Interventions for the management of long covid (post-covid condition): living systematic review

Abstract

Objective: To compare the effectiveness of interventions for the management of long covid (post-covid condition).

Design: Living systematic review.

Data sources: Medline, Embase, CINAHL, PsycInfo, Allied and Complementary Medicine Database, and Cochrane Central Register of Controlled Trials from inception to December 2023.

Eligibility criteria: Trials that randomised adults (≥18 years) with long covid to drug or non-drug interventions, placebo or sham, or usual care.

Results: 24 trials with 3695 patients were eligible. Four trials (n=708 patients) investigated drug interventions, eight (n=985) physical activity or rehabilitation, three (n=314) behavioural, four (n=794) dietary, four (n=309) medical devices and technologies, and one (n=585) a combination of physical exercise and mental health rehabilitation. Moderate certainty evidence suggested that, compared with usual care, an online programme of cognitive behavioural therapy (CBT) probably reduces fatigue (mean difference -8.4, 95% confidence interval (CI) -13.11 to -3.69; Checklist for Individual Strength fatigue subscale; range 8-56, higher scores indicate greater impairment) and probably improves concentration (mean difference -5.2, -7.97 to -2.43; Checklist for Individual Strength concentration problems subscale; range 4-28; higher scores indicate greater impairment). Moderate certainty evidence suggested that, compared with usual care, an online, supervised, combined physical and mental health rehabilitation programme probably leads to improvement in overall health, with an estimated 161 more patients per 1000 (95% CI 61 more to 292 more) experiencing meaningful improvement or recovery, probably reduces symptoms of depression (mean difference -1.50, -2.41 to -0.59; Hospital Anxiety and Depression Scale depression subscale; range 0-21; higher scores indicate greater impairment), and probably improves quality of life (0.04, 95% CI 0.00 to 0.08; Patient-Reported Outcomes Measurement Information System 29+2 Profile; range -0.022-1; higher scores indicate less impairment). Moderate certainty evidence suggested that intermittent aerobic exercise 3-5 times weekly for 4-6 weeks probably improves physical function compared with continuous exercise (mean difference 3.8, 1.12 to 6.48; SF-36 physical component summary score; range 0-100; higher scores indicate less impairment). No compelling evidence was found to support the effectiveness of other interventions, including, among others, vortioxetine, leronlimab, combined probiotics-prebiotics, coenzyme Q10, amygdala and insula retraining, combined L-arginine and vitamin C, inspiratory muscle training, transcranial direct current stimulation, hyperbaric oxygen, a mobile application providing education on long covid.

Conclusion: Moderate certainty evidence suggests that CBT and physical and mental health rehabilitation probably improve symptoms of long covid.

Systematic review registration: Open Science Framework https://osf.io/9h7zm/.

Readers' note: This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.

Fig 1

Selection of trials for inclusion in systematic review

Fig 2

Risk of bias of trials reporting on drug interventions for symptoms of long covid. HADS=Hospital Anxiety and Depression Scale; MFI-20=Multidimensional Fatigue Inventory-20; MoCA=Montreal Cognitive Assessment test; SF-36=short form-36; QIDS-SR-16=Quick Inventory of Depressive Symptomatology-16-item; WHO-5=World Health Organization-5 wellbeing index

Fig 3

Effects of drug interventions, physical activity and rehabilitation, and behavioural interventions on symptoms of long covid. *Classified as no longer severely fatigued according to CIS fatigue subscale (score <35). CBT=cognitive behavioural therapy; CI=confidence interval; CIS=Checklist for Individual Strength; KBILD=King’s Brief Interstitial Lung Disease; MFI-20=Multidimensional Fatigue Inventory-20; MoCA=Montreal Cognitive Assessment test; SF-36=short form-36; QIDS-SR-16=Quick Inventory of Depressive Symptomatology16-item; RR=relative risk; WHO-5=World Health Organization-5 wellbeing index

Fig 4

Effects of dietary interventions, medical devices and technologies, and combined interventions on symptoms of long covid. Effect estimates are mean difference or risk difference per 1000 people (95% CI). *Overall health compared with three months previously. Effect estimates are mean difference or risk difference per 1000 people (95% CI). Those who reported being “much better now” or “somewhat better now” were classified as having improved. †Reduction in severity of fatigue leading to improvement in activities of daily living using PACSQ-14 questionnaire. ‡Alleviation of difficulty in concentration leading to improvement in activities of daily living using PACSQ-14 questionnaire. §Alleviation of shortness of breath leading to improvement in activities of daily living using PACSQ-14 questionnaire. ¶Five point reduction in MFIS (range 0-84, with higher scores indicating greater impairment). **Fatigue was operationalised as the response “most or all the time” to item 7 of the Center for Epidemiological Studies Depression Scale (“I felt that everything I did was an effort”). CI=confidence interval; BSI-18=Brief Symptom Inventory-18; EQ-5D=European quality of life-5 dimensions; GRADE=Grading of Recommendations Assessment, Development and Evaluation; HADS=Hospital Anxiety and Depression Scale; HAM-A=Hamilton Anxiety Rating scale; MFIS=Modified Fatigue Impact Scale; PACSQ-14=post-acute covid-19 syndrome questionnaire; PROMIS=Patient-Reported Outcomes Measurement Information System; PROPr=PROMIS 29+2 Profile version 2.1; RR=relative risk; WHO-5=World Health Organization-5 wellbeing index