and (3) unrefreshing sleep; in addition, at least one cognitive impairment or orthostatic intolerance must be present. The symptoms must be present at least half of the time at moderate to severe intensity [2]. As alternatives, the Canadian Consensus Criteria or the British guideline NICE NG206 are used; NICE allows a clinical suspicion already from 6 weeks (children 4 weeks) and confirms the diagnosis after about 3 months of persisting symptoms, while IOM and the German guidelines tend to use 6 months [1][2].

PEM is the central distinguishing feature. What is meant is a worsening after physical, cognitive or emotional exertion. It can set in immediately, but characteristically appears delayed – often only after hours to one or two days (about 12–48 hours) – and can last days to weeks. PEM must be actively asked about, for example with standardised questionnaires such as the DePaul Symptom Questionnaire [2][14]. It distinguishes ME/CFS from simple deconditioning and from depression.

Exclusion diagnostics: recommended basic lab panel

The German DEGAM S3 guideline "Fatigue" (AWMF 053-002) recommends, in the absence of organ clues, a lean basic lab panel: blood glucose, differential blood count, ESR/CRP, transaminases/gamma-GT and TSH; further tests only in case of abnormalities [3]. NICE NG206 recommends a somewhat broader exclusion panel: urinalysis, full blood count, urea/electrolytes, liver values, TSH, ESR or plasma viscosity, CRP, calcium/phosphate, HbA1c, serum ferritin, coeliac screening and creatine kinase; optionally vitamin D, B12, folate, serologies and a 9 a.m. cortisol [1]. The extent and choice of tests remain a case-by-case medical decision.

Important differential diagnoses to be excluded: hypothyroidism, anaemia/iron deficiency (ferritin), diabetes, coeliac disease, adrenal insufficiency (Addison's disease), obstructive sleep apnoea, multiple sclerosis and other neurological diseases, inflammatory-rheumatic diseases, malignancies and medication side effects [4][5]. Red flags that require extended work-up instead of an ME/CFS diagnosis include weight loss, fever/night sweats, lymphadenopathy, focal neurological signs, clearly pathological lab values and cardiac symptoms [1][3]. Important: an ME/CFS diagnosis does not rule out additional or later-appearing other diseases – new or atypical symptoms should always be reassessed by a doctor.

Orthostatic intolerance and POTS

Orthostatic complaints can be made objective. POTS is present with a sustained heart-rate rise of ≥30 bpm (adults) or ≥40 bpm (adolescents 12–19 yrs) within 10 minutes of standing or on the tilt table, without orthostatic hypotension (no sustained systolic fall ≥20 mmHg or diastolic ≥10 mmHg), with symptoms for ≥6 months [6][7]. Without a tilt table, the active stand test (Schellong) or the 10-minute NASA lean test with serial pulse and blood-pressure measurements are suitable [8][9]. A low ratio of pulse pressure to systolic blood pressure (PP/SBP, sometimes given with a cut-off around 25 %) is discussed in specialised centres as a possible sign of pronounced circulatory dysregulation; this value, however, is not generally validated and should only be interpreted as an addition [8][9].

Safety note: active stand and lean tests can trigger presyncope, syncope, falls or a PEM. They should only be carried out under supervision with a secured option to sit/lie down and should be stopped immediately in case of dizziness, imminent fainting or strong symptom aggravation. In severely affected (e.g. bedridden) people particular restraint is called for.

Exercise tests and the limits of making it objective

The cardiopulmonary exercise test (CPET) as a two-day protocol is used as a research approach to make PEM visible: in specialised studies, those affected showed on the second day a reduced oxygen uptake and performance at the anaerobic threshold, while healthy people reproduce their values. These findings, however, have not been consistently reproduced in all studies and are not yet a diagnostic standard [10]. Because of the substantial risk of triggering a severe and potentially long-lasting PEM in the process, CPET is not a routine instrument but remains reserved for specialised research or assessment contexts with careful weighing of benefit and risk [10]. Newer blood-based approaches (e.g. EpiSwitch 3D genomics, metabolic and immunological signatures) are the subject of research and in part promising, but not yet clinically validated and not recommended for routine care [11][12].

Distinction from depression and Long COVID

The blanket misclassification as "purely psychological" is problematic: it can delay the diagnosis and lead to purely activating therapies being put in the foreground, which where PEM is present can trigger a worsening; it can also make it harder to have reduced earning capacity and care needs recognised [13]. This does not mean that accompanying mental illnesses are ruled out – they can exist in addition and should be treated in their own right. As a distinction: in depression the exertion-triggered, delayed PEM is typically absent, and listlessness/anhedonia are in the foreground; clinically it is described that people with ME/CFS want to be active but physically cannot [2][14]. A simple two-question screening on mood and interest/enjoyment (e.g. PHQ-2) helps not to overlook a treatable depression [3]. Long COVID and ME/CFS overlap strongly; a relevant proportion of Long COVID sufferers meet the ME/CFS criteria. For Long COVID too there is currently no validated biomarker; diagnostics remain clinical and exclusion-oriented [15].

Note: this section serves as information and does not replace medical examination, diagnosis or advice. Diagnostic delays of several years are well documented – a structured, PEM-oriented work-up can shorten this. On medications or supplements, no dosages or promises of a cure are deliberately given here; all diagnostic and treatment decisions belong in a doctor's hands.

12. Guidelines, care & resources (Germany/EU)

Guidelines

The central medical orientation in Germany is the AWMF guideline "Long/Post-COVID" (register number 020-027) under the lead of the German Society for Pneumology and Respiratory Medicine (DGP). Important for context: it currently exists as an S1 guideline (last extended in August 2025) – this is the lowest AWMF level, which is based on expert consensus and does not yet contain a systematic evidence assessment like an S3 guideline [1]. A higher-grade guideline is so far lacking and is being called for by experts and affected people. In terms of content, the guideline is nonetheless significant: it names fatigue, chronic fatigue syndrome (ME/CFS) and post-exertional malaise (PEM) as possible consequences, explicitly recommends pacing/energy management (among other things the "4P principle": pacing, planning, prioritising, positioning) and, where PEM is present, advises against rigid, escalating activation in the sense of a "graded exercise therapy" (GET) [1].

Internationally trend-setting is the British NICE guideline NG206 (2021). For ME/CFS it clearly recommends no GET as a cure and no generalised training programmes with fixed increases; instead, individual energy management/pacing and respecting the exertion limits are in the foreground ("do not push through the symptoms") [2]. PEM is regarded as a core feature; cognitive behavioural therapy is classified as only supportive, not curative [2].

Care situation in Germany

Care is regarded as strongly underdeveloped (a "care desert"). By estimates, several hundred thousand people in Germany live with ME/CFS – the number has roughly doubled since the pandemic [3]. For adults, there is essentially only one specialised university outpatient clinic nationwide, the Charité Fatigue Centrum (CFC) in Berlin [3][4]; for children and adolescents the MRI Chronic Fatigue Centrum (MCFC) of TU Munich (Klinikum rechts der Isar/München Klinik) [5]. Although there are over 100 post-COVID clinics, in many places ME/CFS expertise, funding and staff are lacking; people with ME/CFS after other infections often fall through the net [3]. The consequences are long waiting times, mistreatment and considerable undersupply.

Self-help and patient organisations

Reputable points of contact include the Deutsche Gesellschaft für ME/CFS e.V. (mecfs.de), which has published a practical guide and political demands (among them a national action plan) [3]; Fatigatio e.V., the nationwide self-help association with regional groups and social counselling [6]; and the patient initiative Long COVID Deutschland with directories of clinics and rehabilitation [7]. Specifically for POTS and related dysautonomias, PoTSDys e.V. ("PoTS und andere Dysautonomien e.V.", based in Bochum) is active with education, exchange and advocacy [13]. Internationally, for example #MEAction is active with pacing and management guides [8]. These organisations offer orientation and exchange but do not replace medical advice.

Social-law aspects

Because Long-/post-COVID and ME/CFS have no assessment criteria of their own in the German Care-Medicine Ordinance, the grading of the degree of disability (GdB) is done by analogy to comparable diseases; depending on severity, values from 10 to 100 are possible, and from GdB 50 one counts as severely disabled [9]. Recognition is often difficult in practice and is frequently only achieved through objection or legal action – but social courts have already granted a GdB of 50 for post-COVID syndrome [10]. In case of lasting incapacity to work, sickness benefit, a (partial or full) reduced-earning-capacity pension from the German pension insurance and participation benefits come into consideration [11].

Rehabilitation and severe illness

Rehabilitation can help but carries risks in PEM: activating, training-based rehab concepts can worsen the condition (push-crash). A German survey study concluded that the idea of rehabilitation in this disease must be "completely rethought" and should be PEM-appropriate and pacing-oriented [12]. In severe illness, care benefits, aids and social support are also important; early advice (care insurance fund, social services, self-help) is worthwhile here.

Important note

mypacing is not a medical device and does not replace diagnosis or therapy. Individual medical, social-law and rehabilitation questions belong in medical or expert hands. There is so far no approved cure – caution is called for with expensive "miracle cures" and promises of quick recovery. Gaps in care and open research questions persist; this text reflects the state of 2025/2026 and may change with new guidelines.

Sources

  1. AWMF S1 guideline "Long/Post-COVID" (020-027), lead DGP, as of 08/2025 — register.awmf.org/de/leitlinien/detail/020-027
  2. NICE Guideline NG206 "Myalgic encephalomyelitis/chronic fatigue syndrome: diagnosis and management" (2021) — nice.org.uk/guidance/ng206
  3. Deutsche Gesellschaft für ME/CFS e.V. – "ME/CFS-Versorgungswüste" — mecfs.de/versorgungswueste
  4. Charité Fatigue Centrum (CFC), Charité – Universitätsmedizin Berlin — cfc.charite.de
  5. Münchner Chronische Fatigue Centrum (MCFC), TU München/Klinikum rechts der Isar — mcfc.mri.tum.de
  6. Fatigatio e.V. – Bundesverband ME/CFS — fatigatio.de
  7. Long COVID Deutschland — longcoviddeutschland.org
  8. #MEAction – Pacing & Management Guides — meaction.net/pacing-and-management-guides
  9. REHADAT-Wissen: Long COVID (disability, GdB, participation) — rehadat-wissen.de/ausgaben/12-long-covid
  10. Long COVID-Plattform: Sozialgericht Speyer recognises GdB 50 for post-COVID syndrome — long-covid-plattform.de
  11. Deutsche Rentenversicherung – reduced-earning-capacity pension — deutsche-rentenversicherung.de
  12. ZEFQ (2024): experiences of affected people with inpatient rehabilitation in Long/Post-COVID — zefq-journal.com … S1865-9217(24)00092-8
  13. PoTSDys e.V. – "PoTS und andere Dysautonomien e.V.", Bochum — pots-dysautonomia.net
© 2026 mypacing · Siegfried Gaier. Diese Wissensbasis ist eine allgemeine, quellengestützte Information — keine individuelle Beratung, keine Therapie- oder Dosierungsempfehlung. Bei Beschwerden entscheidet ärztlicher Rat. Im Notfall: 112.