Síntomas de encefalomielitis miálgica/síndrome de fatiga crónica en pacientes con COVID prolongado. Una revisión sistemática

Symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome among long COVID patients. A systematic review

Introducción. El COVID prolongado es un problema de salud global emergente que comprende múltiples desenlaces adversos, siendo frecuente la aparición de novo de varias condiciones, entre ellas la encefalomielitis miálgica/síndrome de fatiga crónica (EM/SFC).

Objetivo. Analizar la prevalencia de síntomas de EM/SFC (duración >6 meses) en pacientes con COVID prolongado.

Materiales y métodos. Esta revisión sistemática se adhirió a las directrices PRISMA 2020 (número de registro en PROSPERO: CDR42024557707). En mayo de 2024 se realizaron búsquedas sistemáticas en Medline, EBSCOhost, Scopus y Web of Science para identificar estudios que reportaran datos sobre la presencia de síntomas de EM/SFC en pacientes con COVID prolongado (>6 meses desde la infección). También se realizaron búsquedas manuales en Google Scholar. La calidad de los estudios se evaluó con la escala Newcastle-Ottawa. Los síntomas de EM/SFC se clasificaron según lo establecido en los criterios diagnósticos del Instituto de Medicina (IOM) 2015.

Resultados. Se incluyeron 11 estudios en la revisión: 10 de cohorte (7 prospectivos y 3 retrospectivos) y 1 transversal. El tamaño muestral agregado fue de 453 586 personas con COVID prolongado. Los síntomas más frecuentes de EM/SFC en estos pacientes fueron fatiga (56.99%), problemas cognitivos (44.54%), malestar post-esfuerzo (41.55%), sueño no restaurativo (41.08%), jaquecas de intensidad no experimentada antes de la infección por SARS-CoV-2 (31.21%) y mialgia (20.59%). Por el contrario, la inflamación o sensibilidad de los ganglios linfáticos, la sensibilidad a la luz y sonido y las náuseas fueron los síntomas menos prevalentes (5.38%, 4.75% y 0.17%, respectivamente). En ningún estudio hubo pacientes con escalofríos, sudor nocturno y alergia o sensibilidad alimentaria.

Conclusión. Una proporción considerable de pacientes con COVID prolongado cumplió con los criterios IOM 2015 de EM/SFC, siendo fatiga, problemas cognitivos, malestar post-esfuerzo, sueño no restaurativo y cefaleas de intensidad no experimentada antes de la infección por SARS-CoV-2 los síntomas más frecuentes, con prevalencias >41% en los estudios individuales. La heterogeneidad metodológica observada resalta la necesidad de realizar estudios multicéntricos longitudinales para precisar la prevalencia de EM/SFC y de sus síntomas en esta población y, de esta forma, poder orientar intervenciones terapéuticas.

Introduction: Long COVID is an emerging global health issue characterized by multiple adverse outcomes, frequently resulting in the onset of several conditions, including Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

Objective: To analyze the prevalence of ME/CFS symptoms (duration >6 months) among patients with long COVID.

Materials and methods: This systematic review adhered to the PRISMA 2020 guidelines (PROSPERO registration: CDR42024557707). In May 2024, a systematic search was conducted in Medline, EBSCOhost, Scopus, and Web of Science to identify studies reporting data on the presence of ME/CFS symptoms in long COVID patients (>6 months post-infection). Manual searches were also performed in Google Scholar. Study quality was assessed using the Newcastle-Ottawa scale. ME/CFS symptoms were classified according to the Institute of Medicine (IOM) 2015 diagnostic criteria.

Results: Eleven studies were included in the review: 10 cohorts (7 prospective, 3 retrospective) and 1 cross-sectional study. The aggregate sample size was 453 586 persons with long COVID. The most frequent ME/CFS symptoms in these patients were fatigue (56.99%), cognitive impairment (44.54%), post-exertional malaise (41.55%), unrefreshing sleep (41.08%), new-onset severe headaches following SARS-CoV-2 infection (31.21%), and myalgia (20.59%). Conversely, the least prevalent symptoms were lymph node tenderness or swelling (5.38%), sensitivity to light and sound (4.75%), and nausea (0.17%). No studies reported patients with chills, night sweats, or food allergies or sensitivities.

Conclusion: A considerable proportion of patients with long COVID met the IOM 2015 criteria for ME/CFS. Fatigue, cognitive impairment, post-exertional malaise, unrefreshing sleep, and new-onset severe headaches following SARS-CoV-2 infection were the most frequent symptoms, with prevalences >41% in individual studies. The observed methodological heterogeneity highlights the need for multicenter longitudinal studies to determine the prevalence of ME/CFS and its symptoms in this population and, thus, to guide therapeutic interventions.

Systematic review

Felipe Soto1 Juan Valenzuela2 Álvaro González1 Álvaro Becerra1,3

1 Universidad Bernardo O’Higgins - Faculty of Health Sciences - Department of Chemical and Biological Sciences - Santiago de Chile - Chile.

2 Universidad Andrés Bello - Faculty of Medicine - Department of Morphology - Santiago de Chile - Chile.

3 Universidad Bernardo O’Higgins - Faculty of Health Sciences - School of Speech-Language Pathology - Santiago de Chile - Chile.

Open access

Received: 27/01/2025

Accepted: 18/12/2025

Corresponding author: Álvaro Becerra. Departamento de Ciencias Químicas y Biológicas & Escuela de Fonoaudiología, Facultad de Ciencias de la Salud, Universidad Bernardo O’Higgins. Santiago de Chile. Chile. E-mail: al.becerra.f@gmail.com.

Keywords: Post-Acute COVID-19 Syndrome; Fatigue Syndrome, Chronic; Myalgic encephalomyelitis (MeSH).

Palabras clave: Síndrome Post Agudo de COVID-19; Síndrome de Fatiga Crónica; Encefalomielitis Miálgica (DeCS).

How to cite: Soto F, Valenzuela J, González A, Becerra A. Symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in patients with Long COVID. A Systematic Review. Rev. Fac. Med. 2026;74:e118516. English. doi: https://doi.org/10.15446/revfacmed.v74.118516.

Cómo citar: Soto F, Valenzuela J, González A, Becerra A. [Síntomas de encefalomielitis miálgica/síndrome de fatiga crónica en pacientes con COVID prolongado. Una revisión sistemática]. Rev. Fac. Med. 2026;74:e118516. English. doi: https://doi.org/10.15446/revfacmed.v74.118516.

Copyright: ©2026 The Author(s). This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, as long as the original author and source are credited.

Abstract

Resumen

Introduction

According to the World Health Organization (WHO), as of December 2024, more than 771 million confirmed cases of Coronavirus Disease 2019 (COVID-19) had been reported worldwide. This disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in more than 6.9 million deaths.1

A considerable proportion of patients report multiple physical, psychological, and cognitive symptoms following complete recovery from SARS-CoV-2 infection. This is referred to as ‘long COVID’ due to the persistence of these symptoms for weeks, months, or even years.2 Long COVID is defined as a multisystem condition that is often debilitating and involves severe symptoms following SARS-CoV-2 infection;3 however, definitions vary across countries. For example, according to the Centers for Disease Control and Prevention (CDC) in the United States, long COVID is characterized by symptoms lasting more than 28 days after the initial COVID-19 diagnosis. In contrast, the National Institute for Health and Care Excellence (NICE) in the United Kingdom and the WHO define it as symptoms persisting for at least 12 weeks post-diagnosis.2

Based on conservative incidence estimates, although it has been suggested that at least 10% of patients who recover from infection develop long COVID,2,3 this figure is likely to be significantly higher as many COVID-19 cases are not documented.3 This condition affects all individuals who are infected regardless of disease severity, but the probability of its occurrence is strongly related to the severity of COVID-19,2 with an estimated incidence of 10-30% in non-hospitalized cases and 50-70% in patients who require hospitalization.2,3 Nevertheless, since the majority of COVID-19 cases are mild, most long COVID cases occur in these patients.3

Over 200 symptoms associated with this multisystemic condition have been identified,2,3 with the most common being general malaise, fatigue, dyspnea, mental confusion, depression, cough, low-grade fever, headache, palpitations, autonomic dysfunction, persistent loss of smell or taste, dizziness, muscle pain, and joint pain.2

Long COVID encompasses multiple adverse outcomes, including the frequent onset of conditions such as cardiovascular, thrombotic, and cerebrovascular diseases; Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS); and dysautonomia, particularly postural orthostatic tachycardia syndrome (POTS). While symptoms can last for years, in cases of ME/CFS and POTS, they are expected to be lifelong.3

ME/CFS is a complex chronic disorder characterized by significant functional impairment (e.g., exercise intolerance), weakness, severe and incapacitating fatigue that does not improve with rest, unrefreshing sleep, cognitive problems, orthostatic intolerance, muscle and joint pain, post-exertional malaise, mental confusion, and difficulty concentrating, among other symptoms, which may worsen with physical or mental activity.4-6 To be diagnosed, symptoms must persist for at least 6 months,4-6 and it is believed that the disease often occurs after a viral infection, being more common in women.4 The disease is progressive and currently incurable; treatment only helps to alleviate symptoms.6,7

According to various studies, the symptoms most frequently reported by patients with long COVID six months after SARS-CoV-2 infection are chronic fatigue, post-exertional malaise, and mental confusion,4 with chronic fatigue being the most common.5 These symptoms are similar to several of those observed in ME/CFS.4 In this regard, the prevalence of ME/CFS in patients with long COVID, according to the Institute of Medicine diagnostic criteria (IOM 2015 criteria), is at least 43%.4,5

The significant functional impairment caused by ME/CFS, in addition to the serious emotional, physical, and economic repercussions for those who experience it, places a heavy burden on healthcare systems, as more than half of these patients require specialized care services.5 However, this scenario could become even more challenging, as the global prevalence of ME/CFS (close to 1%4) is likely to increase in the coming years due to the high number of people who have been infected with SARS-CoV-2, potentially representing a significant global health issue.

In light of the foregoing, the objective of this systematic review was to analyze the prevalence of ME/CFS symptoms (duration >6 months) in patients with long COVID.

Materials and methods

Protocol and registry

This systematic review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines.8 The protocol was registered in the PROSPERO database under number CDR42024557707 (https://www.crd.york.ac.uk/PROSPERO/view/CRD42024557707).

Sources of information and search strategy

In May 2024, systematic searches were conducted in Medline, EBSCOhost, Scopus, and Web of Science to identify studies published between March 2020 and May 2024 that reported data on the presence of persistent symptoms in patients with long COVID. Specific search strategies were developed for each database using the following combinations of terms: "chronic fatigue syndrome" OR "CFS" OR "chronic fatigue syndrome/myalgic Encephalomyelitis" OR "CFS/ME" OR "myalgic encephalomyelitis" OR "myalgic encephalomyelitis/chronic fatigue syndrome" OR "ME/CFS", AND, "COVID-19" OR "Long COVID-19" OR "Post COVID-19 syndrome". Manual searches were also conducted in Google Scholar up to page 99 in order to identify additional studies.

Eligibility, inclusion, and exclusion criteria

Primary studies reporting information on the presence of persistent symptoms in patients with long COVID were considered eligible. In addition, the following inclusion and exclusion criteria were considered:

Inclusion:

• Studies reporting data on symptoms associated with neuromuscular disease and cognitive impairment lasting ≥6 months since SARS-CoV-2 infection.
• Studies in patients diagnosed with COVID-19 confirmed by PCR, serology, or antigen testing.
• Studies published in English. This language was the only one considered to ensure the accurate interpretation of the complex diagnostic criteria for ME/CFS (IOM 2015 criteria) during data extraction.

Exclusion:

• Studies involving patients in whom SARS-CoV-2 infection was confirmed only by clinical diagnosis.
• Studies with low or acceptable methodological quality.

Study screening and selection process

All records identified in the searches were extracted and compiled using Microsoft Excel and Microsoft Word. After removing duplicates, the titles and abstracts of the studies were read to exclude those that were not relevant to the objective of the review. Next, the full text of the retrieved articles was read to assess their eligibility based on the established inclusion and exclusion criteria. The screening and selection of studies was performed independently by two authors (FS and AB); discrepancies were resolved by consensus among all authors.

Quality assessment

Since none of the selected studies were randomized, quality assessment was performed using the Newcastle-Ottawa Scale (NOS),9 which allows for the assessment of risk of bias in three areas: selection of study groups (4 points), comparability of groups (2 points), and outcomes (3 points). Based on a maximum score of 9 points, a study is considered to have sufficient quality for eligibility if it scores 7-9 (good quality or low risk of bias). Studies with scores <7 were excluded.

Data extraction

The following data were extracted from each of the studies included in the review: first author, year of publication, country, study design, sample size, demographic characteristics of the sample (age, sex), method of SARS-CoV-2 infection confirmation, follow-up time/time of symptom assessment, prevalence of different ME/CFS symptoms (≥6 months), and method used to determine the presence of symptoms.

It is worth noting that symptoms were classified in accordance with the IOM 2015 criteria for the diagnosis of ME/CFS.6 Under these criteria, for a person to be diagnosed with the disease, they must experience: 1) a significant decrease in or limitation to perform activities compared to levels prior to the onset of the disease, accompanied by some level of fatigue (in some cases severe); 2) post-exertional malaise; and 3) unrefreshing sleep. Furthermore, patients must present one of the following clinical manifestations: cognitive impairment and/or orthostatic intolerance; however, other common symptoms may also be found, including myalgia, joint pain without inflammation, headaches, tenderness or swelling of the lymph nodes in the neck and armpits, frequent or recurrent sore throat, nausea, among others. Symptoms must persist for 6 or more months with moderate, substantial, or severe intensity for at least half of the time.

Data was systematically organized in a standardized template created in Microsoft Excel. Data were extracted independently by two reviewers (FS and JV); discrepancies were resolved by consensus, thus obtaining a final data matrix.

Data analysis

The lack of data on the prevalence of different ME/CFS symptoms in several articles and the heterogeneity between studies (e.g., substantial differences in population size, sex of participants not indicated in some studies) prevented us from performing a meta-analysis. Instead, descriptive measures for the prevalence of each symptom according to the IOM 2015 criteria are presented, which were calculated by dividing the sum of the percentages for each symptom reported in each article by the total number of studies in which such data were reported.

Results

Study search, screening, and selection

A total of 6 665 records were retrieved in the searches: 5 932 in electronic databases and 733 in Google Scholar. After removing duplicates (n=5 392), 1 273 records were identified, of which 925 were excluded during the title and abstract screening stage; an additional 221 records were excluded as the full text was not available. Of the 127 studies evaluated for eligibility through full-text reading, 24 were selected for inclusion; however, 13 had a NOS score <7, so 11 studies were ultimately included for analysis. The study identification, screening, and selection process is depicted in Figure 1 (PRISMA flowchart), while the results of the NOS quality assessment are available in Annex 1.

Figure 1. PRISMA flow chart of the study identification, screening, and selection process.

NOS: Newcastle-Ottawa Scale.

Source: Adapted from Page et al.8

Study characteristics

All the studies included were observational: 10 cohort studies (7 prospective and 3 retrospective) and 1 cross-sectional study. The aggregate sample size was 453 586 individuals with a confirmed diagnosis of SARS-CoV-2 infection, with individual samples ranging from 10 to 391 990 participants. The post-infection evaluation period ranged from 3 to 24 months. The main characteristics of the 11 studies are described in Table 1.

Table 1. Main characteristics of the included studies (n=11).

Author (year)	Country	Study design	Source or place of data collection	Sample	Method of SARS-CoV-2 infection confirmation	Post-SARS-CoV-2 infection evaluation period	Data collection methods used in the study
Mantovani et al.10 (2021)	Italy	Cross-sectional	Verona University Hospital	37 patients with confirmed SARS-CoV-2 infection Age range: 18-65 years Mean age: 51.9±10.9 years Sex: F: 12 M:25	PCR	>6 months	Semi-structured clinical interview based on the ME International Consensus Criteria. Fatigue was assessed using the Multidimensional Fatigue Inventory (MFI), and cognitive function was assessed using the Montreal Cognitive Assessment (MoCA)
Simani et al.11 (2021)	Iran	Prospective	Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences	120 patients with confirmed SARS-CoV-2 infection Mean age: 54.62±16.94 years Sex: F: 40 M: 80	PCR	6 months	Validated questionnaire based on Fukuda’s diagnostic criteria
Kedor et al.12 (2022)	Germany	Prospective	Charité – Universitätsmedizin Berlin	42 patients with confirmed SARS-CoV-2 infection Mean age: 36.5 years Sex: F: 29 M: 13	PCR	6 months	Clinical assessment questionnaire based on the Canadian Consensus Criteria for ME/CFS. Mental and physical fatigue was assessed using the Chalder Fatigue Score (CFQ)
Sørensen et al.13 (2022)	Denmark	Prospective	Nationwide questionnaire study in Denmark	61 002 patients with confirmed SARS-CoV-2 infection Age: 34-60 years old Mean age: 49 years old Sex: F: 35 830 M: 25 172	PCR	6, 9, and 12 months	Questionnaire designed to assess symptoms following the acute phase of COVID-19 through questions about symptoms in the last 14 days, health conditions diagnosed before and after the COVID-19 diagnostic test, and physical and neurocognitive symptoms 6 months before and up to 6-12 months after testing positive for the infection. Also, regarding the symptoms and health conditions reported by participants, they were asked if they used to experience them regularly before the test
Donnachie et al.14 (2022)	Germany	Retrospective	Bavarian Association of Statutory Health Insurance Physicians	391 990 patients with confirmed SARS-CoV-2 infection Mean age: 42.3±21.0 years Sex: F: 212 087 M: 179 903	PCR	9-24 months (at least 9 months and up to 24 months)	Review of medical consultation data in Bavaria up to March 31, 2022, for patients with a confirmed diagnosis of COVID-19 between January 2020 and June 2021. Information on diagnoses and symptoms related to post-COVID syndrome was collected using the German Modification of the International Classification of Diseases 10th Revision (ICD-10-GM) classification
Oliveira et al.15 (2023)	United States	Prospective	Centro Bateman Horne, Salt Lake City, UTAH	34 patients with confirmed SARS-CoV-2 infection Age: 36-49 years old Mean age: 44 years old Sex: F: 29 M: 5	PCR, antigen, or serology	>12 months	DePaul Symptom Questionnaire (DSQ)
Magel et al.16 (2023)	Canada	Prospective	Post-COVID-19 Recovery Clinic (PCRC) in Vancouver	88 patients with confirmed SARS-CoV-2 infection Age: ≥18 years Mean age: 61.1±16.2 years Sex: F: 32 M: 56	PCR	3 and 6 months	EuroQoL 5-Dimensions (EQ-5D), Frailty Index (FI), University of California San Diego Shortness of Breath Questionnaire (UCSD), Patient Health Questionnaire-9 (PHQ-9) and Pittsburgh Sleep Quality Index (PSQI)
Bonilla et al.17 (2023)	United States	Retrospective	Stanford referral Post-Acute COVID-19 Syndrome (PACS) Clinic	134 patients with confirmed SARS-CoV-2 infection Age: 20-88 years old Mean age: 47 years old Sex: F: 79 M: 55	PCR, antigen, or serology	>6 months	Questionnaire based on the 2015 Institute of Medicine diagnostic criteria for ME/CFS
Legler et al.18 (2023)	Germany	Prospective	Charité’s Fatigue Centre and the Charité’s outpatient clinic for neuroimmunology at Berlin	106 patients with confirmed SARS-CoV-2 infection Age: 19-66 years Mean age: 40 years Sex: F: 85 M: 21	PCR or serology	>9 months	Clinical assessment questionnaire based on the Canadian Consensus Criteria for ME/CFS
Domingo et al.19 (2024)	Spain	Prospective	ME/CFS Clinical Unit, Vall d’Hebron University Hospital, Barcelona	23 patients with confirmed SARS-CoV-2 infection Age: ≥18 years Mean age: 48.7±2.4 years Sex: F: 15 M: 8	PCR	>6 months	Clinical assessment questionnaire based on the international consensus criteria (2011 ICC) for ME/CFS
Peo et al.20 (2024)	Germany	Retrospective	University Hospital of the Technical University of Munich	10 patients with confirmed SARS-CoV-2 infection Age: 11-25 years old Sex: F: 7 M: 3	PCR	3 and 6 months	Munich Berlin Symptom Questionnaires (MBSQs) and supplementary scoring sheets (SSSs). The MBSQ assesses the 2015 Institute of Medicine diagnostic criteria and the Canadian Consensus Criteria for ME/CFS, requiring a disease duration of at least 6 months in adults. Furthermore, the clinical criteria for ME/CFS were assessed using semi-structured interviews

ME/CFS: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Source: Own elaboration.

Geographical distribution of patients is presented on a logarithmic scale (ln), where a lighter blue shade represents a lower volume of patients, while a darker blue shade represents a higher volume. Germany was the country with the highest contribution of patients (12.88), followed by Denmark (11.02), the United States (5.12), Iran (4.79), Canada (4.48), Italy (3.61), and Spain (3.14) (Figure 2). In this regard, 4 (36.36%) studies were conducted in Germany and 2 (18.18%) in the United States, while the remaining 5 studies (45.45%) were conducted in Iran, Canada, Denmark, Italy, and Spain (9.09% each).

Figure 2. Geographical distribution of patients with long COVID from the 11 studies analyzed.

Source: Own elaboration.

Prevalence of ME/CFS symptoms reported in the studies included in the review

All studies reported data on the prevalence of fatigue (9.8%–100%), while the prevalence of cognitive problems was described in 8 studies (0.6%–100%). The prevalence of unrefreshing sleep and new-onset severe headaches following SARS-CoV-2 infection was reported in seven studies (22.9%–85.7% and 6.1%–90.4%). The prevalence of post-exertional malaise was described in six studies (30.0%–100%). Five studies reported data on the prevalence of orthostatic intolerance and myalgia (4.0%–85.7% and 4.2%–84.9%). The prevalence of frequent or recurrent sore throat ranged from 3.7% to 59.5% (4 studies). The prevalence of joint pain, lymph node tenderness or swelling, and visual impairment was reported in 2 studies (62.3%–83.3%, 28.3%–30.9%, and 54.8%–66.9%). Only 1 study provided data on the prevalence of light and sound sensitivity and nausea (52.2% and 1.9%). No study reported patients with chills, night sweats, or food allergies or sensitivities (Table 2).

Table 2. Prevalence of ME/CFS symptoms (according to the 2015 Institute of Medicine criteria) reported in the studies included in the review (n=11).

Symptoms		Prevalence (%) by study
		Mantovani et al.10	Simani et al.11	Kedor et al.12	Sørensen et al.13	Donnachie et al.14	Oliveira et al.15	Magel et al.16	Bonilla et al.17	Legler et al.18	Domingo et al.19	Peo et al.20
Key symptoms	Fatigue	27.0	17.5	100	11.1	9.8	56.2	59.5	85.8	100	100	60.0
	Post-exertional malaise	-	-	100	-	-	46.9	-	82.8	97.2	100	30.0
	Unrefreshing sleep	51.3	-	85.7	22.9	-	45.0	-	76.1	83.9	87	-
Additional manifestations	Cognitive problems	60.9	-	83.3	66.4	0.6	38.1	-	80.6	-	100	60.0
	Orthostatic intolerance	-	-	85.7	4.0	-	23.8	-	-	-	26	17.2
Other common symptoms	Myalgia	-	23.5	83.3	-	4.2	30.6	-	-	84.9	-	-
	Arthralgia without swelling or redness	-	-	83.3	-	-	-	-	-	62.3	-	-
	New-onset severe headaches following SARS-CoV-2 infection	-	9.2	90.4	6.1	-	-	-	64.9	88.7	74	10.0
	Lymph node tenderness or swelling (neck and axillae)	-	-	30.9	-	-	-	-	-	28.3	-	-
	Frequent or recurring sore throat	-	-	59.5	3.7	-	-	-	36.6	16.5	-	-
	Chills and night sweats	-	-	-	-	-	-	-	-	-	-	-
	Visual impairment	-	-	54.8	-	-	-	-	-	66.9	-	-
	Sensitivity to light and sound	-	-	-	-	-	-	-	52.2	-	-	-
	Nausea	-	-	-	1.9	-	-	-	-	-	-	-
	Food allergies or sensitivities	-	-	-	-	-	-	-	-	-	-	-

Source: Own elaboration.

Prevalence of ME/CFS symptoms in patients with long COVID

After calculating the prevalence of each ME/CFS symptom using the methodology described in the statistical analysis subsection, it was found that the most frequent symptoms were fatigue (56.99%), cognitive impairment (44.54%), and post-exertional malaise (41.55%), while the least common were sensitivity to light and sound (4.75%) and nausea (0.17%) (Figure 3).

Figure 3. Prevalence of ME/CFS symptoms in patients with long COVID.

Source: Own elaboration.

Discussion

The results of this systematic review indicate that the most common symptoms of
ME/CFS in patients with long COVID were fatigue (56.99%), cognitive impairment (44.54%), post-exertional malaise (41.55%), unrefreshing sleep (41.08%), and new-onset severe headaches following SARS-CoV-2 infection (31.21%). Furthermore, in some studies, the prevalence of fatigue,12,17,18,19 unrefreshing sleep,12,18,19 post-exertional malaise,12,17,18,19 orthostatic intolerance,12 and new-onset severe headaches following SARS-CoV-2 infection12,18 was >80% or even 100%.

According to the IOM 2015 criteria, for a person to be diagnosed with ME/CFS, they must experience fatigue, post-exertional malaise, and unrefreshing sleep for at least 6 months, as well as at least one of the following clinical manifestations: cognitive impairment and/or orthostatic intolerance. In light of the above, it is estimated that 41.08% of patients with long COVID met the IOM 2015 diagnostic criteria for ME/CFS (i.e., fatigue, post-exertional malaise, unrefreshing sleep, and cognitive impairment) (Figure 1).

These findings are in part consistent with other systematic reviews on the prevalence of persistent symptoms in patients with COVID-19.21,22 For example, the systematic review and meta-analysis conducted by Dehlia et al.21 (13 studies; 1 973 patients in total) reported a higher proportion of patients meeting the diagnostic criteria for ME/CFS (51%, 95%CI: 42%-60%), which could be attributed to methodological differences. While Dehlia et al.21 included studies with various diagnostic criteria (i.e., Fukuda 1994, Canadian Consensus, International Consensus, IOM 2015), in our systematic review, symptoms were classified solely according to the IOM 2015 criteria, and compliance with all criteria in each patient was not evaluated. Another aspect to consider is that Dehlia et al.21 performed a formal meta-analysis of proportions, whereas we calculated aggregate prevalences weighted by sample size. The heterogeneity at the time of post-infection assessment (3–24 months in our review versus variable times in Dehlia et al.21) should also be considered, as it influences estimates, given that some patients may recover over time. However, both reviews concur in identifying fatigue, post-exertional malaise, sleep disturbances, and cognitive impairment as the most prevalent symptoms, supporting the validity of these findings.

Similarly, in a systematic review and meta-analysis on the prevalence and duration of common symptoms in patients with long COVID (19 studies), Luo et al.22 reported prevalences of neurological and systemic symptoms that allow for relevant extrapolation, including cognitive/memory/attention disorders (36%), fatigue (34%), mental health disorders such as anxiety and depression (31%), dyspnea (24%), and chest pain (23%). Although Luo et al.22 did not specifically address the diagnosis of ME/CFS, these prevalences are remarkably similar to those observed in our review for the same key symptoms of this disease according to the IOM 2015 criteria, suggesting that a significant proportion of patients with long COVID exhibit the characteristic symptom profile of ME/CFS, regardless of whether they formally receive that diagnosis. The consistency between these reviews reinforces the validity of our findings and underscores the need to implement specific diagnostic screening tools for ME/CFS in individuals with long COVID, as many patients may meet the criteria without being clinically identified.

This systematic review has several limitations that should be considered when interpreting the results. First, methodological heterogeneity between studies in aspects such as design (7 prospective cohorts, 3 retrospective cohorts, 1 cross-sectional), diagnostic criteria used (IOM 2015, Fukuda 1994, Canadian Consensus, International Consensus), post-infection evaluation times (3-24 months), and sample size (10-391 990 patients) prevented us from performing a formal meta-analysis and restricted the direct comparability between studies. Second, the search process may have been subject to selection bias, as only databases, mainly in English, were used and articles in the same language were included, which could have resulted in the exclusion of relevant studies in other languages or in non-indexed journals. In any case, to somewhat mitigate this limitation, complementary manual searches were conducted in Google Scholar, although this platform does not guarantee the exhaustive retrieval of all available reports. Third, the development of ME/CFS in patients with long COVID is an emerging clinical phenomenon that needs to be better understood. This requires the standardization of symptom definitions and the validation of specific diagnostic criteria for this population.

Conclusion

This systematic review demonstrates that a considerable proportion of patients with long COVID met the IOM 2015 criteria for ME/CFS. The most prevalent symptoms were fatigue, cognitive impairment, post-exertional malaise, unrefreshing sleep, and new-onset severe headaches following SARS-CoV-2 infection, all with prevalences exceeding 30% in individual studies, even reaching 100% in some cases. In contrast, symptoms such as nausea, sensitivity to light and sound, or lymph node tenderness or swelling were rarely reported or virtually absent. These findings reinforce the hypothesis of a pathophysiological overlap between long COVID and ME/CFS. However, methodological heterogeneity and the lack of specific biomarkers make it difficult to accurately estimate global prevalence. Longitudinal, multicenter studies are needed to standardize clinical definitions and inclusion criteria to better understand the pathophysiological progression of ME/CFS in these patients and thus guide more effective diagnostic and therapeutic interventions.

Conflicts of interest

None stated by the authors.

Funding

None stated by the authors.

Acknowledgments

To Dr. Francisco Westermeier for his proofreading and insightful comments on the manuscript.

References

1.World Health Organization (WHO). COVID-19) Cases, World [Internet]. Geneva: WHO; 2024 [cited 2024 May 28]. Available from: https://tinyurl.com/273rmc4x.

2.Chippa V, Aleem A, Anjum F. Postacute Coronavirus (COVID-19) Syndrome. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 [cited 2026 Feb 6]. Available from: https://tinyurl.com/2vffp8f4.

3.Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21(3):133-46. doi: 10.1038/s41579-022-00846-2. Erratum in: Nat Rev Microbiol. 2023;21(6):408. doi: 10.1038/s41579-023-00896-0. PMID: 36639608; PMCID: PMC9839201.

4.Bonilla H, Quach TC, Tiwari A, Bonilla AE, Miglis M, Yang PC, et al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome is common in post-acute sequelae of SARS-CoV-2 infection (PASC): Results from a post-COVID-19 multidisciplinary clinic. Front Neurol. 2023;14:1090747. doi: 10.3389/fneur.2023.1090747. PMID: 36908615; PMCID: PMC9998690.

5.Salari N, Khodayari Y, Hosseinian-Far A, Zarei H, Rasoulpoor S, Akbari H, et al. Global prevalence of chronic fatigue syndrome among long COVID-19 patients: A systematic review and meta-analysis. Biopsychosoc Med. 2022;16(1):21. doi: 10.1186/s13030-022-00250-5. PMID: 36274177; PMCID: PMC9589726.

6.Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Populations; Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness [Internet]. Washington D.C.: National Academies Press (US); 2015 [cited 2026 Feb 6]. Available from: https://tinyurl.com/3cp62v8s.

7.Toogood PL, Clauw DJ, Phadke S, Hoffman D. Myalgic encephalomyelitis/chronic fatigue syndrome
(ME/CFS): Where will the drugs come from? Pharmacol Res. 2021;165:105465. doi: 10.1016/j.phrs.2021.105465. PMID: 33529750.

8.Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi: 10.1136/bmj.n71. PMID: 33782057; PMCID: PMC8005924.

9.Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses [Internet]. The Ottawa Hospital Research Institute; 2024 [cited 2024 May 30]. Available from: https://tinyurl.com/bdz9f4mh.

10.Mantovani E, Mariotto S, Gabbiani D, Dorelli G, Bozzetti S, Federico A, et al. Chronic fatigue syndrome: an emerging sequela in COVID-19 survivors? J Neurovirol. 2021;27(4):631-7. doi: 10.1007/s13365-021-01002-x. PMID: 34341960; PMCID: PMC8328351.

11.Simani L, Ramezani M, Darazam IA, Sagharichi M, Aalipour MA, et al. Prevalence and correlates of chronic fatigue syndrome and post-traumatic stress disorder after the outbreak of the COVID-19.
J Neurovirol. 2021;27(1):154-9. doi: 10.1007/s13365-021-00949-1. PMID: 33528827; PMCID: PMC7852482.

12.Kedor C, Freitag H, Meyer-Arndt L, Wittke K, Hanitsch LG, Zoller T, et al. A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity. Nat Commun. 2022;13(1):5104. doi: 10.1038/s41467-022-32507-6. Erratum in: Nat Commun. 2022;13(1):6009. doi: 10.1038/s41467-022-33784-x. PMID: 36042189; PMCID: PMC9426365.

13.Sørensen AIV, Spiliopoulos L, Bager P, Nielsen NM, Hansen JV, Koch A, et al. A nationwide questionnaire study of post-acute symptoms and health problems after SARS-CoV-2 infection in Denmark. Nat Commun. 2022;13(1):4213. doi: 10.1038/s41467-022-31897-x. PMID: 35864108; PMCID: PMC9302226.

14.Donnachie E, Hapfelmeier A, Linde K, Tauscher M, Gerlach R, Greissel A, et al. Incidence of post-COVID syndrome and associated symptoms in outpatient care in Bavaria, Germany: a retrospective cohort study using routinely collected claims data. BMJ Open. 2022;12(9):e064979. doi: 10.1136/bmjopen-2022-064979. PMID: 36137635; PMCID: PMC9511014.

15.Oliveira CR, Jason LA, Unutmaz D, Bateman L, Vernon SD. Improvement of Long COVID symptoms over one year. Front Med (Lausanne). 2023;9:1065620. doi: 10.3389/fmed.2022.1065620. PMID: 36698810; PMCID: PMC9868805.

16.Magel T, Meagher E, Boulter T, Albert A, Tsai M, Muñoz C, et al. Fatigue presentation, severity, and related outcomes in a prospective cohort following post-COVID-19 hospitalization in British Columbia, Canada. Front Med (Lausanne). 2023;10:1179783. doi: 10.3389/fmed.2023.1179783. PMID: 37457578; PMCID: PMC10344448.

17.Bonilla H, Quach TC, Tiwari A, Bonilla AE, Miglis M, Yang PC, et al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome is common in post-acute sequelae of SARS-CoV-2 infection (PASC): Results from a post-COVID-19 multidisciplinary clinic. Front Neurol. 2023;14:1090747. doi: 10.3389/fneur.2023.1090747. PMID: 36908615; PMCID: PMC9998690.

18.Legler F, Meyer-Arndt L, Mödl L, Kedor C, Freitag H, Stein E, et al. Long-term symptom severity and clinical biomarkers in post-COVID-19/chronic fatigue syndrome: results from a prospective observational cohort. EClinicalMedicine. 2023;63:102146. doi: 10.1016/j.eclinm.2023.102146. PMID: 37662515;
PMCID: PMC10469383.

19.Domingo JC, Battistini F, Cordobilla B, Zaragozá MC, Sanmartin-Sentañes R, Alegre-Martin J, et al. Association of circulating biomarkers with illness severity measures differentiates myalgic encephalomyelitis/chronic fatigue syndrome and post-COVID-19 condition: a prospective pilot cohort study.
J Transl Med. 2024;22(1):343. doi: 10.1186/s12967-024-05148-0. PMID: 38600563; PMCID: PMC11005215.

20.Peo LC, Wiehler K, Paulick J, Gerrer K, Leone A, Viereck A, et al. Pediatric and adult patients with ME/CFS following COVID-19: A structured approach to diagnosis using the Munich Berlin Symptom Questionnaire (MBSQ). Eur J Pediatr. 2024;183(3):1265-76. doi: 10.1007/s00431-023-05351-z. Erratum in: Eur J Pediatr. 2025;184(5):302. doi: 10.1007/s00431-025-06112-w. PMID: 38095713; PMCID: PMC10951047.

21.Dehlia A, Guthridge MA. The persistence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) after SARS-CoV-2 infection: A systematic review and meta-analysis. J Infect. 2024;89(6):106297. doi: 10.1016/j.jinf.2024.106297. PMID: 39353473.

22.Luo S, Lai LY, Zhu R, Gao Y, Zhao Z. Prevalence and duration of common symptoms in people with long COVID: a systematic review and meta-analysis. J Glob Health. 2025;15:04282. doi: 10.7189/jogh.15.04282. PMID: 41104805; PMCID: PMC12532441.

Annex 1. New Castle-Ottawa Scale (NOS).

Study	Selection				Comparability		Results			Total (9/9)
	S1	S2	S3	S4	C1	C2	O1	O2	O3
Simani et al. 2021	★	★	★	-	★	★	★	-	★	7/9
Martínez-Alvarado et al. 2021	★	-	★	-	★	★	★	-	★	7/9
Menna & Heba 2021	★	★	★	-	★	★	★	-	-	6/9
Murga et al. 2021	★	-	★	-	★	★	★	-	★	6/9
Mantovani et al. 2021	★	★	★	-	★	★	★	-	★	7/9
Komaroff 2022	★	-	★	-	★	★	★	-	★	6/9
Rybakova et al. 2022	★	-	★	-	★	-	★	-	★	5/9
Shaheen & Shahen 2022	★	★	★	-	★	-	★	-	★	6/9
Retonaz et al. 2022	★	-	★	-	★	★	★	-	★	6/9
Donnachie et al. 2022	★	★	★	-	★	-	★	★	★	7/9
Sotzny et al. 2022	★	-	★	-	★	★	★	-	★	6/9
Orzuka et al. 2022	★	★	★	-	★	-	★	-	★	6/9
Mirfazeli et al. 2022	★	★	★	-	★	-	★	-	★	6/9
Kedor et al. 2022	★	-	★	-	★	★	★	★	★	7/9
Vedel-Sørensen et al. 2022	★	★	★	-	★	★	★	★	★	8/9
Thomas 2022	★	-	★	-	★	-	★	-	★	5/9
Takakazu 2023	★	-	★	-	-	-	-	★	★	4/9
Olivera et al. 2023	★	★	★	-	★	★	★	★	★	8/9
Maggel et al. 2023	★	-	★	-	★	★	★	★	★	7/9
Bonilla et al. 2023	★	-	★	-	★	★	★	★	★	7/9
Legler et al. 2023	★	-	★	-	★	★	★	★	★	7/9
Reuken et al. 2023	★	-	★	-	★	★	★	★	-	6/9
Peo et al. 2023	★	-	★	★	★	★	★	★	★	8/9
Domingo et al. 2024	★	★	★	-	★	★	★	★	★	8/9

S1: representativeness of the presented cohort; S2: external control selection; S3: exposure determination; S4: result of interest is not available at the start of the study; C1: main factors; C2: additional factors; O1: evaluation of results; O2: sufficient follow-up time; O3: proper follow-up.