A recent systematic review posted to the medRxiv* preprint server investigated the effectiveness of non-pharmacologic interventions for post-viral syndromes (PVS), including the post-coronavirus disease 2019 (COVID-19) syndrome.

Study: Non-pharmacological therapies for post-viral syndromes, including Long COVID: A systematic review. Image Credit: Dmitry Demidovich/Shutterstock
Study: Non-pharmacological therapies for post-viral syndromes, including Long COVID: A systematic review. Image Credit: Dmitry Demidovich/Shutterstock


Globally, COVID-19 cases have surpassed 533 million, with more than 6.30 million deaths to date. This crisis has led to concerted efforts to develop and deliver vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at an unprecedented pace. Although vaccination has substantially decreased mortality, the relapse-remit nature of symptoms like dyspnea, fatigue, etc., that persist even after mild disease, is concerning for both patients and healthcare providers.

Such persistent symptoms following a SARS-CoV-2 infection are termed ‘long COVID.’ This condition is also referred to as post-acute sequelae of COVID-19 (PASC) or post-COVID-19 syndrome. While long COVID is still being studied, most of its clinical features, such as neurological, psychological, and respiratory complications, occur after other acute viral infections. Such persistent sequelae are termed PVS that follow infection with other viruses like the chikungunya virus (CHIKV) and Epstein-Barr virus (EBV).

About the study

In the present study, researchers systematically reviewed the available evidence on non-pharmacologic treatments for PVS, including PASC. The study subjects were children and adults with PVS, including PASC. They included studies where PVS lasted over 12 weeks, albeit other publications that did not provide a timeframe were also included, provided that they indicated an aspect of persistence of symptoms. Studies that determined the efficacy of non-pharmacologic interventions to improve PVS symptoms relative to standard care, alternative non-pharmacologic interventions, or placebo were included.

The included studies were randomized controlled trials (RCTs) for PVS patients. Given the lack of RCTs for SARS-CoV-2, observational studies were included for long COVID. MEDLINE, Embase, cumulative index to nursing and allied health literature (CINAHL), and PsycINFO were searched for RCTs studying treatments for PVS from January 1, 2001, to October 31, 2021. Duplicate studies were removed, and at least two independent reviewers screened titles and abstracts. Relevant data were extracted from selected studies by two reviewers. Two reviewers evaluated the risk of bias in studies using the Cochrane risk of bias tool (RoB 2).


The researchers identified 11,164 studies initially and removed 533 duplicates. From the 10,631 non-duplicate articles, 10,564 were excluded after title/abstract screening, yielding 67 publications for full-text analysis. Further screening resulted in five studies for the systematic review. The five studies were conducted in Brazil (3), China (1), and Norway (1). Adults (18 years or older) were the subjects in four RCTs, whereas children and young individuals aged 12-20 years were included in the Norwegian study.

No study reported ethnicity; one study reported interventions relevant to SARS-CoV-2-exposed patients, another study for EBV-exposed subjects, and three for those with CHIKV. The primary symptoms captured by the studies were arthralgia, dyspnea, fatigue, and general pain. Most studies also collected aggregated data from surveys assessing health-related quality of life.

The methodological risk of bias as quantified using RoB-2 was generally low. Nonetheless, since no study blinded personnel and participants, the risk of performance bias or placebo effect could not be ruled out. The authors could not meta-analyze the combined data because of the substantial data heterogeneity regarding viral exposure, symptoms, and intervention description.

One RCT described an intervention for patients with dyspnea following COVID-19. A telerehabilitation program for patients was recommended for post-discharge COVID-19 patients (TERECO). TERECO was an unsupervised exercise program with breathing control, aerobic exercise, thoracic expansion, and lower limb muscle strength, instructed through a smartphone. The TERECO group was superior to the controls as determined by a 6-minute walking distance (6MWD) test. Improvements in perceived dyspnea were evident after six weeks of treatment but were statistically insignificant after 28 weeks.

Another RCT assessed the efficacy of a 10-week mental health training program encompassing music therapy combined with cognitive-behavioral therapy for patients recruited from the ‘chronic fatigue following EBV infection in adolescents (CEBA) cohort. Patients were randomly assigned to the ‘care as usual’ group and mental health training group. This study did not observe any statistically significant differences in the measured outcomes between the two groups.

The third RCT examined the effectiveness of a resistance exercise for patients with lingering musculoskeletal symptoms following CHIKV infection who also attended a rheumatologist. The intervention group completed a 12-week resistance exercise, and the comparator group continued the standard care prescribed by their rheumatologist(s). The intervention group exhibited significant improvement in the 30s chair stand test (CST) after 12 weeks, while no improvement was noted for other measured outcomes.

The effect of Pilates on pain reduction, joint function improvement, and quality of life in subjects with chronic chikungunya fever was examined. After 12 weeks of the Pilates intervention program, a significant improvement in measured primary and secondary outcomes was observed compared to controls.

The final study investigated the effects of neuromodulation on joint pain reduction in chikungunya patients. Transcranial direct current stimulation (tDCS), a non-invasive neuromodulation technique, conducts a low amplitude direct current (DC) to the cerebral cortex. The tCDS subjects experienced constant DC (2mA) for 20 minutes, and the sham tDCS group experienced it for 30 seconds. Subjects in the tCDS group had a significant reduction in pain measured by the Friendman test, which was not observed for sham subjects. Nevertheless, no improvements were seen in physical function tests, flexibility, or quality of life.


Four non-pharmacologic interventions (telerehabilitation, neuromodulation, resistance exercises, and Pilates) significantly improved primary outcomes. The present study highlighted the limited evidence of non-pharmacologic interventions for patients with PVS or PASC. Therefore, more clinical trials are warranted to examine further treatments/interventions for persistent symptoms following infection with viruses, including SARS-CoV-2.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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