2) Case definitions of ME/CFS should require the presence of post-exertional malaise Post-exertional malaise (PEM) or a marked symptom exacerbation after minimal exertion is considered to be the hallmark symptom of ME/CFS and should therefore be a mandatory requirement in diagnostic criteria for this illness. For several decades, PEM has been described as the characteristic symptom of ME/CFS. In 1985, Behan et al. emphasized that all of the 50 postviral fatigue syndrome patients in their study had “the same primary symptom that of gross fatigue made worse by exercise.”  Thirty years later, an influential report by the National Academy of Medicine described ME/CFS as a systemic exertion intolerance disease, noting there to be “sufficient evidence that PEM is a primary feature that helps distinguish ME/CFS from other conditions.”  PEM helps to differentiate ME/CFS from related conditions such as depression , multiple sclerosis  or chronic idiopathic fatigue  and is predictive of a poor prognosis . Some of the characteristics of PEM may be unique to the ME/CFS patient population. An in-depth investigation of PEM by researchers at Stanford University concluded: “There exists no medical condition the authors are familiar with where exertion or emotional distress causes immune/ inflammatory-related symptoms like sore throat, tender lymph nodes, or flu-like feelings, yet 60% and 36% of our subjects, respectively, reported these symptoms with either stimuli and about a quarter experienced all 3 with exertion.”  We therefore recommend that diagnostic criteria for ME/CFS require the presence of PEM. The most commonly used case definition, the so-called Fukuda-criteria , do not meet these standards and should therefore be amended or retired. References:  Behan PO, Behan WM, Bell EJ. The postviral fatigue syndrome--an analysis of the findings in 50 cases. J Infect. 1985 May;10(3):211-22.  Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, D.C.: The National Academies Press, 2015.  Hawk C, Jason LA, Torres-Harding S. Differential diagnosis of chronic fatigue syndrome and major depressive disorder. Int J Behav Med. 2006;13(3):244-51.  Cotler J, Holtzman C, Dudun C, Jason LA. A Brief Questionnaire to Assess Post-Exertional Malaise. Diagnostics (Basel). 2018 Sep 11;8(3). pii: E66.  Maes M, Twisk FN, Johnson C. Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS), and Chronic Fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data. Psychiatry Res. 2012 Dec 30;200(2-3):754-60.  Taylor RR, Jason LA, Curie CJ. Prognosis of chronic fatigue in a community-based sample. Psychosom Med. 2002 Mar-Apr;64(2):319-27  Chu L, Valencia IJ, Garvert DW, Montoya JG. Deconstructing post-exertional malaise in myalgic encephalomyelitis/ chronic fatigue syndrome: A patient-centered, cross- sectional survey. PLoS One. 2018 Jun 1;13(6):e0197811.  Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994 Dec 15;121(12):953-9.