The effectiveness of non-pharmacological treatments for post-viral syndromes and long COVID


A recent systematic review published on the medRxiv* The preprint server studied the effectiveness of non-pharmacological interventions for post-viral syndromes (PVS), including 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


Globally, COVID-19 cases have topped 533 million, with more than 6.30 million deaths so far. 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 rate. Although vaccination has significantly reduced mortality, the relapsing-remitting nature of symptoms such as dyspnea, fatigue, etc., which persist even after mild illness, is of concern to both patients and healthcare providers. .

These persistent symptoms after SARS-CoV-2 infection are called “long COVIDs”. This condition is also called 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. These persistent sequelae are called PVS which follow an infection by other viruses such as the chikungunya virus (CHIKV) and the Epstein-Barr virus (EBV).

About the study

In the present study, the researchers systematically reviewed the available evidence on non-pharmacological treatments for SVP, including PASC. Study subjects were children and adults with SVP, including PASC. They included studies where PVS lasted longer than 12 weeks, although other publications that did not provide a time frame were also included, provided they indicated some aspect of symptom persistence. Studies that determined the effectiveness of non-pharmacological interventions in improving symptoms of PVS compared with standard care, alternative non-pharmacological interventions, or placebo were included.

Included studies were randomized controlled trials ( RCTs ) for patients with PVS. Given the lack of RCTs for SARS-CoV-2, observational studies were included for the long COVID. MEDLINE, Embase, the Cumulative Index of Nursing and Allied Health Literature (CINAHL), and PsycINFO were searched for RCTs investigating treatments for SVP from 1 January 2001 to 31 October 2021. Duplicate studies were removed and at least two independent reviewers were selected. titles and abstracts. Relevant data were extracted from studies selected by two reviewers. Two reviewers assessed the risk of bias in the studies using the Cochrane risk of bias tool (RoB 2).


The researchers initially identified 11,164 studies and removed 533 duplicates. Of the 10,631 unduplicate articles, 10,564 were excluded after title/abstract screening, resulting in 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 of four RCTs, while children and young people aged 12 to 20 were included in the Norwegian study.

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

The methodological risk of bias quantified using RoB-2 was generally low. Nevertheless, since neither study blinded staff and participants, the risk of performance bias or placebo effect could not be ruled out. The authors could not perform a meta-analysis of the pooled data due to significant heterogeneity in the data regarding viral exposure, symptoms, and description of the intervention.

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

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

The third RCT investigated the effectiveness of resistance exercise for patients with persistent musculoskeletal symptoms following CHIKV infection who also consulted a rheumatologist. The intervention group performed 12 weeks of resistance exercise, and the comparison group continued standard care prescribed by their rheumatologist(s). The intervention group showed significant improvement in the Standing Chair Test of 30s (CST) after 12 weeks, while no improvement was noted for the other outcomes measured.

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, significant improvement in measured primary and secondary outcomes was observed compared to controls.

The latest study looked at the effects of neuromodulation on reducing joint pain in patients with chikungunya. Transcranial direct current stimulation (tDCS), a noninvasive neuromodulation technique, conducts low amplitude direct current (DC) to the cerebral cortex. The tCDS subjects experienced constant DC (2 mA) 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 the sham subjects. However, no improvements were seen in physical function tests, flexibility, or quality of life.


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

*Important Notice

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


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