Non-Pharmacological Therapies for Post-Viral Syndromes, Including Long COVID: A Systematic Review
2. Materials and Methods
- Population: The population of interest consisted of adults and children with a PVS (including Long COVID). There is no universally agreed definition of PVS, as there is heterogeneity in the temporal description of PVS onset following the initial viral exposure and additional overlap with the definition of post-viral fatigue syndrome (PVFS; ICD-10 G93.3) [18,19,20]. In line with the minimum timeframe for Long COVID used by the World Health Organization (WHO), where the temporal criteria were described, we included only those studies where post-viral symptoms lasted beyond 12 weeks . However, we also included publications that provided no firm timeframe but indicated an aspect of chronicity or prolonged persistence of symptoms, as it should be noted conditions, such as PVFS, are usually denoted as a condition lasting for more than 6 months .
- Intervention and comparator: We included studies that assessed the effectiveness of non-pharmacological interventions designed to improve the symptoms of PVS against standard care, an alternative non-pharmacological therapy, or a placebo.
- Outcomes: The outcomes were changes in symptoms, exercise capacity, quality of life (including changes in mental and physical wellbeing) and work capability.
- Study type: Only randomised controlled trials (RCT) were included for patients with PVS, for conditions other than COVID-19. However, as we anticipated a lack of RCTs for SARS-CoV-2, we also included observational studies where the viral pathogen was SARS-CoV-2.
2.1. Information Sources and Search Strategy
2.2. Study Selection
- Randomised controlled trials of non-pharmacological treatments/interventions for those with PVS.
- Randomised controlled trials and non-randomised observational studies report non-pharmacological treatments/interventions specifically designed for Long COVID.
- Pharmacological interventions;
- In vitro and animal studies;
- Case reports/series;
- Systematic reviews;
- Non-pharmacological treatments/interventions in non-viral conditions;
- Protocols of trials.
2.3. Data Extraction and Quality Appraisal
2.4. Narrative Synthesis
2.5. Patient and Public Involvement
3.1. Description of Studies
3.2. Risk of Bias in Included Studies
3.3. Effects of Interventions
3.5. Music Therapy in Combination with Cognitive Behavioural Therapy
3.6. Resistance Exercises
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
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|Study Characteristics||Viral Definitions||Inclusion/Exclusion Criteria||Baseline Characteristics|
|Authors||Virus Being Studied||Definition of Post-Viral Syndrome and Symptoms Reported by Patient Groups:||Inclusion||Exclusion||Intervention Group||Comparator Group||Overall|
|Authors: Li et al.  2021|
Study period: 2020
|SARS-CoV-2||Definition: No time length specified but average time from hospital discharge to baseline was 70.07 days|
|18–75 years old; Discharged from one of the three participating hospitals (three major hospitals in Jiangsu and Hubei provinces in China: Jiangsu Province Hospital/Nanjing|
Medical University First Affiliated Hospital, Hubei Province Hospital of Integrated Chinese and Western Medicine, and Hubei Huangshi Hospital of Chinese Medicine) after having inpatient treatment for COVID-19; and had a modified British Medical Research Council (mMRC) dyspnoea score of 2–3.
|Patients with an mMRC score of 4–5 were excluded for safety reasons; Other exclusion: resting heart rate over 100 bpm, uncontrolled hypertension, uncontrolled chronic disease (e.g., diabetes with random blood glucose >16.7mmol/L, haemoglobin A1C >7.0%), cerebrovascular disease within 6 months, intra-articular drug injection or surgical treatment of lower extremities within 6 months, taking medication affecting cardiopulmonary function such as bronchodilators or beta-blockers, unable to walk independently with assistive device, unable or unwilling to collaborate with assessments, enrolled or participated in other trials within the past 3 months, having a history of severe cognitive or mental disorder or substance abuse, enrolment in other rehabilitation programme.||N = 59|
Male: 27 (46%)
Female: 32 (54%)
Age: 49.2 (SD 10.8)
|N = 60|
Male: 26 (43%)
Female: 34 (57%)
Age: 52.0 (SD 11.1)
|N = 119|
Male: 53 (45%)
Female: 66 (55%)
Age: 50.6 (SD 11.0)
|Authors: Malik et al.  2020|
Setting: Not described
Study period: 2015–17
|Epstein–Barr virus (EBV)||Definition: Patients had to have chronic fatigue syndrome (CF) for at least 6 months after acute infection with EBV.|
Symptoms: Fatigue, post-exertional malaise and pain
|Developed CF 6 months after an acute EBV infection; A serological pattern indicating acute EBV infection; Age between 12 and 20 years; Living in one of the Norwegian counties Oslo, Akershus, or Buskerud||More than 6 weeks since debut of symptoms suggesting acute EBV infection; Any chronic disease that needed regular use of medication; Pregnancy.||N = 21|
Male: 4 (19%)
Female: 17 (81%)
Age: 17.7 (SD 1.4)
|N = 22|
Male: 6 (27%)
Female: 16 (73%)
Age: 16.9 (SD 1.7)
|N = 43|
Male: 10 (23%)
Female: 33 (77%)
Age: Overall age not provided
|Authors: Neumann et al.  2021 |
Study period: 2018–19
|Chikungunya||Definition: Musculoskeletal symptoms lasting beyond three months|
|Aged 18–75 years; Serological diagnosis of Chikungunya fever and symptoms lasting 3+ months||Cognitive impairment as assessed by mini-mental state examination (MMSE); Contraindication for physical exercise (e.g., unstable angina, uncontrolled hypertension, or kidney disorder); Neurological disorders; Previous diagnosis of rheumatic disorders (except osteoarthritis); Physical impairment preventing intervention; Pregnancy; Receiving other physical modality treatments during research period; Engagement in regular physical exercise (mild- or moderate-intensity aerobic activities for 30 min five times a week or vigorous physical activity for at least 20 min three times a week)||N = 15|
Male: 1 (7%)
Female: 14 (93%)
Age: 54.9 (SD 9.6)
|N = 16|
Male: 2 (12.5%)
Female: 14 (87.5%)
Age: 56.7 (SD 11.0)
|N = 31|
Male: 3 (10%)
Female: 28 (90%)
Age: 56.0 (SD 10.0)
|Authors: Silva-Filho et al.  2018 |
Study period: 2016–17
|Chikungunya||Definition: Positive CHIK virus for at least 6 months|
|Positive laboratory tests for the CHIK virus for at least 6 months (chronic phase); Preserved intellectual capacity determined by the mini mental state examination (MMSE); Physical capacity to do physical evaluation; 18 and 65 years old||Pain clearly related to any other aetiology, such as dengue, zika, rheumatoid arthritis, gout, lupus, neurologic and muscular diseases, psychiatric illness, and history of drug abuse; Signs or history of dizziness or epileptic disease; Pregnancy; Signs of severity and/or indication of hospitalization and metal implants in the head||N = 10|
Male: 0 (0%)
Female: 10 (100%)
Age: 46.1 (SD 16.0)
|N = 10|
Male: 1 (10%)
Female: 9 (90%)
Age: 44.1 (SD 13.5)
|N = 20|
Male: 1 (5%)
Female: 19 (95%)
Age: Overall age not provided
|Authors: de Oliveria et al.  2019 |
Setting: Outpatient clinical, Hospital
Study period: 2017
|Chikungunya||Definition: Symptoms lasting more than 3 months|
|18+ years; Confirmed diagnosis of Chikungunya fever; Patient in clinical treatment at Chikungunya outpatient clinic; Chronic phase of the disease (symptoms lasting more than three months)||Contraindication for physical exercise according to the treating physician; A severely limiting cognitive, auditory, visual, or motor deficit confirmed by a specialist physician; History of inflammatory, rheumatic, neurological, or neoplastic disorders||N = 22|
Male: 3 (14%)
Female: 19 (86%)
Age: 54.4 (SD 10.6)
|N = 20|
Male: 0 (0%)
Female: 20 (100%)
Age: 59.6 (SD 9.4)
|N = 42|
Male: 3 (7%)
Female: 39 (83%)
Age: 56.9 (SD 10.6)
|Authors||Description of Intervention and Comparator||Outcome of Interest (Including Method of Measurement)||Description of Key Findings|
|Li et al. ||Intervention: Telerehabilitation programme in post-discharge COVID-19 patients (TERECO) is an unsupervised home-based 6-week exercise programme comprising breathing control and thoracic expansion, aerobic exercise, and lower limb muscle strength (LMS) exercise, delivered via smartphone, and remotely monitored with heart rate telemetry.|
Comparator: One-off short educational instruction at baseline
The mean 6MWD in the control group increased by 17.1 m (SD 63.9) from baseline to post-treatment assessment, whereas 6MWD in the TERECO group improved by 80.2 m (SD 74.7). The adjusted between-group difference in change in 6MWD from baseline (treatment effect) was 65.5 m (95% CI 43.8 to 87.1; p < 0.001).
|Malik et al. ||Intervention: The intervention consisted of a 10-week mental training programme. The patients had one introductory session followed by nine individual therapy sessions (one per week) for 1.5 h and related homework, combining elements from CBT and music therapy. Of the nine therapy sessions, four were given by a music therapist and five were given by a cognitive therapist.|
Comparator: Care as usual—As reported by the authors “neither General Practitioners or paediatricians in Norway schedule appointment with postinfectious CF patients unless they have strongly reduced physical function. Thus, ‘care as usual’ implies that the relevant individuals would not receive any healthcare for their CF condition in the follow-up period apart from the follow-up visits in the present study.”
|There were no statistically significant differences between the two groups for any outcomes.|
The mean number of steps per day decreased in the treatment group from 3 months post-baseline (7217) to 5680 at 15 months post-baseline. A decrease was also seen in the control group from 8515 at 3 months post-baseline to 7587 at 15 months. The difference between the two groups was not statistically significant: difference (95% CI) = −1298 (−4874 to 2278)).
|Neumann et al. ||Intervention: The intervention group underwent resistance exercises with elastic bands (24 sessions over 12 weeks) supervised by a physical therapist. The exercise begins with a 5-min warm up on a stationary bike with no load, followed by resistance exercises for muscle groups that stabilize the shoulders, elbows, wrists, knees, and ankles.|
Comparator: Participants maintained their usual care of treatment and only received phone calls to monitor their symptoms.
There was a significant improvement between the groups on the 30-s CST, with the resisted exercise group improving their performance compared to the control group (p = 0.04, d = 0.39) at 12 weeks follow-up. However, there was no significant improvement in the FPWT, 4SCPT, or DASH.
|Silva-Filho et al. ||Intervention: Patients randomised to intervention arm were given transcranial direct current stimulation (tDCS) arm where they experienced a constant current of 2 mA for 20 min.|
Comparator: Sham-tDCS was performed on 5 consecutive days with electrodes placed on the same position, and a constant current of 2 mA was delivered only for 30 s (10-s ramp-up) of the 20 min.
|Primary outcome:||Primary outcome:|
There was a statistically significant improvement in VAS in the tDCS group.
|de Oliveira et al. ||Intervention: The intervention group received 24 sessions of Pilates over a 12-week period. Patients had two sessions per week for 50 min per session, and of light-to-moderate intensity (increasing the number of repetitions, starting with 6 and increasing to 12 repetitions). The exercises involved coordination, strength, flexibility, and balance.|
Comparator: Usual follow-up at the Chikungunya outpatient clinic, with standard clinical care for the treatment of the disease.
|Regarding the primary and secondary outcomes, in the intragroup analysis, a significant improvement was observed in all parameters after 24 Pilates sessions (week 12) in relation to the baseline (week 0), but the same was not observed in the control group.|
The relative risk of an individual having been treated with Pilates and having decreased pain (measured by VAS) was 0.48 (95% CI = 0.28–0.82, p < 0.0001) with a number needed to treat two patients (95% CI 7–2, p < 0.0001).
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Chandan, J.S.; Brown, K.R.; Simms-Williams, N.; Bashir, N.Z.; Camaradou, J.; Heining, D.; Turner, G.M.; Rivera, S.C.; Hotham, R.; Minhas, S.; et al. Non-Pharmacological Therapies for Post-Viral Syndromes, Including Long COVID: A Systematic Review. Int. J. Environ. Res. Public Health 2023, 20, 3477. https://doi.org/10.3390/ijerph20043477
Chandan JS, Brown KR, Simms-Williams N, Bashir NZ, Camaradou J, Heining D, Turner GM, Rivera SC, Hotham R, Minhas S, et al. Non-Pharmacological Therapies for Post-Viral Syndromes, Including Long COVID: A Systematic Review. International Journal of Environmental Research and Public Health. 2023; 20(4):3477. https://doi.org/10.3390/ijerph20043477Chicago/Turabian Style
Chandan, Joht Singh, Kirsty R. Brown, Nikita Simms-Williams, Nasir Z. Bashir, Jenny Camaradou, Dominic Heining, Grace M. Turner, Samantha Cruz Rivera, Richard Hotham, Sonica Minhas, and et al. 2023. "Non-Pharmacological Therapies for Post-Viral Syndromes, Including Long COVID: A Systematic Review" International Journal of Environmental Research and Public Health 20, no. 4: 3477. https://doi.org/10.3390/ijerph20043477