Efficacy of non-pharmacological treatments for post-viral syndromes and prolonged COVID

A recent systematic review has been published on medRxiv* The prepress server investigated the effectiveness of non-pharmacological interventions for post-viral syndromes (PVS), including post-coronavirus disease 2019 (COVID-19).

The study: Non-pharmacological treatments for post-viral syndromes, including Long COVID: a systematic review. Image Credit: Dmitriy Demidovich / Shutterstock


Globally, COVID-19 cases have exceeded 533 million, with more than 6.30 million deaths to date. This crisis has led to concerted efforts to develop and deliver vaccines against SARS-CoV-2 (SARS-CoV-2) at an unprecedented pace. Although vaccination has significantly reduced mortality, the relapsing and 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 following infection with SARS-CoV-2 are called ‘long-term COVID’. This condition is also referred to as post-acute sequelae of COVID-19 (PASC) or post-COVID-19 syndrome. While the Covid virus has been under study for a long time, most of its clinical manifestations, such as neurological, psychiatric and respiratory complications, occur after other acute viral infections. These persistent sequelae are called PVS that follow infection with other viruses such as chikungunya virus (CHIKV) and Epstein-Barr virus (EBV).

about studying

In this study, researchers systematically reviewed the available evidence for non-pharmacological treatments for PVS, including PASC. The study subjects were children and adults with PVS, including PASC. It included studies where PVS lasted more than 12 weeks, although other publications that did not provide a time frame were also included, provided they indicated an aspect of symptom persistence. Studies that determined the effectiveness of non-drug interventions for improving symptoms of PVS related to standard care, alternative non-drug interventions, or placebo were included.

The included studies were randomized controlled trials (RCTs) for PVS patients. Since there were no randomized controlled trials for SARS-CoV-2, observational studies of the long COVID virus were included. MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and PsycINFO were searched for randomized controlled trials examining PVS treatments from January 1, 2001 to October 31, 2021. Duplicate studies were removed and at least two independent reviewers examined titles and abstracts. Relevant data from selected studies were extracted by two reviewers. Two reviewers assessed the risk of bias in studies using the Cochrane Risk of Bias (RoB 2) tool.

the findings

The researchers initially identified 11,164 studies and removed 533 duplicates. Of the 10,631 non-duplicate articles, 10,564 were excluded after title/abstract examination, yielding 67 publications for full-text analysis. Additional screening led to five studies for 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 randomized controlled trials, while children and young adults aged 12-20 years were included in the Norwegian study.

No study mentioned race. One study reported relevant interventions for SARS-CoV-2-exposed patients, another study for EBV-exposed patients, and three for CHIKV patients. The primary symptoms picked up by the studies were joint pain, shortness of breath, fatigue and general pain. Most studies also collected aggregated data from surveys assessing health-related quality of life.

The systemic risk of bias as determined with RoB-2 was generally low. However, since no study has blinded individuals and participants, the risk of performance bias or a placebo effect cannot be excluded. The authors were unable to meta-analyze the pooled data due to intrinsic data heterogeneity with regard to viral exposure, symptoms, and description of the intervention.

One randomized controlled trial described an intervention for patients with shortness of breath after COVID-19. The Remote Patient Rehabilitation Program for COVID-19 Patients After Discharge (TERECO) is recommended. TERECO was an unsupervised exercise program with controlled breathing, aerobic exercise, thoracic expansion, and lower limb muscle strength, directed through a smartphone. The TERECO group outperformed the controls as determined by the 6-minute walk (6MWD) test. Improvements in marked dyspnea appeared after six weeks of treatment but were not statistically significant after 28 weeks.

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

The third randomized controlled trial examined the efficacy of resistance exercise for patients with long-standing musculoskeletal symptoms after CHIKV infection who also attended a rheumatologist. The intervention group completed resistance exercise for 12 weeks, and the comparison group continued the standard care prescribed by the rheumatologist(s). The intervention group showed a significant improvement in the chair holder test (CST) after 12 weeks, while no improvement was observed in the other measured outcomes.

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

The final study investigated the effects of neuromodulation on reducing joint pain in chikungunya patients. Transcranial direct current stimulation (tDCS), a non-invasive neuromodulation technique, delivers a low-amplitude direct current (DC) to the cerebral cortex. Subjects tested tCDS constant current (2 mA) for 20 min, and the tDCS sham group experienced this for 30 s. People in the tCDS group had a significant reduction in pain as measured by the Friendman test, which was not observed for the sham subjects. However, no improvement was observed in tests of physical function, flexibility, or quality of life.


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

*Important note

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


Leave a Reply

Your email address will not be published.