Non-Pharmacological Therapies for Post-Viral Syndromes, Including Long COVID: A Systematic Review

Background: Post-viral syndromes (PVS), including Long COVID, are symptoms sustained from weeks to years following an acute viral infection. Non-pharmacological treatments for these symptoms are poorly understood. This review summarises evidence for the effectiveness of non-pharmacological treatments for symptoms of PVS. It also summarises the symptoms and health impacts of PVS in individuals recruited to studies evaluating treatments. Methods and findings: We conducted a systematic review to evaluate the effectiveness of non-pharmacological interventions for PVS, as compared to either standard care, alternative non-pharmacological therapy, or placebo. The outcomes of interest were changes in symptoms, exercise capacity, quality of life (including mental health and wellbeing), and work capability. We searched five databases (Embase, MEDLINE, PsycINFO, CINAHL, MedRxiv) for randomised controlled trials (RCTs) published between 1st January 2001 to 29th October 2021. We anticipated that there would be few RCTs specifically pertaining to Long COVID, so we also included observational studies only if they assessed interventions in individuals where the viral pathogen was SARS-COV-2. Relevant outcome data were extracted, study quality appraised using the Cochrane Risk of Bias tool, and the findings were synthesised narratively. Quantitative synthesis was not planned due to substantial heterogeneity between the studies. Overall, five studies of five different interventions (Pilates, music therapy, telerehabilitation, resistance exercise, neuromodulation) met the inclusion criteria. Aside from music-based intervention, all other selected interventions demonstrated some support in the management of PVS in some patients. Conclusions: In this study, we observed a lack of robust evidence evaluating non-pharmacological treatments for PVS, including Long COVID. Considering the prevalence of prolonged symptoms following acute viral infections, there is an urgent need for clinical trials evaluating the effectiveness and cost-effectiveness of non-pharmacological treatments for patients with PVS as well as what may work for certain sub-groups of patients with differential symptom presentation. Registration: The study protocol was registered with PROSPERO [CRD42021282074] in October 2021 and published in BMJ Open in 2022. Keywords: Post-viral syndromes, PVS, COVID-19, Long COVID, post-COVID-19 condition, post-acute sequelae of SARS-CoV-2 infection (PASC), rehabilitation, systematic review, non-pharmacological intervention

[1]  O. Aiyegbusi,et al.  Development and validation of the symptom burden questionnaire for long covid (SBQ-LC): Rasch analysis , 2022, BMJ.

[2]  E. Sapey,et al.  Therapies for Long COVID in non-hospitalised individuals: from symptoms, patient-reported outcomes and immunology to targeted therapies (The TLC Study) , 2022, BMJ Open.

[3]  K. Khunti,et al.  Non-pharmacological therapies for postviral syndromes, including Long COVID: a systematic review and meta-analysis protocol , 2022, BMJ Open.

[4]  L. Gómez,et al.  Successful Treatment of Post-COVID Symptoms With Transcranial Direct Current Stimulation. , 2021, The primary care companion for CNS disorders.

[5]  Janet Diaz,et al.  A clinical case definition of post-COVID-19 condition by a Delphi consensus , 2021, The Lancet Infectious Diseases.

[6]  D. Harrop,et al.  A mixed-methods systematic review of post-viral fatigue interventions: Are there lessons for long Covid? , 2021, PloS one.

[7]  J. Vilaró,et al.  Effectiveness of a Primary Care Telerehabilitation Program for Post-COVID-19 Patients: A Feasibility Study , 2021, Journal of clinical medicine.

[8]  Markus C. Hayden,et al.  Effectiveness of a Three-Week Inpatient Pulmonary Rehabilitation Program for Patients after COVID-19: A Prospective Observational Study , 2021, International journal of environmental research and public health.

[9]  C. Whaley,et al.  Vaccinations Against COVID-19 May Have Averted Up To 140,000 Deaths In The United States. , 2021, Health affairs.

[10]  Xiao-Bo Zhang,et al.  Baduanjin exercise can alleviate anxiety and depression of patients with COVID-19 in Square cabin hospital , 2021, Medicine.

[11]  O. Bienvenu,et al.  Intensive Care Unit–Specific Virtual Reality for Critically Ill Patients With COVID-19: Multicenter Randomized Controlled Trial , 2021, Journal of medical Internet research.

[12]  J. Reinhardt,et al.  A telerehabilitation programme in post-discharge COVID-19 patients (TERECO): a randomised controlled trial , 2021, Thorax.

[13]  E. Sapey,et al.  Symptoms, complications and management of long COVID: a review , 2021, Journal of the Royal Society of Medicine.

[14]  Juan José González-Gerez,et al.  Short-Term Effects of a Conditioning Telerehabilitation Program in Confined Patients Affected by COVID-19 in the Acute Phase. A Pilot Randomized Controlled Trial , 2021, Medicina.

[15]  Juan José González-Gerez,et al.  Short-Term Effects of a Respiratory Telerehabilitation Program in Confined COVID-19 Patients in the Acute Phase: A Pilot Study , 2021, International journal of environmental research and public health.

[16]  N. Moraveji,et al.  Post-acute care management of a patient with COVID-19 using remote cardiorespiratory monitoring , 2021, Respiratory Medicine Case Reports.

[17]  A. Santos,et al.  Transcranial direct current stimulation as a strategy to manage COVID-19 pain and fatigue. , 2021, Revista da Associacao Medica Brasileira.

[18]  L. Battistella,et al.  Rehabilitation of patients after COVID-19 recovery: An experience at the Physical and Rehabilitation Medicine Institute and Lucy Montoro Rehabilitation Institute , 2021, Clinics.

[19]  K. Maheshkumar,et al.  Yoga and Naturopathy intervention for reducing anxiety and depression of Covid-19 patients – A pilot study , 2021, Clinical Epidemiology and Global Health.

[20]  Z. Demetrovics,et al.  Mental Health Support in the Time of Crisis: Are We Prepared? Experiences With the COVID-19 Counselling Programme in Hungary , 2021, Frontiers in Psychiatry.

[21]  G. Lee,et al.  A Well-Structured Follow-Up Program is Required after Recovery from Coronavirus Disease 2019 (COVID-19); Release from Quarantine is Not the End of Treatment , 2021, Journal of clinical medicine.

[22]  I. Gilmutdinova,et al.  Telemedicine platform COVIDREHAB for remote rehabilitation of patients after COVID-19 , 2021, European journal of translational myology.

[23]  D. Swerdlow,et al.  Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data , 2021, The Lancet.

[24]  D. Gommers,et al.  Effect of intensive care unit-specific virtual reality (ICU-VR) to improve psychological well-being and quality of life in COVID-19 ICU survivors: a study protocol for a multicentre, randomized controlled trial , 2021, Trials.

[25]  M. Landini,et al.  Post-COVID-19 Syndrome: The Persistent Symptoms at the Post-viral Stage of the Disease. A Systematic Review of the Current Data , 2021, Frontiers in Medicine.

[26]  Yi Jiang,et al.  The Efficacy of Computerized Cognitive Behavioral Therapy for Depressive and Anxiety Symptoms in Patients With COVID-19: Randomized Controlled Trial , 2021, Journal of medical Internet research.

[27]  Shuping Tan,et al.  Self-help cognitive behavioral therapy application for COVID-19-related mental health problems: A longitudinal trial , 2021, Asian Journal of Psychiatry.

[28]  S. Belli,et al.  Effectiveness of aerobic exercise training program on cardio-respiratory fitness and quality of life in patients recovered from COVID-19 , 2021, European Journal of Physiotherapy.

[29]  C. Vogelmeier,et al.  Benefits of pulmonary rehabilitation in COVID-19: a prospective observational cohort study , 2021, ERJ Open Research.

[30]  Ricardo Yudi Tateno,et al.  Photobiomodulation therapy and antimicrobial photodynamic therapy for orofacial lesions in patients with COVID-19: A case series , 2021, Photodiagnosis and Photodynamic Therapy.

[31]  N. Ambrosino,et al.  Pulmonary Rehabilitation in Patients Recovering from COVID-19 , 2021, Respiration.

[32]  E. Mayo-Wilson,et al.  The PRISMA 2020 statement: an updated guideline for reporting systematic reviews , 2021, BMJ.

[33]  Hong Li,et al.  Pulmonary rehabilitation focusing on the regulation of respiratory movement can improve prognosis of severe patients with COVID-19. , 2021, Annals of palliative medicine.

[34]  E. Dupont-Versteegden,et al.  Physical Therapy Management of an Individual With Post-COVID Syndrome: A Case Report , 2021, Physical therapy.

[35]  Alison W. Rebman,et al.  Long-haul COVID: heed the lessons from other infection-triggered illnesses , 2021, The Lancet.

[36]  N. Parizad,et al.  Effect of guided imagery on anxiety, muscle pain, and vital signs in patients with COVID-19: A randomized controlled trial , 2021, Complementary Therapies in Clinical Practice.

[37]  Moyi Li,et al.  Liuzijue is a promising exercise option for rehabilitating discharged COVID-19 patients , 2021, Medicine.

[38]  G. N. Marzuca-Nassr,et al.  Effectiveness of Telerehabilitation in Physical Therapy: A Rapid Overview , 2021, Physical therapy.

[39]  F. Pisano,et al.  Authors' reply to: Rivera-Lillo et al. comment on: Early rehabilitation in post-acute COVID-19 patients: data from an Italian COVID-19 rehabilitation unit and proposal of a treatment protocol , 2021, European Journal of Physical and Rehabilitation Medicine.

[40]  Dominikus David Biondi Situmorang.  Music Therapy for the Treatment of Patients With COVID-19 , 2021, Infectious diseases in clinical practice.

[41]  E. Playford,et al.  Managing the long term effects of covid-19: summary of NICE, SIGN, and RCGP rapid guideline , 2021, BMJ.

[42]  D. A. de Oliveira,et al.  Resistance exercises improve physical function in chronic Chikungunya fever patients: a randomized controlled trial. , 2021, European journal of physical and rehabilitation medicine.

[43]  K. Seers,et al.  Rehabilitation Exercise and psycholoGical support After covid-19 InfectioN’ (REGAIN): a structured summary of a study protocol for a randomised controlled trial , 2021, Trials.

[44]  B. Morton,et al.  An Improvised Pulmonary Telerehabilitation Program for Postacute COVID-19 Patients Would Be Feasible and Acceptable in a Low-Resource Setting , 2021, American journal of physical medicine & rehabilitation.

[45]  Sally J. Singh,et al.  Early experiences of rehabilitation for individuals post-COVID to improve fatigue, breathlessness exercise capacity and cognition – A cohort study , 2021, Chronic respiratory disease.

[46]  T. Voshaar,et al.  Conservative management of COVID-19 associated hypoxaemia , 2021, ERJ Open Research.

[47]  A. Iloreta,et al.  Letter to the editor: Study Summary - Randomized Control Trial of Omega-3 Fatty Acid Supplementation for the Treatment of COVID-19 Related Olfactory Dysfunction , 2020, Trials.

[48]  Fanyang Kong,et al.  Effect of Psychological–Behavioral Intervention on the Depression and Anxiety of COVID-19 Patients , 2020, Frontiers in Psychiatry.

[49]  J. Raj,et al.  Dance and Music as a Therapy to Heal Physical and Psychological Pain: An Analytical Study of COVID-19 Patients during Quarantine , 2020 .

[50]  S. Kautz,et al.  Update on the Use of Transcranial Electrical Brain Stimulation to Manage Acute and Chronic COVID-19 Symptoms , 2020, Frontiers in Human Neuroscience.

[51]  A. Saghazadeh,et al.  Potential Prophylactic and Therapeutic Effects of Respiratory Physiotherapy for COVID-19 , 2020, Acta bio-medica : Atenei Parmensis.

[52]  Jincheng Xu,et al.  The Effect of Cognitive Behavioral Therapy on Depression, Anxiety, and Stress in Patients With COVID-19: A Randomized Controlled Trial , 2020, Frontiers in Psychiatry.

[53]  Stephanie I Cheng.  Medical Acupuncture as a Treatment for Novel COVID-19-Related Respiratory Distress: Personal Experience from a Frontline Anesthesiologist. , 2020, Medical acupuncture.

[54]  J. Alison,et al.  COVID‐19 rehabilitation delivered via a telehealth pulmonary rehabilitation model: a case series , 2020, Respirology case reports.

[55]  E. Skovlund,et al.  Cognitive–behavioural therapy combined with music therapy for chronic fatigue following Epstein-Barr virus infection in adolescents: a randomised controlled trial , 2020, BMJ paediatrics open.

[56]  Li-Xiang Ye,et al.  Acupuncture strategies to tackle post covid-19 psychological and neuropsychiatric disorders , 2020 .

[57]  Long COVID: let patients help define long-lasting COVID symptoms , 2020, Nature.

[58]  F. Callard,et al.  Why the Patient-Made Term 'Long Covid' is needed [version 1;peer review: awaiting peer review] , 2020 .

[59]  I. Boutron,et al.  The COVID-NMA Project: Building an Evidence Ecosystem for the COVID-19 Pandemic , 2020, Annals of Internal Medicine.

[60]  G. Qiao,et al.  Modified rehabilitation exercises for mild cases of COVID-19. , 2020, Annals of palliative medicine.

[61]  F. Pisano,et al.  Early rehabilitation in post-acute COVID-19 patients: data from an Italian COVID-19 rehabilitation unit and proposal of a treatment protocol. A cross-sectional study. , 2020, European journal of physical and rehabilitation medicine.

[62]  V. Artounian,et al.  The Effect of Brief Crisis Intervention Package on Improving Quality of Life and Mental Health in Patients with COVID-19 , 2020, Iranian journal of psychiatry.

[63]  D. Krewski,et al.  Feasibility and Preliminary Results of Effectiveness of Social Media-based Intervention on the Psychological Well-being of Suspected COVID-19 Cases during Quarantine , 2020, Canadian journal of psychiatry. Revue canadienne de psychiatrie.

[64]  Zhi-Yong Wang,et al.  The Application of Eight-Segment Pulmonary Rehabilitation Exercise in People With Coronavirus Disease 2019 , 2020, Frontiers in Physiology.

[65]  J. Tulsky,et al.  Development of a Palliative Care Toolkit for the COVID-19 Pandemic , 2020, Journal of Pain and Symptom Management.

[66]  S. Sarıkaya,et al.  Pulmonary rehabilitation principles in SARS-COV-2 infection (COVID-19): A guideline for the acute and subacute rehabilitation. , 2020, Turkish journal of physical medicine and rehabilitation.

[67]  Kai Liu,et al.  Respiratory rehabilitation in elderly patients with COVID-19: A randomized controlled study , 2020, Complementary Therapies in Clinical Practice.

[68]  E. Skovlund,et al.  Cognitive–behavioural therapy combined with music therapy for chronic fatigue following Epstein-Barr virus infection in adolescents: a feasibility study , 2020, BMJ Paediatrics Open.

[69]  T. Duong,et al.  People with Suspected COVID-19 Symptoms Were More Likely Depressed and Had Lower Health-Related Quality of Life: The Potential Benefit of Health Literacy , 2020, Journal of clinical medicine.

[70]  Natalie S Blencowe,et al.  RoB 2: a revised tool for assessing risk of bias in randomised trials , 2019, BMJ.

[71]  C. Marques,et al.  Pilates method in the treatment of patients with Chikungunya fever: a randomized controlled trial , 2019, Clinical rehabilitation.

[72]  E. Skovlund,et al.  Predictors of chronic fatigue in adolescents six months after acute Epstein-Barr virus infection: A prospective cohort study , 2019, Brain, Behavior, and Immunity.

[73]  M. Bikson,et al.  Neuromodulation treats Chikungunya arthralgia: a randomized controlled trial , 2018, Scientific Reports.

[74]  J. Manson,et al.  36‐Item Short Form Survey (SF‐36) Versus Gait Speed As Predictor of Preclinical Mobility Disability in Older Women: The Women's Health Initiative , 2018, Journal of the American Geriatrics Society.

[75]  D. G. Altman,et al.  GRIPP2 reporting checklists: tools to improve reporting of patient and public involvement in research , 2017, Research Involvement and Engagement.

[76]  G. Bleijenberg,et al.  Effectiveness of Long-term Doxycycline Treatment and Cognitive-Behavioral Therapy on Fatigue Severity in Patients with Q Fever Fatigue Syndrome (Qure Study): A Randomized Controlled Trial , 2017, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[77]  S. Opal,et al.  Middle East respiratory syndrome (MERS) , 2014, Virulence.

[78]  R. Glazier,et al.  A randomized controlled trial of a multifaceted integrated complementary-alternative therapy for chronic herpes zoster-related pain. , 2012, Alternative medicine review : a journal of clinical therapeutic.

[79]  Chenyao Wang,et al.  [Analysis on therapeutic effect of variable-frequency electroacupuncture combined with herbal-moxa moxibustion for post-zoster neuralgia]. , 2012, Zhen ci yan jiu = Acupuncture research.

[80]  M. Meeus,et al.  Pain physiology education improves pain beliefs in patients with chronic fatigue syndrome compared with pacing and self-management education: a double-blind randomized controlled trial. , 2010, Archives of physical medicine and rehabilitation.

[81]  Michele Tarsilla.  Cochrane Handbook for Systematic Reviews of Interventions , 2010, Journal of MultiDisciplinary Evaluation.

[82]  Felipe Fregni,et al.  Modulation of emotions associated with images of human pain using anodal transcranial direct current stimulation (tDCS) , 2009, Neuropsychologia.

[83]  G. Guyatt,et al.  GRADE: an emerging consensus on rating quality of evidence and strength of recommendations , 2008, BMJ : British Medical Journal.

[84]  N. Tsiskarishvili,et al.  [Local phototherapy and pulse current in complex treatment of relapsing herpes simplex]. , 2007, Georgian medical news.

[85]  P. White.  What causes prolonged fatigue after infectious mononucleosis: and does it tell us anything about chronic fatigue syndrome? , 2007, The Journal of infectious diseases.

[86]  J. Leduc,et al.  SARS, the First Pandemic of the 21st Century , 2004, Emerging Infectious Diseases.

[87]  A. Berger,et al.  Das SARS-assoziierte Coronavirus – Die erste Pandemie des 21. Jahrhunderts / The SARS-associated coronavirus – The first pandemic of the 21st century , 2004 .

[88]  S. McCormack,et al.  Individual differences in personality, immunology and mood in patients undergoing self-hypnosis training for the successful treatment of a chronic viral illness, HSV-2 , 2002 .

[89]  P. Drummond,et al.  The effects of stress management on symptoms of upper respiratory tract infection, secretory immunoglobulin A, and mood in young adults. , 2001, Journal of psychosomatic research.

[90]  P. Drummond,et al.  Psychological treatment for recurrent symptoms of colds and flu in children. , 2001, Journal of psychosomatic research.

[91]  R Neumann,et al.  Low-intensity laser therapy is an effective treatment for recurrent herpes simplex infection. Results from a randomized double-blind placebo-controlled study. , 1999, The Journal of investigative dermatology.

[92]  H. Folgering,et al.  Pulmonary rehabilitation in chronic obstructive pulmonary disease. , 1998, The European respiratory journal.

[93]  Huijuan Pan.  Respiratory rehabilitation assisted by respiratory trainers in patients with coronavirus disease 2019: an analysis of efficacy , 2021 .

[94]  R. Joshi,et al.  Physiotherapy rehabilitation in post-COVID-19 phase: A case report , 2021 .

[95]  T. L. Olenskaya,et al.  Application of altitude chamber adaptation as a component of the medical rehabilitation patients after COVID-19 , 2021 .

[96]  Manisha Rathi,et al.  Post-COVID-19 Physiotherapy Rehabilitation: A Case Report , 2021, JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH.

[97]  G. Pal,et al.  Acute effects of prone asanas and Pal’s pranayama on myalgia, headache, psychological stress and respiratory problems in the COVID-19 patients in the recovery phase , 2020 .