Last reviewed: 18 Sep 2021
Last updated: 12 Jan 2021



History and exam

Key diagnostic factors

  • persistent disabling fatigue
  • post-exertional malaise/fatigue (PEM), exertional exhaustion
  • short-term memory and/or concentration impairment
  • sore throat
  • generalised arthralgia without inflammation
  • headache/migraine with onset after the fatigue
  • unrefreshing sleep
  • orthostatic intolerance
  • diffuse muscular, tendon, fascial, and other pain
  • tender lymph nodes

Other diagnostic factors

  • age of onset (adolescence and 30 to 50 years)
  • flu-like symptoms (malaise, myalgia, feverishness)
  • dizziness/lightheadedness
  • anxiety, affective disorder, atypical depression
  • sensations of altered temperature
  • exertion-induced cognitive dysfunction (affecting working memory, not persistent)
  • irritant sensitivities
  • feverishness

Risk factors

  • female sex
  • Epstein-Barr infection in adolescents
  • positive family history of CFS/ME
  • genetic factors
  • specific infectious diseases in adults
  • autoimmunity
  • gut microbiome
  • psychological factors
  • major depressive disorder
  • ancestry
  • joint hypermobility/laxity

Diagnostic investigations

1st investigations to order

  • DePaul symptom questionnaire
  • FBC with WBC differential
  • erythrocyte sedimentation rate
  • CRP
  • comprehensive metabolic panel
  • thyroid-stimulating hormone
  • antinuclear antibody (ANA), rheumatoid factor
  • HIV antibody test

Investigations to consider

  • heads-up tilt-table test if symptomatic orthostatic intolerance
  • serum ferritin
  • HbA1c
  • urine toxicology screen
  • antibody tests for gluten sensitivity/coeliac disease

Emerging tests

  • 2-day cardiopulmonary exercise testing

Treatment algorithm



James N. Baraniuk, MD
James N. Baraniuk


Division of Rheumatology, Immunology, and Allergy

Georgetown University




JNB declares that he has no competing interests.


Dr James N. Baraniuk would like to gratefully acknowledge Dr Craig N. Sawchuk and Dr Dedra Buchwald, previous contributors to this topic.


CNS declares that he has no competing interests. DB is an author of a number of references cited in this topic. This topic was reviewed in 2018 by a patient with CFS/ME, and their feedback was considered as part of the topic update. The patient peer reviewer does not wish to be named.

Peer reviewers

Alastair Santhouse, MA (Cantab), MB, B.Chir, FRCP, FRCPsych

Consultant Psychiatrist in Psychological Medicine

South London and Maudsley NHS Foundation Trust

Denmark Hill




AS declares that he was a guideline development group member for NICE CFS/ME 2007 guidelines CG53.

Ben Z. Katz, MD

Professor of Pediatrics

Division of Infectious Diseases

Northwestern University Feinberg School of Medicine

Attending Physician

Ann & Robert H. Lurie Children’s Hospital of Chicago




BZK declares that he has no competing interests.

Indre Bileviciute-Ljungar, MD, PhD

Associated Professor in Rehabilitation Medicine

Department of Clinical Sciences

Danderyd University Hospital

Karolinska Institutet




IB-L declares that he has no competing interests.

Tarek Gaber, MB, BCh, MSc, FRCP

Consultant Physician in Rehabilitation Medicine

Wrightington, Wigan and Leigh NHS Trust

Leigh Infirmary




TG declares that he has no competing interests.

Malcolm Hooper, PhD, B Pharm, MRIC, C Chem

ME patient advocate

Emeritus Professor of Medicinal Chemistry

University of Sunderland




MH has lectured on ME and made national and international presentations to groups concerned with ME in Denmark, Sweden, Australia, US, and UK. He has acted as a witness for the GMC (UK) and received payment for this (travel and subsistence). He has also received payment from a family he supported in legal proceedings relating to vaccine damage, after the case was settled in their favour. He is a founder member of the Academy Of Nutritional Medicine, which has a special interest in Lyme disease. Their guidelines mention ME/CFS several times. He has given their keynote address for 3 years. He is the author of the paper Hooper M. Myalgic encephalomyelitis: a review with emphasis on key findings in biomedical research. J Clin Pathol. 2007;60:466-71. He is a member of the trustees for the John Richardson Research Group and the ME research group. He is also a trustee of European Services for People with Autism (ESPA) and a member of ESPA-Research, which is developing techniques to help with this condition. All of this work is voluntary.

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