Diagnostics, Biomarkers & Differentiation

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.