Guideline sources The following summarized guidelines for the evaluation and management of long COVID are prepared by our editorial team based on guidelines from the World Health Organization (WHO 2023; 2022), the European Respiratory Society (ERS 2022), and the European Society for Microbiology and Infectious Diseases (ESCMID 2022). 1 2 3 4 Guidelines 1. Screening and diagnosis Definition: define post-COVID-19 as a condition in patients with a history of probable or confirmed SARS-CoV-2 infection presenting with symptoms (including fatigue, shortness of breath, cognitive dysfunction, and other symptoms affecting everyday functioning; either with a new onset after initial recovery from an acute COVID-19 episode or persisting from the initial illness; fluctuating or relapsing over time) lasting for at least 2 months, usually 3 months from the onset of COVID-19, not explained by an alternative diagnosis. E Differential diagnosis: exclude other serious/life-threatening conditions including prior overlooked conditions (such as malignancy) and complications of acute COVID-19 (such as thromboembolic events, myopericarditis, and encephalitis) before diagnosing long COVID in https://web.pathway.md/diseases/recJ5OO8f9aUFCGuS 1/7 6/29/23, 5:54 AM Long COVID Pathway symptomatic patients. Evaluate for other conditions guided by symptoms, signs, and other tests, obtained according to the physician's discretion. E 2. Diagnostic investigations Medical history: elicit clinical history to rule out previous underlying conditions, as well as iatrogenic causes or complications related to the acute episode. E Pulmonary function testing: As per ERS 2022 guidelines, consider obtaining pulmonary function testing, including static lung volumes, expiratory flow rates, and diffusion capacity of the lung for CO assessment, to assess long-term lung function sequelae in patients with COVID-19. E As per ESCMID 2022 guidelines: Consider obtaining routine pulmonary function testing, including diffusion capacity, in all patients with severe and critical COVID-19 at 3 months from diagnosis, regardless of symptoms. E Consider obtaining pulmonary function testing, including diffusion capacity, in patients reporting persistent dyspnea 3 months after acute disease and in patients with known prior lung disease. E Cardiopulmonary function testing: consider obtaining cardiopulmonary function tests (6MWD or cardiopulmonary stress testing) at the beginning of an interventional/rehabilitation program to assess progress. E Laboratory tests: Consider obtaining the following tests in symptomatic patients according to symptoms: CBC CRP LFTs kidney function tests thyroid function tests cardiac markers (troponin, creatine phosphokinase-MB, and BNP) arterial blood gases (in case of decreased oxygen saturation). E Show 2 more Repeat PCR testing: consider obtaining recurrent PCR testing after acute COVID-19 in specific subgroups of patients on a case-by-case basis. E Chest imaging: As per ERS 2022 guidelines, obtain contrast-enhanced CT to identify pulmonary vascular involvement in patients with persistent exertional dyspnea not explained by CT or pulmonary function testing abnormalities 3-6 months after discharge. E Show 2 more As per ESCMID 2022 guidelines: https://web.pathway.md/diseases/recJ5OO8f9aUFCGuS 2/7 6/29/23, 5:54 AM Long COVID Pathway Consider obtaining a CXR in patients with long COVID and persistent respiratory symptoms at 3 months to rule out other diagnoses and for a possible early diagnosis of pulmonary fibrosis. E Consider obtaining chest CT at 3-6 months in patients with dyspnea or abnormal pulmonary function tests, regardless of symptoms, to rule out other causes and identify fibrotic changes. E Cardiac imaging: As per ERS 2022 guidelines, obtain echocardiography to identify pulmonary vascular involvement in patients with persistent exertional dyspnea not explained by CT or pulmonary function testing abnormalities 3-6 months after discharge. E As per ESCMID 2022 guidelines, consider obtaining a TTE in patients presenting with persistent symptoms suggestive of perimyocardial injury (chest pain, palpitations, signs and symptoms of HF). E Show 3 more Brain imaging: avoid obtaining brain imaging for the evaluation of long-COVID complaints, other than to rule out other causes or for research purposes. D 3. Medical management General principles: Consider including the following core components in the rehabilitation services for post-COVID-19 condition: multidisciplinary rehabilitation teams continuity and coordination of care people-centered care and shared decision-making. C Show 3 more Extended thromboprophylaxis: obtain individualized risk stratification of the risk for thrombotic versus hemorrhagic events. Consider extending post-discharge anticoagulation prophylaxis in patients with a low risk of bleeding and an elevated risk for VTE (active malignancy, immobility, history of VTE, recent major surgery, thrombophilia). E Antifibrotic agents: insufficient evidence to recommend for or against antifibrotic agents in patients with persistent pulmonary symptoms after acute COVID-19. I Management of breathlessness: As per WHO 2023 guidelines: Consider offering a combination of education and skills training on self-management strategies (such as nasal breathing and pacing approaches), and physical exercise training (in the absence of post-exertional symptom exacerbation) for the clinical rehabilitation management of breathing impairment in adult patients with post-COVID-19 condition. C Consider offering breathing control techniques in patients presenting with a suboptimal breathing pattern, as well as psychological support to address contributing factors such as anxiety. C https://web.pathway.md/diseases/recJ5OO8f9aUFCGuS 3/7 6/29/23, 5:54 AM Long COVID Pathway As per ESCMID 2022 guidelines, consider following available consensus statements regarding multidisciplinary rehabilitation in the post-acute stage, although insufficient evidence to recommend for or against physical and respiratory rehabilitation specifically for COVID-19. E Management of persistent cough: insufficient evidence to recommend for or against any intervention in patients with persistent cough after acute COVID-19. I Management of fatigue: As per WHO 2023 guidelines, assess for and manage exertional desaturation and cardiac impairment following COVID-19 before offering physical exercise training in adult patients with post-COVID-19 condition. Recognize that the presence of orthostatic intolerance and post- exertional symptom exacerbation, although amenable to rehabilitation, will require interventions to be modified in view of these diagnoses for rehabilitation to be safe. B Show 2 more As per ESCMID 2022 guidelines, insufficient evidence to recommend for or against any intervention for the management of fatigue in patients with long COVID. I Management of arthralgia: consider offering a combination of pain education, skills training on self-management strategies, prescription of short-term anti-inflammatory drugs, and physical exercise training (in the absence of post-exertional symptom exacerbation) for the clinical rehabilitation management of arthralgia in adult patients with post-COVID-19 condition. C Management of orthostatic intolerance: consider offering a combination of education and skills training on self-management strategies and physical exercise training (in the absence of post- exertional symptom exacerbation) for the clinical rehabilitation management of orthostatic intolerance in adult patients with post-COVID-19 condition. Consider advising environmental modifications to support activities of daily living in patients experiencing difficulties with upright positions or standing. C Management of olfactory impairment: As per WHO 2023 guidelines, consider offering education and skills training for olfactory training for the clinical rehabilitation management of olfactory impairment in adult patients with post- COVID-19 condition. C As per ESCMID 2022 guidelines: Consider offering olfactory training in patients with smell disturbances. Discuss the likelihood of spontaneous recovery with patients, and consider offering other interventions only in clinical trials. E Advise smoking cessation in all patients, including in the context of smell and taste disturbances. E Management of swallowing impairment: consider offering a combination of education and skills training on positioning, maneuvres and dietary modifications, and swallowing exercises for the clinical rehabilitation management of swallowing impairment in adult patients with post-COVID-19 condition. C Management of voice impairment: consider offering education and skills training about voice rest and vocal behaviours for the clinical rehabilitation management of voice impairment in adult https://web.pathway.md/diseases/recJ5OO8f9aUFCGuS 4/7 6/29/23, 5:54 AM Long COVID Pathway patients with post-COVID-19 condition. Consider offering any combination of respiratory exercises and vocal training. C Management of neurocognitive sequelae: As per WHO 2023 guidelines, consider offering a combination of education, skills training on self-management strategies, and cognitive exercises for the clinical rehabilitation management of cognitive impairment in adult patients with post-COVID-19 condition. Consider providing training in the use of assistive products and environmental modifications to address the cognitive dysfunctions as they apply to daily functioning. C As per ESCMID 2022 guidelines, insufficient evidence to recommend for or against any intervention for the management of neurological/cognitive long COVID sequelae. I Management of pyschological/psychiatric sequelae: As per WHO 2023 guidelines: Consider offering psychological support and physical exercise training (in the absence of post- exertional symptom exacerbation) for the clinical rehabilitation management of anxiety and depression in adult patients with post-COVID-19 condition. C Consider offering mindfulness-based approaches and peer support groups to reduce distress in selected patients with post-COVID-19 condition when managing long-term symptoms. C As per ESCMID 2022 guidelines, insufficient evidence to recommend for or against any intervention for the management of emotional/psychiatric long COVID sequelae. I 4. Follow-up and surveillance Indications for referral: As per WHO 2023 guidelines, consider referring adult patients with post-COVID-19 condition for appropriate rehabilitation services when experiencing symptoms and impairments that are likely to be managed effectively and have an impact on everyday functioning, if red flags for safe rehabilitation have been considered. C As per ESCMID 2022 guidelines, refer patients with persisting or new symptoms lasting > 12 weeks after acute COVID-19 to medical care. Consider assessing patients with symptoms 4-12 weeks after acute infection on a case-by-case basis according to the severity and course of symptoms. E Return to normal activities: consider offering education and skills training on energy conservation techniques and provide training in the use of assistive products in patients requiring further assistance with activity management and mobility for the rehabilitation for a return to everyday activities in post-COVID-19 condition. Consider providing a return to work action plan with a prolonged and flexible phased return. Consider advising environmental modifications at work based on an individualized workplace risk assessment of personal capabilities matched to work requirements. C https://web.pathway.md/diseases/recJ5OO8f9aUFCGuS 5/7 6/29/23, 5:54 AM Long COVID Pathway Clinical findings Symptoms Past medical history Abdominal pain Covid-19 infection Anosmia Depression Anxiety Arthralgia Cacosmia Change in smell Change in taste Chest pain Cough Diarrhea Dizziness Fatigue Fever Headache Hearing loss Hyposmia Limb numbness Memory impairment Mood changes Myalgia Palpitations Paresthesia Shortness of breath Skin rash Sleeping disorder Tremor Visual disturbances Neurological exam Cognitive impairment Studies 2023 ReCOVer In patients being severely fatigued 3-12 months following COVID-19, CBT was superior to care as usual with respect to reduction in fatigue severity. Tanja A Kuut et al. Clin Infect Dis. 2023 May 8. https://web.pathway.md/diseases/recJ5OO8f9aUFCGuS 6/7 6/29/23, 5:54 AM Long COVID Pathway 2022 SCENT2 In adult patients with chronic olfactory dysfunction following suspected COVID-19 infection, theophylline nasal irrigation was not superior to placebo nasal irrigation with respect to the percentage of patients who experienced slightly better improvement in the clinical global impression-improvement scale. Shruti Gupta et al. JAMA Otolaryngol Head Neck Surg. 2022 Sep 1. References 1. Katerina M Antoniou, Eirini Vasarmidi, Anne-Marie Russell et al. European Respiratory Society statement on long COVID follow-up. Eur Respir J. 2022 Aug 4;60 2 2102174. Open 2. Dana Yelin, Charalampos D Moschopoulos, Ili Margalit et al. ESCMID rapid guidelines for assessment and management of long COVID. Clin Microbiol Infect. 2022 Jul;28 7 955 972. Open 3. No authors listed. Therapeutics and COVID 19 living guideline. Geneva: World Health Organization; 2023. Open 4. Joan B Soriano, Srinivas Murthy, John C Marshall et al. A clinical case definition of post-COVID 19 condition by a Delphi consensus. Lancet Infect Dis. 2022 Apr;22 4):e102-e107. Open https://web.pathway.md/diseases/recJ5OO8f9aUFCGuS 7/7