Clinical standards for diagnosis, treatment and prevention of post-COVID-19 lung disease

BACKGROUND: The aim of these clinical standards is to provide guidance on ‘best practice’ care for the diagnosis, treatment and prevention of post-COVID-19 lung disease. METHODS: A panel of international experts representing scientific societies, associations and groups active in post-COVID-19 lung disease was identified; 45 completed a Delphi process. A 5-point Likert scale indicated level of agreement with the draft standards. The final version was approved by consensus (with 100% agreement). RESULTS: Four clinical standards were agreed for patients with a previous history of COVID-19: Standard 1, Patients with sequelae not explained by an alternative diagnosis should be evaluated for possible post-COVID-19 lung disease; Standard 2, Patients with lung function impairment, reduced exercise tolerance, reduced quality of life (QoL) or other relevant signs or ongoing symptoms ≥4 weeks after the onset of first symptoms should be evaluated for treatment and pulmonary rehabilitation (PR); Standard 3, The PR programme should be based on feasibility, effectiveness and cost-effectiveness criteria, organised according to local health services and tailored to an individual patient’s needs; and Standard 4, Each patient undergoing and completing PR should be evaluated to determine its effectiveness and have access to a counselling/health education session. CONCLUSION: This is the first consensus-based set of clinical standards for the diagnosis, treatment and prevention of post-COVID-19 lung disease. Our aim is to improve patient care and QoL by guiding clinicians, programme managers and public health officers in planning and implementing a PR programme to manage post-COVID-19 lung disease.

of further investigation and treatment, even if usually treatable and reversible, are defined as moderate.Severe sequelae include deep vein thrombosis, strokes or pulmonary embolism. 4,24,25Furthermore, rare severe sequelae are those presenting with chronic organ failure, such as cardiovascular events, including myocarditis, postural orthostatic tachycardia syndrome, renal failure or pulmonary fibrosis.Pathophysiological processes impacting long COVID include organ damage, resulting from acute phase infection, complications from a dysregulated inflammatory state and inadequate antibody response against SARS-CoV-2. 26Although it is acknowledged that long COVID affects several organs and/or body systems, here we primarily focus on lung damage.14

AIM OF THE CLINICAL STANDARDS
Our aim is to provide expert guidance on 'best practice' for diagnosis, treatment and prevention of post-COVID-19 lung disease.Developing standards for a new, incompletely characterised disease is challenging, as we have only limited long-to medium-term experience of the condition.3][34][35] Evidence on post-COVID lung disease is still lacking in areas such as benefits/risks evaluations, and costs and costanalysis.We present an 'optimal' set of standards (recommendations for the best possible approach), but acknowledge that implementing this approach may be difficult in some settings.We therefore include adaptations for special settings and situations to indicate how the approach can be modified as needed.
This consensus-based document describes the following process for patients with a previous history of COVID-19: 1 Patients with sequelae not explained by an alternative diagnosis should be evaluated for possible post-COVID-19 lung disease (Standard 1). 2 Patients with lung function impairment, reduced exercise tolerance, reduced quality of life (or other relevant signs or ongoing symptoms) 4 weeks after the onset of the first symptoms should be evaluated for treatment and pulmonary rehabilitation (PR) (Standard 2). 3 The PR programme should be based on feasibility, effectiveness and cost-effectiveness criteria, organised according to local health services and tailored to the patient's needs (Standard 3). 4 Each patient undergoing and completing PR should be evaluated to determine its effectiveness and have access to a counselling/health education session (Standard 4).
In addition, consensus-based research priorities were identified.

METHODS
A panel of 63 global experts were invited to represent the main scientific societies, associations and groups active in post-COVID-19 lung disease.Of the 63 experts, 4 declined, and 12 did not respond after one invitation reminder.All respondents (n ¼ 47) were asked to comment on an initial set of six draft standards developed by a core team (n ¼ 7) of researchers via a Delphi process.Of these, 45 researchers provided valid answers; following the Delphi process, the six draft standards were reduced to four.The final writing panel included the following 40 experts: COVID/infectious diseases and respiratory clinicians (n ¼ 32), public health specialists, including respiratory epidemiologists (n ¼ 4), a physiotherapist, an occupational physician, a paediatrician and a methodologist.A 5-point Likert scale (5: high agreement; 1: low agreement) was used to indicate agreement with the standards.At the first Delphi round, agreement was high, with a median value of >4 (for all standards).Based on substantial initial agreement, the expert panel developed an initial draft, which underwent five rounds of revisions.The final version was approved by consensus (100% agreement).As evidence in this field is rapidly accumulating, this document will be updated once significant new evidence emerges.

STANDARD 1
Patients with sequelae not explained by an alternative diagnosis should be evaluated for possible post-COVID-19 lung disease.
A wide range of symptoms and clinical outcomes occur in people with varying degrees of illness from post-COVID-19 conditions.7][38][39] In special settings and situations, this evaluation can be simplified and/or modified to include a set of core examinations with the aim to identify patients with sequelae at risk for deterioration and those likely to benefit most from PR.
The relationship between thoracic images and persisting abnormalities in lung function requires further study.In patients with normal chest radiography and oxygen saturation, computed tomography (CT, or high-resolution CT, HRCT) imaging of the chest might have some role for assessing pulmonary disease. 40,416][47] For patients who may require imaging based on clinical findings, symptom management and a rehabilitation plan can often be initiated simultaneously with the imaging workup.However, it is important to point out that CT imaging is not available in many countries, and be aware that patients could present with clinical symptoms and radiological signs evoking post-COVID-19 without a previous diagnosis of COVID-19.
Patients, especially those with severe COVID-19, may develop micro-clots that persist months after the initial infection. 48Assessment and treatment with antiplatelet therapies and or anticoagulants are outside the scope of this document and is fully addressed in guidelines for antithrombotic treatment for COVID-19. 49ntibody tests, when available, could help to confirm diagnosis, especially when reverse transcription polymerase chain reaction or rapid antigen test was not done for the initial diagnosis of COVID-19, although many individuals will since have been vaccinated. 23 comprehensive assessment should be done in individuals experiencing new or ongoing symptoms at least 4-12 weeks or more after the acute phase (see Table 1) to identify subjects suitable for a PR Clinical standards for post-COVID-19 programme 10,50,51 involving nurses, physiotherapists and psychologists.The presence of respiratory signs and symptoms will aid the identification of patients with respiratory sequelae at risk of deterioration and most likely to benefit from PR as discussed below.

STANDARD 2
Patients with lung function impairment, reduced exercise tolerance, reduced QoL or other relevant signs or ongoing symptoms ‡4 weeks after the onset of the first symptoms, should be evaluated for treatment and PR.
PR is described as a 'comprehensive intervention based on a thorough patient assessment, followed by patient-tailored therapies that include, but are not limited to, exercise training, education and behaviour change, designed to improve the physical and psychological condition of people with chronic respiratory disease and to promote the long-term adherence to health-enhancing behaviours'. 52Treatment of post-COVID-19 lung disease should focus on managing the patient's symptoms, improving function and healthrelated QoL.Recent evidence supports the need for prompt referral to rehabilitation in patients hospitalised for COVID-19 disease, while for non-hospitalised patients, referral should follow an assessment by healthcare workers or a watch and wait/self-management approach for at least 6 weeks.An overall evaluation of functional impact and physical performance in post-COVID-19 patients should focus on symptoms limiting daily activities, pulmonary function tests (PFT), diffusion capacity of the lung for carbon monoxide (DLCO), blood gas analysis (BGA), pulse oximetry at rest and on exertion, QoL, anxiety and depression (Table 2). 9,17,23,36,37, Patints presenting with lung function impairment (airflow obstruction or restriction or mixed and/or impaired DLCO and/or gas exchange), reduced exercise tolerance and related impairment in QoL and other relevant signs or symptoms (fatigue, exhaustion, asthenia or weakness; respiratory symptoms such as dyspnoea, cough, chest pain; respiratory failure at rest and/or on exertion) should be evaluated for PR.A pilot study from 2021 evaluated COVID-19 patients 6 months after discharge from hospital and showed that persistent dyspnoea was associated with reduced physical fitness. 68Patients in need of early and effective PR are those who had suffered from the severe acute forms of COVID-19 and those with persistent abnormal chest X-ray or CT or reduced DLCO. 17atients with COVID-19 admitted to intensive care unit (ICU) may develop a post-intensive care syndrome (PICS), with impaired physical, exercise-induced oxygen desaturation, muscle weakness and reduced mobility. 53uch patients are likely to benefit from PR. Finally, patients experiencing severe lung impairment during COVID-19 acute illness, prone to altered PFT and 6-min walk test (6MWT) results, are a subgroup of patients that could also benefit from PR. 69

STANDARD 3
The PR programme should be based on feasibility, effectiveness and cost-effectiveness criteria, organised according to local health services and tailored to the patient's needs.
PR is a multidisciplinary, non-pharmacological intervention aiming to improve symptoms, health status, and exercise capacity and reduce disability in postacute and chronic respiratory diseases. 52There is strong evidence that PR is also successful when multiple comorbidities are present. 78PR should be completed within the framework of a multidisciplinary programme.Based on the experience with other respiratory conditions, this programme consists of physical and exercise therapy, along with psychology, nursing and medical interventions, as needed.0][81][82][83][84][85][86] A dysfunctional or abnormal breathing pattern has also been reported by patients with long COVID, both at rest and during exercise testing.][89] PR programmes for long COVID have been proposed in different settings according to the local organisation of health services, ranging from in-and out-patients, home and tele-rehabilitation. 57,58,62,73,74,77,90 Such programmes should be tailored to the patient's needs and include some minimum and essential requirements. 91hese include areas of rehabilitation and interventions focused on the baseline assessment, exercise training, education to support self-management, psychological counselling as required, and recommendations for homebased exercise and physical activity, 50,57,58,62,[90][91][92] with a programme length ranging from 1-12 weeks. 73,74,77A follow-up plan is recommended to maintain benefits from PR and evaluate additional clinical problems arising at a later stage.][95][96][97][98][99][100] They should also be organised according to feasibility, effectiveness and costeffectiveness criteria, 91,101 and adapted to the context and resources available in different settings to ensure that they are as accessible as possible for patients, including children and adolescents. 91,102,103PR programmes Clinical standards for post-COVID-19 can also be delivered in person, through tele-rehabilitation, depending on each patient's individual context.Both during and after the COVID-19 pandemic, there has been an accelerated interest in alternative forms of exercise training, such as yoga and dance, integrated with or as an adjunct to PR programmes.Dance improves motor function (balance, strength, exercise capacity and QoL) in older patients in other disease contexts and is being evaluated as an adjunct to PR in respiratory conditions. 104Yoga, incorporating breathing exercises, stretching and gentle chair and standing exercises, is offered by patient advocacy organisations such as the Irish Lung Fibrosis Association (https://ilfa.ie/blog/online-yoga-class/) as an adjunct to PR and warrants further evaluation.The benefits of structured singing programmes for lung health, which are offered outside the traditional health service model, are also emerging. 105ur understanding of the benefits of PR is mostly derived from the experience of people affected by chronic respiratory diseases, especially chronic obstructive pulmonary disease (COPD), where it has proven to be cost-effective in preventing hospital readmission. 106R could accelerate recovery in post-COVID-19 patients, but further studies are needed to identify effective and cost-effective strategies to deliver PR in the different settings.The core components of a PR programme are summarised in Table 3. 16,57,58,62,73,74,77,82,90,[107][108][109][110][111][112][113]

STANDARD 4
Each patient undergoing and completing pulmonary rehabilitation should be evaluated to determine its effectiveness and have access to a counselling/health education session.
Studies with strong evidence on the efficacy of interventions, in particular, PR and long-term monitoring for post-COVID-19 lung disease are lacking.No guidelines for post-COVID-19 interventions exist, and standardised methods for evaluating their efficacy have not been developed.Standard 4 includes a short description on how to evaluate the effectiveness of PR, comparing core variables pre-and post-rehabilitation.The standard also suggests how to organise the patient's follow-up to maintain or improve the results achieved, organised according to feasibility and cost-effectiveness criteria, based on the local organisation of health services and tailored to an individual patient's needs.For patients with long COVID, the objective of PR is to increase functional independence.This can be evaluated (as for all respiratory diseases) by a significant improvement in PFT results 50,114,115 and respiratory symptoms.In this context, the strongest independent predictors of persistent respiratory impairment with need for followup 114,115 are patients with COVID-19 presenting with dyspnoea 3 weeks after hospital discharge and those with impaired gas exchange on admission to hospital.Data show that functional capacity and QoL should not be neglected, 114,116,117 and a multidisciplinary rehabilitation strategy is essential to address this.
Community-based PR interventions and monitoring may also be beneficial during pandemics. 114Community health workers can contribute to the COVID-19 response by providing screening, facilitating referrals, arranging support for home care, staffing communitybased isolation centres, and being involved in surveillance, contact tracing, service delivery to people with disabilities, home visits, outreach activities and advocacy campaigns. 23,114EVENTION There are points in the sequence of events spanning SARS-COV-2 infection to reporting prolonged and persistent suffering due to post-COVID sequelae, at which there is the possibility of a preventive intervention/strategy.9][120][121][122][123] The secondary area of prevention includes intervening during acute disease to prevent sequelae: pharmacological treatment with antivirals and corticosteroids, selective prophylactic anticoagulants, critical care and early rehabilitation in acute care. 9,49,118,124ertiary prevention interventions, including disability limitation and rehabilitation, are post-acute disease.Quaternary interventions include activities that help in preventing treatment and vaccine side effects.

PRIORITIES FOR FUTURE RESEARCH
Examples of future research priorities 125 are summarised below.

Diagnosis
Identification of predictors of post-COVID lung disease: patient characteristics (disabilities, comorbidities, genetics), biomarkers, extrinsic factors (biological, including air pollution; psychological and social), radiological patterns during acute disease, manifestations and severity of COVID disease; Development and evaluation of diagnostic tools and algorithms for post-COVID lung disease; Evaluation of the effectiveness of multidisciplinary, post-COVID-19 clinics vs. traditional GPs' assessment with referral to organ specialists; Definition of criteria for severity of post-COVID disorders; Assessment of knowledge on post-COVID lung disease of health workers in primary care centres and public hospital clinics; Development and validation of tools for auditing activities on post-COVID lung disease; T E X T E : L'objectif de ces normes cliniques est de fournir des conseils sur les « meilleures pratiques » en mati ere de diagnostic, de traitement et de pr evention des maladies pulmonaires post-COVID-19.M É T H O D E S : Un groupe d'experts internationaux repr esentant des soci et es scientifiques, des associations et des groupes actifs dans le domaine des maladies pulmonaires post-COVID-19 a et e constitu e ; 45 d'entre eux ont particip e a un processus Delphi.Une echelle de Likert en 5 points a permis d'indiquer le niveau d'accord avec les projets de normes.La version finale a et e approuv ee par consensus (100% d'accord).R É S U L T A T S : Quatre normes cliniques ont et e approuv ees pour les patients ayant des ant ec edents de COVID-19 : Norme 1, les patients pr esentant des s equelles non expliqu ees par un autre diagnostic doivent être evalu es en vue d'une eventuelle maladie pulmonaire post-COVID-19 ; Norme 2, les patients pr esentant une alt eration de la fonction pulmonaire, une diminution de la tol erance a l'effort, une r eduction de la qualit e de vie (QoL) ou d'autres signes pertinents ou des symptômes persistants, quatre semaines ou plus apr es l'apparition des premiers symptômes, doivent être evalu es en vue d'un traitement et d'une r eadaptation pulmonaire (PR, de l'anglais 'pulmonaire rehabilitation') ; Norme 3, le programme de PR doit être bas e sur des crit eres de faisabilit e, d'efficacit e et de rentabilit e, organis e en fonction des services de sant e locaux et adapt e aux besoins individuels des patients ; et Norme 4, chaque patient qui suit et termine un programme de PR doit être evalu e pour d eterminer son efficacit e et avoir acc es a une session de conseil/ education a la sant e. C O N C L U S I O N : Il s'agit du premier ensemble consensuel de normes cliniques pour le diagnostic, le traitement et la pr evention des maladies pulmonaires post-COVID-19.Notre objectif est d'am eliorer les soins et la qualit e de vie des patients en guidant les cliniciens, les responsables de programmes et les responsables de la sant e publique dans la planification et la mise en oeuvre d'un programme de relations publiques pour la prise en charge des maladies pulmonaires post-COVID-19.International Union Against Tuberculosis and Lung Disease i

Table 1
Selected assessment tools for evaluating people with post-COVID-19 at the end of the acute phase FEV 1 ¼ forced expiratory volume in 1 sec; FVC ¼ forced vital capacity; EuroQOL ¼ Euro Quality of Life; SaO 2 ¼ oxygen saturation; PTSD ¼ post-traumatic stress disorder; DSM ¼ Diagnostic and Statistical Manual of Mental Disorders.

Table 2
Indications for pulmonary rehabilitation COPD ¼ chronic obstructive pulmonary disease; PEF ¼ peak expiratory flow; ADL ¼ activity of daily life.

Table 3
Summary of the core components of a rehabilitation programme edged as effective, there is a strong need to accumulate and evaluate the increasing evidence on the use of PR for post-COVID-19 lung disease and investigate innovative PR interventions.There is also a need for research on the underlying mechanisms of post-COVID-19 pulmonary sequelae.As the currently available evidence is