The Strategic preparedness and response plan outlines the World Health Organization (WHO) strategic objectives to end the COVID-19 pandemic and assists national stakeholders with developing a structured approach to their response. WHO's main objectives for COVID-19 are to: 1) suppress transmission; 2) provide optimized care for all patients, and save lives; 3) minimize the impact of the epidemic on health systems, social services and economic activity.
To achieve these objectives, the WHO Operational considerations for case management of COVID-19 in health facility and community (1) describes key actions that should be taken in different scenarios: no cases; sporadic cases; clusters of cases; and community transmission, in order to enable delivery of clinical and public health services in a timely fashion. This guideline is based on the above strategic priorities, and is intended for clinicians involved in the care of patients with suspected or confirmed COVID-19. It is not meant to replace clinical judgment or specialist consultation but rather to strengthen frontline clinical management and the public health response. Considerations for special and vulnerable populations, such as paediatric patients, older people and pregnant women, are highlighted throughout the text. This guideline is a product of the contributions of several WHO team members and independent experts from all over the world. WHO is deeply grateful to each of the contributors for their time and expertise.
In this document we refer to the COVID-19 care pathway (Annex 1). This describes a coordinated and multidisciplinary care pathway that a patient enters after they are screened for COVID-19 and becomes a suspect/confirmed COVID-19 case, and follows the continuum of their care until release from the pathway. The objective is to ensure delivery of safe and quality care while stopping onwards viral transmission. All others enter the health system in the non-COVID-19 pathway. For the most up-to-date technical guidance related to the COVID-19 response, visit WHO
SARS-CoV-2 continues to infect several thousands of people daily leading to preventable morbidity and mortality across the world (547). The development of vaccines and treatment for COVID-19 has substantially reduced hospitalization, severity of disease, and mortality. However, the virus continues to evolve with variable infectivity, immune escape and disease severity. This has led to changes in the protection afforded by vaccines, and the loss of activity of some previously effective drugs (549) (550).
This changing landscape underlines the need for continual development of treatments and management strategies for COVID-19, and their ongoing evaluation as new evidence emerges. These regularly updated "living" guidelines aim to provide trustworthy, accessible and clear recommendations for clinical practice (6).
to 3.8/100 000 during Omicron (554). Features include persistent fever, hypotension, gastrointestinal symptoms, rash, myocarditis, and laboratory evidence of increased inflammation often without respiratory symptoms (48) (49).
expertise) and one clinical chair (content expertise) guided the GDG discussions.

# How to access and use this guideline?
This is a living guideline from WHO. The guideline is written, disseminated and updated in MAGICapp, with a format and structure that ensures user-friendliness and ease of navigation (56). It accommodates dynamic updating of evidence and recommendations that can focus on what is new while keeping existing recommendations, as appropriate, within the guideline. Section 2 outlines key methodological aspects of the living guideline process.
The guideline is available via:
- WHO website in PDF format;
- MAGICapp in online, multilayered format.
The purpose of the online formats and additional tools, is to make it easier to navigate and make use of the guideline in busy clinical practice. The online multilayered formats are designed to allow end-users to find recommendations first and then drill down to find supporting evidence and other information pertinent to applying the recommendations in practice, including tools for shared decision-making (clinical encounter decision aids) (56).
Additional educational modules and implementation tools for health workers can be found via:
- WHO COVID-19 essential supplies forecasting tool (COVID-ESFT);
- WHO Clinical care for severe acute respiratory infection toolkit: COVID-19 adaptation;
- WHO Openwho.org clinical management course series;
- WHO Academy;
The GREEN symbol denotes a strong recommendation of a best practice statement in favour of an intervention.
The YELLOW symbol denotes a conditional recommendation in favour of an intervention, or a recommendation where special care is required in implementation.
The RED symbol denotes a recommendation or best practice statement against an intervention.

# Related guidelines
This living WHO guideline for the clinical management of COVID-19 is reflected in the Therapeutics and COVID-19: living guideline (120), also published in the BMJ (58) and available in MAGICapp.
This guideline aims to be trustworthy and living; dynamically updated and globally disseminated as new evidence warrants a change in recommendations for COVID-19, expecting at least two updates per year.

# Identifying recommendations
Each recommendation in this document is identified by a coloured box (which describes the strength of a GRADE methodology-based recommendation), or a green tick, yellow exclamation, or red cross as below which indicates that the recommendation was not formulated from a full GRADE-based approach).

# Icons used where GRADE methodology does not apply

# Current update
Stepwise approach Here we outline the stepwise approach we take to improve efficiency and timeliness of the living, trustworthy guideline, in the development and dissemination of the recommendations. To do so, various processes occurred simultaneously.

# For this version (v7),
Step 1: Evidence monitoring and mapping and triggering of evidence synthesis Regular monitoring of evidence around key topics occurs with support from the WHO rapid review team and their network of collaborators. In January 2023, the WHO Steering Committee triggered this guideline update process, including PICO development.
The trigger for producing or updating specific recommendations is based on the following:
- Likelihood to change practice;
- Relevance to a global audience.
Step 2: Convening the GDG WHO selected GDG members to ensure global geographical representation, gender balance, and appropriate technical and clinical expertise. The technical unit collected and managed declarations of interests (DOIs) and found no GDG member to have a conflict of interest. In addition to the distribution of a DOI form, during the meeting, the WHO Secretariat described the DOI process, and an opportunity was given to GDG members to declare any interests not provided in written form. No verbal conflicts were declared. Web searches did not identify any additional interests that could be perceived to affect an individual's objectivity and independence during the development of the recommendations.
The pre-selected expert GDG (see Acknowledgements) convened on 5 May 2023, to address the awake prone positioning PICO.
Step 3: Evidence synthesis The WHO unit requested the University of Alberta and Alberta Health Services to undertake an update of systematic review and meta-analysis publication with the PICO, about non-intubated hypoxaemic acute respiratory failure due to COVID-19 awake prone positioning as compared with usual care. The summary of evidence based on the review (545) and updated (546) for patient important outcome mortality, endotracheal intubation, ICU length of stay, and hospital length of stay. A narrative synthesis of the evidence was presented to the GDG to inform recommendation development.
Step 4: Development of recommendations The GDG panel members are responsible for the following critical activities:
- to advise on the priority questions and scope of the guideline;
- to advise on the choice of important outcomes for decision-making;
- to comment on the evidence used to inform the guideline;
- to advise on the interpretation of the evidence, with explicit consideration of overall balance of risks and benefits;
- to formulate recommendations, taking into account diverse values and preferences according to GRADE.
The GRADE approach provided the framework for establishing evidence certainty and generating both the direction and strength of recommendations (123) (125). Good practice statements can be made in addition to, or instead of a recommendation when a large body of indirect evidence, made up of linked evidence including several indirect comparisons, strongly supports the net benefit of the recommended action, if deemed that it will be an onerous and unproductive exercise to collect the indirect linked evidence supporting the recommendations. However, it still requires transparency and explicitness, with a clear rationale for the approach. Although a priori voting procedures were established at the outset, in case consensus was not reached, these procedures were not necessary for these recommendations which reached consensus amongst the panel.
The following key factors were used to formulate transparent and trustworthy recommendations:
- absolute benefits and harms for all patient-important outcomes through structured evidence summaries (e.g. GRADE summary of findings tables); - quality/certainty of the evidence (123) (127); - values and preferences of patients (59); - resources and other considerations (including considerations of feasibility, applicability, equity) (59);
- each outcome will have an effect estimate and confidence interval, with a measure of certainty in the evidence, as presented in summary of findings tables. If such data are not available narrative summaries will be provided; - recommendations will be rated as either conditional or strong, as defined by GRADE. If the panel members disagree regarding the evidence assessment or strength of recommendations, WHO will apply voting according to established methods.
The GDG meeting was organized with the following agenda for each topic: presentation of summary of evidence, consensus and discussion, infectious period and de-isolation.
Step 5: External and internal review The WHO guideline was then reviewed by pre-specified internal and external reviewers (see Acknowledgements) and then approved by the WHO Guideline Review Committee. The Members of the External Review Group reviewed the final guideline document to identify any factual errors, and to comment on clarity of the language, contextual issues and implications for implementation. The technical unit collected and managed declarations of interests (DOIs) and found no External Review Group member to have a conflict of interest.

# Benefits and harms
For these recommendations, the GDG members prioritized outcomes (rating from 9  to 1 with severe and critical COVID-19, taking a patient perspective (Table 14.1).

# Minimum important thresholds
Pre-defined thresholds for minimum important clinical differences were agreed by the GDG before formulating recommendations. These were:
- endotracheal intubation: 1.5% (15 per 1000 patients),
- hospitalization: 1.5% (15 per 1000),
- reduction in symptoms: 1 day,
- mortality: 5% (50 deaths per 1000 patients).

# Values and preferences
Clinical management of COVID-19: living guideline -World Health Organization (WHO)
Based on careful analysis of benefits, health systems, and patient preferences, the GDG concluded that informed individuals possess the following values and preferences.
- The panel placed a relatively high value on a modest reduction in invasive mechanical ventilation, and a lower value on the discomfort patients experience using awake prone positioning. - From a systems perspective, the panel also appreciated, on the one hand, the variable workload that awake prone positioning places on staff and, on the other hand, advantages from fewer patients needing invasive mechanical ventilation.
In considering a patient perspective, the GDG was mindful of the burden awake prone positioning imposes on health care provision when large numbers of patients undergo awake prone positioning.
On the other hand, it is likely awake prone positioning reduces endotracheal intubation and such a reduction would avoid some ICU admissions/stay with consequent reduction in resource utilization.
Aside considering patient and health systems perspectives, the GDG also considered the feasibility, acceptability, and equity, as well as the burden on the health system.
Specific deliberations on values and preferences and associated feasibility and resource-related considerations are presented for each recommendation.

# Previous versions
Earlier versions (v1, v2) of this document were developed in consultation with the International Forum for Acute Care Trialists (InFACT), the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) and the Surviving Sepsis Campaign 2019 and were adapted from the previously published Clinical management of severe acute respiratory infection when Middle East respiratory syndrome coronavirus (MERS-CoV) infection is suspected: interim guidance (117).
For the third version (v3) of the COVID-19 clinical guideline the WHO Steering Committee expanded the scope from the previous versions to include recommendations on the full spectrum of disease (mild, moderate in addition to severe) and the full patient care pathway, from screening to rehabilitation. A GDG comprising individuals with broad expertise spanning multiple specialties and all regions was convened. Because of the accelerated timeline and very broad scope of the third version of the guideline, it was not feasible to undertake a formal GRADE process (PICO questions; systematic reviews; formal documentation of values and preferences; and incorporation of considerations of costs, resources, and feasibility) for each recommendation. Instead, PICOs were drafted and published evidence was synthesized under the coordination of the Science Division. The WHO Steering Committee drafted the recommendations about interventions based on these reviews. These draft recommendations and evidence summaries were pre-circulated to the GDG. The GDG was convened over multiple meetings, and consensus was achieved for all recommendations. The direction and strength of recommendations were presented using symbols rather than formal GRADE terminology (strong and conditional recommendations with grading of certainty of evidence, or best practice statements).
Subsequent versions of the guideline made new recommendations, using an innovative dynamic updating process. The methods are aligned with the WHO Handbook for guideline development (57).
In version (v4), three recommendations were made to use non-invasive (HFNO and continuous positive airway pressure) devices in hospitalized patients with COVID-19 that are severe or critical with acute hypoxic respiratory failure. Two systematic reviews/metaanalyses, one based on direct PICO (COVID-19 patients), and the other based on an indirect PICO (patients with ARDS and hypoxaemic respiratory failure) provided the data for the development of these recommendations.
For version (v5), the guideline development considered one overarching PICO for adult post COVID-19 condition population (WHO clinical case definition, 19 years old), disaggregated by age and gender. The GDG made 16 conditional recommendations and one strong recommendation. Following a scoping review commissioned by the WHO Rehabilitation Programme with support from the Quality Assurance of Norms and Standards (QNS) unit, recommendations were derived from the independent systematic review and indirect evidence by Cochrane systematic reviews (Annex 6, 7 and 8)
Concerning Version (v6), three recommendations were made based on direct and indirect systematic review and meta-analysis, and a scoping review (3). PICOs were: 1) isolation for 5 days; and 2) removal of isolation based on negative rapid antigen test as compared with earlier WHO recommendations (for symptomatic patients: 10 days after symptom onset plus 3 additional days without symptoms; and for asymptomatic patients: 10 days after positive test). Moreover, subgroup analysis for asymptomatic and symptomatic patients, and the use of antigen testing for de-isolation and estimation of number for hospitalization and/or death by simple modelling was conducted.

# Who the recommendations apply to
The recommendations in the clinical management living guidelines are broadly applicable to anyone involved directly or indirectly in the care of patients with COVID-19, i.e. clinicians, allied health care workers and hospital administrators.
This guideline applies to all patients with COVID-19. Recommendations may differ based on the severity of COVID-19, according to WHO severity definitions (see below) (6). These definitions avoid reliance on access to health care to define patient subgroups.

# WHO definitions of disease severity for COVID-19
- Critical COVID-19 -Defined by the criteria for acute respiratory distress syndrome (ARDS), sepsis, septic shock, or other conditions that would normally require the provision of life-sustaining therapies such as mechanical ventilation (invasive or noninvasive) or vasopressor therapy.
- Severe COVID-19 -Defined by any of:
- oxygen saturation < 90% on room air;
- severe pneumonia;
- signs of severe respiratory distress (in adults, accessory muscle use, inability to complete full sentences, respiratory rate > 30 breaths per minute; and, in children, very severe chest wall in-drawing, grunting, central cyanosis, or presence of any other general danger signs including inability to breastfeed or drink, lethargy, convulsions or reduced level of consciousness).
- Non-severe COVID-19 -Defined as the absence of any criteria for severe or critical COVID-19.
Caution : The GDG noted that the oxygen saturation threshold of 90% to define severe COVID-19 was arbitrary, and should be interpreted cautiously when defining disease severity. For example, clinicians must use their judgment to determine whether a low oxygen saturation is a sign of severity or is normal for a given patient with chronic lung disease. Similarly, clinicians may interpret a saturation of 90-94% on room air as abnormal in the patient with normal lungs, and as an early sign of severe disease in patients with a downward clinical trajectory. Generally, in cases where there is doubt, the GDG suggested erring on the side of considering disease as severe.
The infographic illustrates these three disease severity groups and key characteristics to apply in practice.
Infographic co-produced by the BMJ and MAGIC; designer Will Stahl-Timmins (see BMJ Rapid Recommendations).
Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. Symptoms may be new onset following initial recovery from an acute COVID-19 episode, or persist from the initial illness period (WHO clinical case definition). Symptoms and impairments can present as either clusters or isolated symptoms, that limit daily activities and restrict social participation. Symptoms may be present for prolonged timeframes and/or relapse over time.

# COVID-19 care pathway (see Annex 1)
Isolation and care

# Infectious period and de-isolation Evidence To Decision
We recommend that COVID-19 care pathways be established at local, regional and national levels. COVID-19 care pathways are for persons with suspected or confirmed COVID-19.
- A person enters the COVID-19 care pathway after they are screened, based on a standardized case definition, including assessment of symptoms, and meeting criteria for a suspect case.
- Suspect cases may be referred to as "persons or patients under investigation" (PUIs) in some contexts.

# Conditional recommendation for
We suggest 10 days of isolation for individuals who are symptomatic due to SARS-CoV-2 infection (very low certainty evidence).
We suggest 5 days of isolation for individuals who are asymptomatic with SARS-CoV-2 infection (very low certainty evidence).
The benefits outlined by the GDG relate to the impact on subsequent hospitalization and mortality across contacts (very low certainty evidence) of a 10-day, compared with a 5-day, isolation period for symptomatic individuals. Symptomatic

# Benefits and harms
Clinical management of COVID-19: living guideline -World Health Organization (WHO)
The GDG emphasized that the available evidence for review was inadequate to issue a substantial change in recommendation from existing WHO guidance on duration of isolation for symptomatic individuals. The GDG emphasized that, from reviewing the evidence, there were likely important differences between symptomatic and asymptomatic individuals in the likelihood of transmitting infectious virus between 5 and 10 days of isolation. The marked apparent substantially greater likelihood of transmission between days 5 to 10 in symptomatic versus asymptomatic patients led to separate recommendations for these two populations. There remains a high degree of uncertainty in accurately classifying patients into symptomatic and asymptomatic groups, but not so great as to render the differentiation inappropriate for decision-making.
The role of rapid antigen tests in determining infectivity, and inter-individual variation in duration of positivity, was highlighted as a major challenge in justifying a major change to the recommendations. This was highlighted as another major evidence gap.
The GDG discussed that hospitalization and mortality among contacts remain the crucial outcomes for consideration. Other important outcomes were not formally incorporated into the evidence evaluation, such as post-COVID-19 condition or COVID-19 disease among contacts, given the available evidence. Future iterations of this guidance may incorporate alternate outcomes such as those.
individuals are much more likely to test positive than asymptomatic individuals and thus much more likely to transmit SARS-CoV-2. This provides the rationale, despite the very low certainty evidence on the impact of isolation on subsequent transmission, hospitalization, and mortality, for the suggestion for 10 days in symptomatic and 5 days in asymptomatic cases. A shortened isolation period, where safe, was agreed-upon as preferable as part of the values and preferences, which further informed the recommendation for 5 days of isolation for asymptomatic individuals.
Harms of varying periods of isolation, such as mental health, financial or social impacts, were not formally incorporated into the evidence review, given the uncertainty involved.
The evidence reviewed to inform this recommendation was deemed to be of very low certainty, rated down due to the high degree of uncertainty in the parameters that inform the model and the indirectness of the data. Specifically, there is a great deal of uncertainty across the following assumptions: i) the infectivity of individuals with positive rapid antigen test; ii) the effective reproduction number; iii) the assumed hospitalization rate of infected individuals; and iv) the assumed case-fatality rate of infected individuals. Additional sources of uncertainty lie in understanding the contributing role of different public health measures in place in different regions of the world, vaccination status, history of prior infection and the infecting SARS-CoV-2 VoC and resultant changes to infectivity and severity. Evidence was reviewed regarding the duration of viral culture positivity and PCR positivity, which were both deemed to be of very low certainty.
A large source of uncertainty, as voiced by the GDG and not consistently defined in the available evidence, was the definition of what constituted symptomatic infection. From clinical experience, noted by the GDG, classifying patients as either symptomatic or asymptomatic was not always straightforward.

# Certainty of the Evidence
- Given anticipated strong preferences in most individuals for shorter periods of isolation, and the positive social and economic consequences of shorter periods of isolation, the GDG placed a high value on shorter periods of isolation. - Despite the very low certainty evidence, the GDG placed a high value on the possible increase, in symptomatic patients, of transmission and resulting hospitalization from a shorter period of isolation. - The GDG nevertheless acknowledged the substantial variability in these values and preferences that are likely to exist.

# Values and preferences
The GDG emphasized that there are substantial resource considerations in asking individuals with mildly symptomatic disease to isolate for 5 days. These resource considerations should be incorporated into policies to ensure that the impact of periods of isolation on individuals is minimized as it relates to financial, social, or mental health specific impacts.

# Resources and other considerations

# Very low
Due to certainty of parameters in the model and indirectness.
Whether Isolation for 5 days would increase onward transmission leading to death of secondary cases is very uncertain compared with isolation for 10 days.

# Conditional recommendation for
We suggest the use of rapid antigen testing to reduce the period of isolation (very low certainty evidence).
The possible benefit is on average a reduction of 3 days' isolation period by using rapid tests to determine the period of isolation (very low certainty evidence).
There are minimal harms of employing rapid tests to determine the period of isolation.

# Benefits and harms
The evidence was of very low certainty, rated down for indirectness and uncertainty in the included model parameters. Additional sources of uncertainty from the above recommendations that were not formally evaluated included evaluations of the sensitivity and specificity of various types of rapid tests, the swab technique employed, vaccination status, history of prior infection or the infecting variant, leading to greater uncertainty as assessed by the GDG.

# Certainty of the Evidence
Given anticipated strong preferences in most individuals for shorter periods of isolation, and the positive social and economic consequences for shorter periods of isolation, the GDG placed a high value on shorter periods of isolation.
The GDG nevertheless acknowledges the substantial variability in these values and preferences that are likely to exist.

# Values and preferences
The GDG acknowledged that the resource implications of prolonged periods of isolation may be considerable and reach beyond the individual, with varying social, economic, and mental health impacts. Implementation of the above

# Resources and other considerations
Clinical management of COVID-19: living guideline -World Health Organization (WHO)
There is very low certainty evidence that using rapid antigen tests to decrease duration of isolation will have trivial effects on transmission and subsequent hospitalization.
With values and preferences of the GDG preferring shorter periods of isolation, given the uncertainty of the data, incorporating rapid antigen tests into algorithms for discontinuing isolation periods was deemed reasonable, acknowledging very low certainty of the available evidence regarding the impact of shorter periods of isolation on transmission and resulting hospitalization. There was no apparent difference across symptomatic or asymptomatic individuals in the use of rapid antigen tests to shorten the period of isolation.

# Research Needs
Uncertainties, emerging evidence, and future research Despite the guidance for discontinuation of transmission-based precautions (including isolation) and release from the COVID-19 care pathway, there remain uncertain outcomes associated with the onward transmission of SARS-CoV-2 infection, as well as implications for the duration of isolation required for patients. Future research could be influenced by these uncertainties, i.e. the generation of more credible and relevant evidence for policy and practice in relation to onward transmission and adverse outcomes.
- Role and effectiveness of antigen test to accurately predict SARS CoV-2 onward transmission in symptomatic and asymptomatic patients; - Evaluation of the sensitivity and specificity of various types of rapid tests on the onward transmission of SARS CoV-2; - Determination of outcomes, hospitalization, ICU admission, mortality, and post COVID-19 condition and the moderation role of symptomatic and asymptomatic, variants, vaccination, and reinfections; - Determination of optimal duration of isolation. recommendations should incorporate policies to ensure those considerations are addressed.

# Immediate implementation of appropriate infection prevention and control measures
This guidance brings together infection prevention and control (IPC) technical guidance developed and published since the beginning of the COVID-19 pandemic. IPC guidelines are currently under review and an updated version will be released soon.
For additional information please see the following links:

# Infection prevention and control during health care when coronavirus disease (COVID-19) is suspected or confirmed (137).

# Infection prevention and control in the context of coronavirus disease (COVID-19): A living guideline (in MAGICapp).
IPC measures for patients with suspected or confirmed COVID-19: Health facilities should adhere to key WHO recommended IPC measures, in particular, adhering to respiratory etiquette and hand hygiene best practices, contact, droplet and airborne precautions, adequate environmental cleaning and disinfection; ensuring adequate ventilation; isolation facilities of COVID-19 patients; in addition, where possible, maintaining a physical distance among all individuals in health facilities of at least 1 metre (increasing it whenever feasible), especially in indoor settings.

# Apply standard precautions for all patients
Apply standard precautions according to risk assessment for all patients, at all times, when providing any diagnostic and care services. Standard precautions include but are not limited to, hand and respiratory hygiene and the appropriate use of PPE; universal masking is required for all persons in areas of known or suspected community or cluster SARS-CoV-2 transmission. Standard precautions also include appropriate patient placement; environmental cleaning; prevention of needle-stick or sharps injury and safe waste management.
Carefully practice hand hygiene frequently using an alcohol-based hand rub (ABHR). Wash hands if visibly dirty with soap and water and disposable towels. Perform hand hygiene, before PPE use and after PPE removal, and when indicated while providing care, according to the WHO Five Moments for hand hygiene.
If possible, use either disposable or dedicated equipment (e.g. stethoscopes, blood pressure cuffs, pulse oximeters and thermometers). If equipment needs to be shared among patients, clean and disinfect between each patient use. Ensure that health care workers avoid contaminating environmental surfaces that are not directly related to patient care (e.g. door handles and light switches) and refrain from touching their eyes, nose and mouth with potentially contaminated gloved or ungloved hands. All surfaces should be routinely cleaned and disinfected, especially high touch surfaces, those surfaces touched by patients and whenever visibly soiled or if contaminated with blood and body fluids.
Best practices for safely managing health care waste, including waste related to surgeries and obstetric care, should be followed.

# Screen for early recognition of suspected COVID-19 patients and rapid implementation of source control measures
Screen all persons at first point of contact in health facility to allow for early recognition followed by immediate isolation/separation. Suspected or confirmed COVID-19 patient to wear a medical mask and placement in a separate, well-ventilated area, ideally an isolation room/area if available. Keep at least 1 m distance between patients. Instruct all patients to cover nose and mouth during coughing or sneezing with tissue or flexed elbow, dispose of tissues safely immediately after and perform hand hygiene after contact with respiratory secretions. In areas with COVID-19 community transmission, restrict visitors to those that are essential such as the parents of pediatric patients and caregivers and ask them to wear a mask.
Adequate ventilation rates within defined spaces in health facilities are generally addressed by national regulations. Environmental and engineering controls play a key role in reducing the concentration of infectious respiratory aerosols in the air and the contamination of surfaces and inanimate objects.

# Mask use in health care facilities
WHO recommends using face protection as part of a comprehensive package of IPC measures to limit the spread of SARS-CoV-2. National policies and health facilities must continue to achieve and maintain IPC measures, including having an IPC programme or, at minimum, a dedicated and trained IPC focal point in place. Other necessary measures include engineering, environmental and administrative controls, standard and transmission-based precautions, screening and triage for early identification of cases and COVID-19 surveillance and vaccination of health workers. For full recommendation on mask use in health care facilities, see Infection prevention and control in the context of coronavirus disease (COVID-19): A living guideline (in MAGICapp).

# Isolate and cohort patients with suspected or confirmed COVID-19
Where possible, designate a team of health workers to care for patients with suspected or confirmed COVID-19 and restrict their contact with COVID-19 patients. Place all cases in well ventilated single rooms if feasible. When single rooms are not available or bed occupancy rate is anticipated to be 100% or more, suspected, probable or confirmed COVID-19 patients should be grouped together (cohorted) in adequately ventilated areas with bed space at least 1 m apart.
Limit patient movement within the institution and ensure that patients wear medical masks when outside of their care area (e.g. when being transported).

# Apply transmission-based precautions
In addition to standard precautions, apply transmission-based precautions (contact, droplet and/or airborne precautions) where indicated. Use contact and droplet precautions before entering a room where there is a patient with suspected or confirmed COVID-19. In settings where aerosol-generating procedures (AGP) are performed among patients with suspected or confirmed COVID-19, perform procedures in an adequately ventilated room and use appropriate PPE (N95 respirator, FFP2 or equivalent).

# Strong recommendation for

# Universal and targeted continuous masking

# In areas of known or suspected community or cluster SARS-CoV-2 transmission, universal masking is recommended (very low certainty evidence) in health care facilities:
In settings where caring for non-COVID-19 patients, unless differently specified (e.g. AGP), all health workers, including community health workers and caregivers, other staff, visitors, outpatients and service providers, should wear a well-fitting medical mask at all times within the health facility and in any common area (e.g. cafeteria, staff rooms).
Inpatients are not required to wear a medical mask unless physical distancing of at least 1 metre cannot be maintained (e.g. during examinations or bedside visits) or when outside of their care area (e.g. when being transported), provided the patient is able to tolerate the mask and there are no contraindications.

# For full recommendations and additional details, see: Infection prevention and control in the context of coronavirus disease (COVID-19): A living guideline (in MAGICapp).
Clinical management of COVID-19: living guideline -World Health Organization (WHO)

# Conditional recommendation for

# In areas of known or suspected sporadic SARS-CoV-2 transmission, targeted continuous medical mask use is recommended (very low certainty evidence) in health care facilities:
In settings when caring for non-COVID-19 patients, health workers, including community health workers and caregivers who work in clinical areas, should continuously wear a well-fitting medical mask during routine activities throughout the entire shift, unless differently specified (e.g. when performing AGP) and apart from when eating and drinking.
In non-patient areas, staff are not required to wear a medical mask during routine activities if they have no patient contact.
For full recommendations and additional details, see: Infection prevention and control in the context of coronavirus disease (COVID-19): A living guideline (in MAGICapp).

# Conditional recommendation for
A respirator or a medical mask should be worn (very low certainty evidence) by health workers along with other PPE (gown, gloves and eye protection) before entering a room where there is a patient with suspected or confirmed COVID-19.

# For full recommendations and additional details, see: Infection prevention and control in the context of coronavirus disease (COVID-19): A living guideline (in MAGICapp).
Respirators should be worn in the following situations:
- In care settings where ventilation is known to be poor or cannot be assessed, or the ventilation system is not properly maintained - Based on health workers' values and preferences and on their perception of what offers the highest protection possible to prevent SARS-CoV-2 infection.

# Screening, triage and clinical assessment: early recognition of patients with COVID-19
The primary objective of the COVID-19 global response is to slow and stop transmission, find, isolate and test every suspect case, and provide timely appropriate care of patients with COVID-19. The recommended location of care will depend on the epidemiologic scenario and be either at a designated COVID-19 health facility, community facility or, where not possible, at home. Refer to the WHO Operational considerations for case management of COVID-19 in health facility and community (1).
We recommend screening all persons at the first point of contact with the health system in order to identify individuals that have suspected or confirmed COVID-19.

# Practical Info
Existing prognostic models are reviewed in a living systematic review, available at /.
Available prognostic models need to be validated in other populations.

# Evidence To Decision
In community settings, community health workers should continue to follow usual protocols for recognition and treatment of other common illnesses and danger signs while activating the COVID-19 care pathway (including for referral as needed) for suspect cases. Refer to WHO/IFRC/UNICEF guidance on community-based health care, including outreach and campaigns, in the context of the COVID-19 pandemic (157).
At a health facility, after screening and isolation, triage patients with suspected COVID-19 using a standardized triage tool (such as the WHO/IFRC Interagency Integrated Triage Tool); and evaluate the patient to determine disease severity (see Table 6.3).
- Initiate timely care for the acutely ill using a systematic approach, as described in WHO/ICRC Basic emergency care (159)

# Conditional recommendation for
For patients COVID-19 of any severity assessed in a clinic or hospital, we suggest clinical judgment, including consideration of patients' values and preferences and local and national policy if available, to guide management decisions including admission to hospital and to the ICU, rather than currently available prediction models for prognosis (conditional recommendation, very low certainty).
Clinical judgment and policy developed locally or nationally are typically used to make decisions regarding admission of patients with COVID-19 to hospital and to the ICU. Judgment and policy may include ethical considerations regarding allocation of

# Important harms

# Benefits and harms
Clinical management of COVID-19: living guideline -World Health Organization (WHO)
The GDG emphasized the very low certainty evidence supporting the use of prognostic models to enhance clinical decision-making and patient outcomes, and recognized the lack of studies and uncertain feasibility in resource-constrained settings and potential negative impact on health equity, depending on how prognostic models are used to inform clinical decisions. Accordingly, the GDG made a conditional recommendation in favour of usual practice to guide decision-making, consisting of clinical judgement, patients' values and preferences, and local and national policy, if available.

# Subgroup analyses
The GDG did not find any evidence bearing on subgroup effects across patients with different levels of COVID-19 disease severity or between children and adults. In other words, the conditional recommendation is applicable across all these subgroups.

# Special populations
There is insufficient information on the performance and impact of prognostic models in pregnant women. Therefore, the GDG concluded that the recommendation applies to pregnant women.
resources. Over the course of the pandemic, many models have been developed for patients with COVID-19 to predict hospital admission, ICU admission, need for mechanical ventilation, mortality, or other outcomes. All existing models are at unclear or high risk of bias using the multiple domain PROBAST assessment tool (28), and there are as yet no studies of whether the use and implementation of these models improves (shared) decision-making and subsequent patient outcomes. With respect to their effects on patient outcomes, the certainty of evidence for any of these prognostic models is very low.
The GDG considered the evidence in favour of prognostic models in patients with COVID-19 to be of very low certainty, due to risk of bias, insufficient predictive accuracy with many models (range of C-statistics for prognosis models 0.54 to 0.99), lack of validation studies, and lack of evidence of the impact of using models on decision-making and patient outcomes. A review and assessment of existing models on their applicability and risks of bias is available (/). These prediction models for patient prognosis are distinct from triage models that have been developed to decide which patients are offered admission (typically to an ICU); triage models were not reviewed.
The GDG acknowledged that ongoing model development and validation, along with studies of predictive accuracy and impact on decision-making and patient outcomes of those selected models with sufficient predictive accuracy, may change the certainty of evidence in the future.

# Very low

# Certainty of the Evidence
Applying the agreed values and preferences, the GDG inferred that the majority of well-informed physicians and patients would not want care decisions to be based on existing prognostic models, due to the very low certainty of evidence for benefit on patient outcomes. Given the lack of evidence of harm, some patients may choose to have their care informed by the use of such models.

# Substantial variability is expected or uncertain

# Values and preferences

# Important considerations
Commonly included predictors in these prognostic models include age, sex, comorbidities, vital signs (e.g. temperature, heart rate, respiratory rate, oxygen saturation, blood pressure), imaging features, lymphocyte count, and C reactive protein (/). Some laboratory tests and imaging modalities may not be available in resourceconstrained settings, and existing models have not been validated such settings.

# Resources and other considerations
Clinical management of COVID-19: living guideline -World Health Organization (WHO)  (66). Loss of smell (anosmia) or loss of taste (ageusia) preceding the onset of respiratory symptoms has also been reported (14)(176) (67).
Additional neurological manifestations reported include dizziness, agitation, weakness, seizures, or findings suggestive of stroke including trouble with speech or vision, sensory loss, or problems with balance in standing or walking (15) (16).
Older people and immunosuppressed patients in particular may present with atypical symptoms such as fatigue, reduced alertness, reduced mobility, diarrhoea, loss of appetite, confusion, and absence of fever (61)(142) (144).
Symptoms such as dyspnoea, fever, gastrointestinal (GI) symptoms or fatigue due to physiologic adaptations in pregnant women, adverse pregnancy events, or other diseases such as malaria, may overlap with symptoms of COVID-19 (68).
Children might not have reported fever or cough as frequently as adults (69).

# Moderate disease Pneumonia
Adolescent or adult with clinical signs of pneumonia (fever, cough, dyspnoea, fast breathing) but no signs of severe pneumonia, including SpO2  90% on room air.
Child with cough or difficulty breathing + fast breathing and/or chest indrawing and no signs of severe pneumonia.
Fast breathing: < 2 months:  60 breaths/min; 2-11 months:  50; 1-5 years:  40.
The diagnosis can be made on clinical grounds; chest imaging (radiograph, CT scan, ultrasound) may assist in diagnosis and identify or exclude pulmonary complications.
The oxygen saturation threshold of 90% to define severe COVID-19 is arbitrary and should be interpreted cautiously. For example, clinicians must use their judgment to determine whether a low oxygen saturation is a sign of severity or is normal for a given patient with chronic lung disease. Similarly, a saturation between 90-94% on room air may be abnormal (in patient with normal lungs) and can be an early sign of severe disease, mainly if patient is on a downward trend. Generally, if there is any doubt, the panel suggested erring on the side of considering the illness as severe..

# Severe disease

# Severe pneumonia
Adolescent or adult with clinical signs of pneumonia (fever, cough, dyspnoea) plus one of the following: respiratory rate > 30 breaths/min, severe respiratory distress, or SpO2 < 90% on room air.
Child: with clinical signs of pneumonia (cough or difficulty breathing + fast breathing or chest wall indrawing) + at least one of the following:
- SpO2 < 90%
- Very severe chest indrawing, grunting, central cyanosis, or presence of any other general danger sign (inability to breastfeed or drink, lethargy or unconsciousness or convulsions).
The diagnosis can be made on clinical grounds; chest imaging (radiograph, CT scan, ultrasound) may assist in diagnosis and identify or exclude pulmonary complications. a Oxygenation Index (OI) is an invasive measurement of the severity of hypoxaemic respiratory failure and may be used to predict outcomes in paediatric patients. It is calculated as follows: percentage of fraction of inhaled oxygen multiplied by the mean airway pressure (in mmHg), divided by the partial pressure of arterial oxygen (in mmHg), divided by the partial pressure of arterial oxygen (in mmHg). Oxygen Saturation Index (OSI) is a non-invasive measurement and has been shown to be a reliable surrogate marker of OI in children and adults with respiratory failure. OSI replaces PaO2 with oxygen saturation as measured by pulse oximetry (SpO2) in the OI equation.
Sepsis   Adults: acute life-threatening organ dysfunction caused by a dysregulated host response to suspect or proven infection. Signs of organ dysfunction include: altered mental status (delirium), difficult or fast breathing, low oxygen saturation, reduced urinary output, fast heart rate, weak pulse, cold extremities or low blood pressure, skin mottling, laboratory evidence of coagulopathy, thrombocytopenia, acidosis, high lactate or hyperbilirubinaemia.
Children: suspected or proven infection and  2 age-based systemic inflammatory response syndrome (SIRS) criteria, b of which one must be abnormal temperature or white blood cell count.
b SIRS criteria: abnormal temperature (> 38.5 C or  10% bands.   Adults: persistent hypotension despite volume resuscitation, requiring vasopressor to maintain MAP  65 mmHg and serum lactate level > 2 mmol/L.

# Septic shock
Children: any hypotension (SBP  150 bpm in children); prolonged capillary refill (> 2 sec) or weak pulse; fast breathing; mottled or cool skin or petechial or purpuric rash; high lactate; reduced urine output; hyperthermia or hypothermia.

# Acute thrombosis
Acute venous thromboembolism (i.e. pulmonary embolism), acute coronary syndrome, acute stroke.
Preliminary case definition: children and adolescents 0-19 years of age with fever  3 days AND two of the following: rash or bilateral non purulent conjunctivitis or muco-cutaneous inflammation signs (oral, hands or feet); hypotension or shock; features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including ECHO findings or elevated troponin/NT-proBNP); evidence of coagulopathy (PT, PTT, elevated D-dimers); acute gastrointestinal problems (diarrhoea, vomiting or abdominal pain); AND elevated markers of inflammation such as ESR, C-reactive protein, or procalcitonin AND no other obvious microbial cause of shock syndrome AND evidence of COVID-19 (RT-PCR, antigen test or serology positive), or likely contact with patients with COVID-19.

# Laboratory diagnosis
This guidance brings together diagnostic technical guidance developed and published since the beginning of the COVID-19 pandemic.
- Antigen-detection in the diagnosis of SARS-CoV-2 infection (184); 2. Use of SARS-CoV-2 antigen-detection rapid diagnostic tests for COVID-19 self-testing (186); and 3. Diagnostic testing for SARS-CoV-2 interim guidance regarding specimen collection, processing and laboratory testing and the diagnostic algorithm (188).
We recommend, for all suspect COVID-19 cases, at minimum the collection of respiratory specimens for nucleic acid amplification testing (NAAT) for example reverse transcription polymerase chain reaction (RT-PCR). Repetitive testing of upper respiratory tract (URT) and/or lower respiratory tract (LRT) might be needed to establish a diagnosis (190). Additional samples that might aid the diagnosis of COVID-19 can be faecal specimens (if appropriately validated by the receiving laboratory). If deceased consider the collection of postmortem specimens (188). In addition, testing for other respiratory viruses and bacteria should be considered when clinically indicated according to local guidelines.

# SARS-CoV-2 antibody tests are not recommended for diagnosis of current infection with COVID-19.
Remarks: For COVID-19 patients with severe or critical disease, also collect blood cultures, ideally prior to initiation of antimicrobial therapy (70).
If blood cultures cannot be taken timely before the administration of antimicrobial therapies, indicate the details of administered antibiotics on the laboratory request.

# COVID-19 Self-testing
Strong recommendation for COVID-19 self-testing, using SARS-CoV-2 Ag-RDTs, should be offered in addition to professionally administered testing services (low to moderate certainty evidence)
For full recommendations and additional details, see: Use of SARS-CoV-2 antigen-detection rapid diagnostic tests for COVID-19 selftesting (186).

# Management of mild COVID-19: symptomatic treatment
Patients with mild disease may present to an emergency unit, primary care/outpatient department, or be encountered during community outreach activities, such as home visits or by telemedicine.
We recommend that patients with suspected or confirmed mild COVID-19 be isolated to contain virus transmission according to the established COVID-19 care pathway. This can be done at a designated COVID-19 health facility, community facility or at home (self-isolation).
- In areas with other endemic infections that cause fever (such as malaria, dengue, etc.), febrile patients should be tested and treated for those endemic infections per routine protocols (148)

# Management of moderate COVID-19
Patients with moderate disease may present to an emergency unit or primary care/outpatient department, or be encountered during community outreach activities, such as home visits or by telemedicine. See Table 6.3 for definition of non-severe pneumonia.

# Practical Info
The GDG made a conditional recommendation for the use of home pulse oximetry monitoring. This recommendation is predicated on the availability and accessibility of high-quality and reliable pulse oximeters for home use; the integration of home pulse oximetry into a health system, from a training and human resources perspective; and targeting the intervention to patients who would likely get the most benefit, namely those at high-risk and those who are symptomatic. Also, no recommendation was made on the frequency or duration of pulse oximetry monitoring. Note: training on appropriate IPC (cleaning and disinfection) should be included.
The panel encourage further research to clarify uncertainties, especially in low-resource settings. Research gaps remain as to ensuring standards of quality across pulse oximeter devices.

# Evidence To Decision
We recommend that patients with suspected or confirmed moderate COVID-19 (pneumonia) be isolated to contain virus transmission. Patients with moderate illness may not require emergency interventions or hospitalization; however, isolation is necessary for all suspect or confirmed cases.
- The location of isolation will depend on the established COVID-19 care pathway and can be done at a health facility, community facility or at home. - The decision on location should be made on a case-by-case basis and will depend on the clinical presentation, requirement for supportive care, potential risk factors for severe disease, and conditions at home, including the presence of vulnerable persons in the household.
- For patients at high risk for deterioration (see Table 6.2), isolation in hospital is preferred.
In areas with other endemic infections that cause fever (such as malaria, dengue, etc.), febrile patients should be tested and treated for those endemic infections per routine protocols (62)(148)(117), irrespective of the presence of respiratory signs and symptoms. Coinfection with COVID-19 may occur.

# Conditional recommendation for
For symptomatic patients with COVID-19 and risk factors for progression to severe disease who are not hospitalized, we suggest the use of pulse oximetry monitoring at home as part of a package of care, including patient and provider education and appropriate follow-up (conditional recommendation, very low certainty evidence).

# Uncertain benefits or harms
Possible theoretical benefits of home oximetry monitoring include earlier detection of and intervention for severe disease (such as more intense monitoring for deterioration or starting corticosteroid therapy), patient reassurance in case of normal values, limiting hospital strain due to prevented admission of patients who may not need acute care, and increased opportunities for patient-provider educational conversations (very low certainty).
Possible harms of home oximetry monitoring include the possibility of increased patient anxiety and stress, the possibility of increased hospital visits for patients who would otherwise not seek out hospital care, and the possibility of false reassurance with misinterpretation of the data. Low quality or inaccurate pulse oximeters, particularly with pulse oximeters not validated in different skin colours, may provide false reassurance or false alarms (very low certainty). The GDG suggested that the possible benefits would outweigh the possible harms, and this may be most likely in specific subgroups of patients, i.e. those with symptoms and those with risk factors for severe disease. The GDG also suggested that the

# Benefits and harms
Clinical management of COVID-19: living guideline -World Health Organization (WHO)
When moving from evidence to the conditional recommendation for the use of home pulse oximetry monitoring for patients with COVID-19, the panel emphasized the lack of evidence in either direction and the need for high-quality clinical trials examining both patient symptoms of stress, as well as other clinical outcomes listed above. The panel also emphasized contextual factors, such as resource-considerations, accessibility, feasibility, and impact on health equity as important considerations. Ultimately, the panel thought that the theoretical benefit targeted to symptomatic and high-risk populations was notable only as part of a larger package of care including education and follow-up. Important caveats raised by the panel included the importance of integrating any intervention with education between providers and patients about the meaning of relevant output from the pulse oximeter and ability to act on results.

# Subgroup analyses
There were insufficient data based on the presented data to perform any subgroup analyses.

# Special populations
There is no evidence for home pulse oximetry monitoring for patients with COVID-19 in special populations. Considerations for implementation and applicability centred around focusing on higher-risk populations, where benefits would be most notable. Please see Table 7.2 for information on definitions of who would be considered high-risk for this implementation. intervention would only have benefit in symptomatic patients with COVID-19, and that asymptomatic patients would have no benefit.
For key outcomes of hospitalization, mortality, mechanical ventilation, and ICU admission the panel considered the evidence to be of very low certainty.

# Very low

# Certainty of the Evidence
Applying the agreed values and preferences, the GDG inferred that well-informed patients would consider the minimal possible harms associated with home oximetry monitoring to not outweigh the possible, theoretical benefits on the outcomes of hospitalization and patient satisfaction. Patient members of the panel agreed with this standard.

# No substantial variability expected

# Values and preferences

# Important considerations
Home oximetry monitoring is not accessible to many patients, due to lack of available equipment, lack of relevant personnel to monitor it, lack of ability to interpret the results at home, or lack of knowledge about implementation. Home pulse oximetry may be useful in certain settings, including low resource settings, particularly when hospitals are strained and where it may be necessary to effectively monitor patients in a home-based setting. However home oximetry monitoring will only be of value if the users are adequately informed on how to interpret the readings and have ready access to providers who can advise on the response to readings. Considerations for education and training of patients and providers, as well as adequate staffing, to implement care pathways with available access to acute care will need to be integrated.

# Resources and other considerations

# Very low
Due to serious risk of bias, Due to serious imprecision 5 No data re whether home SpO2 monitoring vs no monitoring affects hospitalization rates
Clinical management of COVID-19: living guideline -World Health Organization (WHO)
We recommend for patients with suspected or confirmed moderate COVID-19, that antibiotics should not be prescribed unless there is clinical suspicion of a bacterial infection.
- Evidence from a living rapid review and meta-analysis of bacterial co-infection in patients who were assessed for bacterial infection presenting with COVID-19 to hospital indicates that 4.4% of patients (95%CI 3.0-6.4%; n=125 212) had coinfection identified at hospital admission (216).

# Management of severe COVID-19

# Awake prone positioning (updated 18 August 2023)
Prone positioning is an intervention aimed at ameliorating poor oxygenation in patients with acute hypoxaemic respiratory failure. It has been mostly used in patients receiving mechanical ventilation (542) (543). During the pandemic, interest in awake prone positioning peaked as a result of the previously demonstrated benefit in mechanically ventilated patients. The physiological objective of prone positioning is to improve lung mechanics and gas exchange, with improved downstream clinical outcomes.
Awake prone position may be a treatment possibility in patients who are conscious, cooperative, breathing spontaneously, nonintubated and with stable cardiovascular status. Its appeal stems from potential utility in all resource settings, since it does not require complex devices or specialist critical care expertise to implement.
We recommend immediate administration of supplemental oxygen therapy to any patient with emergency signs during resuscitation to target SpO2  94% and to any patient without emergency signs and hypoxaemia (i.e. stable hypoxaemic patient) to target SpO2 > 90% or  92-95% in pregnant women.

# Practical Info
The GDG made a conditional recommendation for awake prone positioning in severely ill patients with COVID-19 requiring supplemental oxygen (including HFNO) or non-invasive ventilation.
Monitoring of patients and training of providers in caring for patients who are awake and prone, as part of multifaceted training for acute care management, are essential for implementation. Proning of severely ill and awake patients should be limited to those who do not have an immediate need for intubation due to concerns regarding airway protection, severe respiratory failure, or haemodynamic instability. In addition, patients being considered for proning should not be receiving non-invasive ventilation with high inflation pressures or be experiencing desaturation despite very high inspired oxygen concentrations. Patients for whom the safety of proning is considered borderline should be closely monitored. Supported side-lying can be considered in some patients as a reasonable alternative to full proning.
The optimal duration of proning was discussed by the panel, acknowledging that the median duration of proning received in the trials was 2.8 hours per day. This period was felt to be a reasonable target and noted that patients' motivation to turn prone and their and ability to turn supine in case of discomfort were important implementation considerations.

# Ongoing uncertainties and opportunities for future research:
The GDG acknowledged remaining uncertainties regarding awake prone positioning that need to be addressed, including:
- discomfort that patients may experience during the intervention;
- treatment effects in specific subgroups, such as children and older persons;
- optimal duration of prone positioning;
- quantitative estimates of health system resources needed for awake prone positioning, compared with invasive mechanical ventilation; - effectiveness of awake prone positioning for other infectious causes of acute respiratory failure not requiring immediate invasive mechanical ventilation.

# Evidence To Decision

# Conditional recommendation for
We suggest awake prone positioning for severely ill patients hospitalized with COVID-19 requiring supplemental oxygen (includes HFNO) or non-invasive ventilation (conditional recommendation for, moderate/low certainty evidence).
Twenty-one RCTs have addressed awake prone positioning for patients with COVID-19 not requiring invasive ventilation on supplemental oxygen. Awake prone positioning possibly reduces mortality (low certainty evidence) and probably reduces the need for invasive ventilation (moderate certainty evidence). Awake prone positioning possibly reduces ICU length of stay (low certainty evidence) and has little or no effect on hospital length of stay (high certainty evidence).
The possible harms of awake prone positioning are patient discomfort and pain, nausea, skin breakdown and dislodgement of vascular catheters. Inconsistent definitions and reporting precluded meta-analysis and formal GRADE assessment of these outcomes.
Small net benefit, or little difference between alternatives

# Benefits and harms
For patient-important outcomes of mortality and the need for mechanical ventilation, the panel considered the direct evidence to be of low and moderate certainty, respectively. For mortality, the certainty of evidence was rated down twice due to imprecision because the confidence interval was consistent with both important benefit and important harm. For need for invasive ventilation, the confidence interval was consistent with both important benefit and unimportant benefit

# Certainty of the Evidence
Clinical management of COVID-19: living guideline -World Health Organization (WHO)
When moving from evidence to the conditional recommendation for the use of awake prone positioning in severely ill hospitalized patients with COVID-19 requiring supplemental oxygen, the panel emphasized the moderate certainty evidence of reduction in the need for invasive mechanical ventilation. It also noted the limited evidence of harm with widespread experience with this intervention across different resource settings thus far.

# Subgroup analyses
No specific subgroups with a hypothesized direction of effect were highlighted by the panel.
and was thus rated down once for imprecision. For the outcomes of ICU and hospital length of stay, the panel considered the direct evidence to be of low and high certainty, respectively. The certainty in the evidence was rated down once for inconsistency and once for imprecision for ICU length of stay.
Given the available direct randomized evidence, indirect evidence from non-COVID-19 populations was not used in this assessment.
The panel placed a relatively high value on a modest reduction in invasive mechanical ventilation, and, since patients experiencing discomfort would be able to return to the supine position, a lower value on the discomfort patients experience using awake prone positioning.
From a systems perspective, the panel also appreciated, on the one hand, the variable workload that awake prone positioning places on staff (particularly nurses) and, on the other hand, advantages from fewer patients needing invasive mechanical ventilation.
No substantial variability expected

# Values and preferences
Patients who are able to follow instructions can often self-prone, without assistance from health care workers. Discomfort may arise in some circumstances; as these patients are awake, returning to the supine position would be a viable option. For patients who require assistance to be proned, personnel (primarily nurses) trained in the prone manoeuvre and in careful monitoring of patient respiratory status are required. The panel believed that this intervention should be feasible in all settings, but implementation requires resources for training and patient monitoring. The panel also believed that implementation of the intervention may be dependent on staffing requirements.
The panel also emphasized that there may be local cultural or contextual factors that may impact the implementation of prone positioning.
Important issues, or potential issues not investigated

# Resources and other considerations
Clinical Question/ PICO Population: Non-intubated patients with COVID-19 hypoxaemic respiratory failure
Awake prone positioning + usual care
No awake prone positioning
Data informing the Summary of Findings tables were extracted in an updated systematic review, available here (571).

# Study results and measurements

# No awake prone positioning

# Awake prone positioning + usual care

# Certainty of the Evidence (Quality of evidence)
Plain language summary 1. Inconsistency: no serious. Indirectness: no serious. Imprecision: very serious. The panel judged the confidence interval as consistent with both an important reduction in mortality and an important increase in mortality. Publication bias: no serious.
- Inconsistency: no serious. Indirectness: no serious. Imprecision: serious. The panel judged the confidence interval as consistent with both an important and an unimportant reduction in endotracheal intubation. Publication bias: no serious.
- Inconsistency: serious. Inspection of the forest plots showed important variation in point estimated and non-overlapping CIs for some trials. Indirectness: no serious. Imprecision: serious. The 95% CI was consistent with large benefit (3.8 fewer days) and small harm (0.24 more days). Publication bias: no serious. Use cautious fluid management in patients with COVID-19 without tissue hypoperfusion and fluid responsiveness.

# Attached Images
Patients with COVID-19 should be treated cautiously with intravenous fluids; aggressive fluid resuscitation may worsen oxygenation, especially in settings where there is limited availability of mechanical ventilation (131). This applies to both children and adults.

# Management of critical COVID-19: acute respiratory distress syndrome (ARDS)
The mortality in hospitalized and critically ill patients has varied substantially in different case series throughout the pandemic. The following recommendations are aligned with current international standards for management of all cause ARDS (70).

# Assessment and recognition

# Advanced non-invasive respiratory support
We recommend prompt recognition of progressive acute hypoxaemic respiratory failure when a patient with respiratory distress is failing to respond to standard oxygen therapy and adequate preparation to provide advanced oxygen/ventilatory support.
Patients may continue to have increased work of breathing or hypoxaemia even when oxygen is delivered via a face mask with reservoir bag (flow rates of 10-15 L/min, which is typically the minimum flow required to maintain bag inflation; FiO2 0.60-0.95). Hypoxaemic respiratory failure in ARDS commonly results from intrapulmonary ventilation-perfusion mismatch or shunt and usually requires mechanical ventilation (70).
All areas where severe patients may be cared for should be equipped with pulse oximeters, functioning oxygen systems and disposable, single-use, oxygen-delivering interfaces (nasal cannula, Venturi mask and mask with reservoir bag).
This includes areas in any part of health facilities, including emergency units, critical care units, primary care/outpatient clinics, as well as pre-hospital settings and ad hoc community facilities that may receive patients with severe COVID-19. See WHO Oxygen sources and distribution for COVID-19 treatment centres (132).

# Practical Info
There is no specific recommendation for the initial flow rate, FiO2, or titration scheme. Based on clinical experience of the panel, initial flow rates of between 50 and 60 L/min and initial FiO2 of 100% are suggested, titrated to patient SpO2 and work of breathing. In children, a fixed rate of 2 L/min/kg of body weight is suggested.
For infection prevention precautions related to the use of these respiratory support devices, please refer to Section 5 on IPC. See also research needs.

# What are advanced non-invasive respiratory support devices?
Broadly, these are devices that can provide respiratory support through their ability to provide higher oxygen flows or positive pressure or a combination of both. They are referred to as non-invasive as they do not involve the placement of a tube (e.g, endotracheal tube or tracheostomy tube) in the patient's airway (referred to as invasive approach).
There are three broad categories of devices that are referred to in our guidelines: high-flow nasal oxygen (HFNO); continuous positive airway pressure (CPAP); and non-invasive ventilation (NIV), also referred to as bilevel positive airway pressure (BiPAP). HFNO provides respiratory support predominantly through higher flows whereas CPAP and NIV provide support through a combination of higher flows and higher pressure.

# Summary of recommendations (see sections below for additional details and in-depth explanation)
- In hospitalized patients with severe or critical COVID-19 and acute hypoxaemic respiratory failure (AHRF) not needing emergent intubation, we suggest high-flow nasal oxygen (HFNO) rather than standard oxygen therapy (SOT) (conditional recommendation). - In hospitalized patients with severe or critical COVID-19 and acute hypoxaemic respiratory failure (AHRF) not needing emergent intubation, we suggest continuous positive airway pressure (CPAP) rather than standard oxygen therapy (SOT) (conditional recommendation). - In hospitalized patients with severe or critical COVID-19 and acute hypoxaemic respiratory failure (AHRF) not needing emergent intubation, we suggest non-invasive ventilation (NIV) rather than standard oxygen therapy (SOT) (conditional recommendation).
The GDG chose not to make a recommendation regarding HFNO versus CPAP vs NIV due to the uncertainty of the data. Clinicians should therefore choose between the these devices on the basis of considerations such as availability of devices and the supply of oxygen, their personal comfort and experience, and patient-specific considerations (such as claustrophobia that some patients experience with CPAP masks, and nasal discomfort that some patients experience with HFNO).

# Conditional recommendation for
In hospitalized patients with severe or critical COVID-19 and acute hypoxaemic respiratory failure (AHRF) not needing emergent intubation, we suggest high-flow nasal oxygen (HFNO) rather than standard oxygen therapy (SOT) (conditional recommendation).

# The GDG chose not to make a recommendation regarding high-flow nasal oxygen (HFNO) versus continuous positive airway pressure (CPAP) due to uncertainty of the data. Clinicians should therefore choose between the two on the basis of considerations such as availability of devices and the supply of oxygen, their personal comfort and experience, and patient-specific considerations (such as claustrophobia that some patients experience with CPAP masks, and nasal discomfort that some patients experience with HFNO).
The GDG elected to extend this recommendation to the paediatric age range (despite the absence of data), given the likely similar direction of benefit, but emphasized the need for more research in this population.

# Evidence To Decision
High-flow nasal oxygen, in comparison to standard oxygen therapy, may reduce mortality and need for invasive ventilation (direct PICO, low certainty evidence), probably reduces hospital length-of-stay and ICU length of stay (direct PICO, moderate certainty evidence) in patients with severe or critical COVID-19 experiencing AHRF but not requiring emergent intubation. Based on overall clinical experience with the device and its use among critically ill patients, the GDG was of the opinion that benefits are likely to supersede any potential harms.

# Benefits and harms

# Comparisons with SOT:
Among trials in patients with AHRF and COVID-19, for the outcomes of mortality and need for invasive mechanical ventilation there is low certainty in the evidence, due to very serious imprecision. For the outcome of hospital length of stay and ICU length-of-stay, there is moderate certainty in the evidence, due to serious imprecision.
Trials in non-COVID-19 ARDS provided low certainty evidence that high-flow nasal oxygen had little or no difference on mortality, compared with standard oxygen therapy, due to very serious imprecision. These trials also, however, also provided moderate certainty evidence of a decrease in the need for invasive mechanical ventilation and hospital length of stay. Effect on ICU length of stay was uncertain.

# Comparisons between devices or interfaces:
Trials in patients with COVID-19 and AHRF provided very low certainty evidence for the comparison between HFNO and helmet NIV for outcomes of mortality, hospital length of stay, ICU length of stay due to extremely serious imprecision; whereas there is low certainty evidence for outcome of need for invasive ventilation due to very serious imprecision, and low certainty evidence for the outcome of device-related comfort due to serious risk of bias and serious imprecision.
One trial in patients with COVID-19 and AHRF for the comparison of HFNO and CPAP provided very low certainty evidence for the outcome of mortality due to extremely serious imprecision. For the outcomes of need for invasive mechanical ventilation, hospital and ICU length of stay, the certainty of the evidence is low due to very serious imprecision.
Trials in non-COVID-19 ARDS provided very low certainty evidence for the comparison of HFNO and face mask NIV on the outcomes of mortality and need for invasive mechanical ventilation due to a combination of serious indirectness, serious risk of bias and very serious or serious imprecision. For the outcome of ICU length of stay, the certainty of evidence is low due to very serious imprecision.

# Certainty of the Evidence
Applying the agreed upon values and preferences, the GDG inferred that most well-informed patients with AHRF not requiring emergent intubation would choose to receive HFNO rather than standardoxygen therapy.

# Values and preferences
Studies of HFNO, CPAP, and NIV were conducted in high-resource settings with ICUs, health care workers experienced in these interventions, and resources for patient monitoring and rescue in case of clinical deterioration. The GDG emphasized that implementation of any non-invasive respiratory support intervention requires consideration of the local context of oxygen supply, training of health care providers, additional equipment for patient monitoring, considerations around maintenance of equipment, cost, and organization of service delivery. Availability of these additional resources has traditionally been restricted to areas within hospitals that provide intensive care. The GDG believed that the availability of these additional resources should be expanded to facilitate safe delivery of non-invasive respiratory support interventions globally.
A specific consideration for HFNO is that these devices may require a higher oxygen flow compared with other non-invasive respiratory support devices. Appropriate calculations of oxygen needs should be made at the facility level when expanding

# Resources and other considerations
Clinical management of COVID-19: living guideline -World Health Organization (WHO)
When moving from evidence to the conditional recommendation for patients hospitalized for COVID-19 with AHRF and not requiring emergent intubation, the panel emphasized the low certainty of evidence from direct comparisons in patients with COVID-19 for the important outcomes of mortality and need for invasive mechanical ventilation. The GDG incorporated the indirect evidence from patients without COVID-19 and AHRF, which had moderate certainty evidence for reducing invasive mechanical ventilation and hospital length-of-stay.
The GDG integrated the available evidence on the risk to health care workers due to infection transmission with the use of highflow nasal oxygen. There is currently insufficient evidence to inform recommendations for the outcome of health care worker transmission.

# Choosing between devices:
The GDG chose not to make recommendations among non-invasive respiratory support devices because of the very low or low certainty of evidence and variable contextual factors of oxygen supply, staff training, and patient monitoring that would weigh more heavily in utilization decisions, compared with evidence of clinical effectiveness.

# Research Needs
Further research is needed about:
- Between-device comparisons such as between HFNO and CPAP;
- The impact of varying levels of positive pressure provided by these devices on evolving lung injury in patients with ARDS;
- The risks of aerosol generation and risk of transmission to HCWs based on choice of respiratory support device;
- Staffing requirements and skills in deploying these devices in resource-limited settings as well as on cost and oxygen requirements from the use of these devices; - Specific populations such as children and pregnant women. clinical use of HFNO and other non-invasive respiratory devices.

# Clinical Question/ PICO Population:
Hospitalized patients with severe or critical COVID-19 and AHRF not needing emergent intubation

# Intervention: HFNO

# Comparator: SOT

# Summary Evidence Summary
The meta-analysis for the comparison of HFNO vs SOT was informed by 4 RCTs (74)(230)(75)(233) which enrolled a total of 1053 participants (direct PICO, i.e. COVID-19 patients with AHRF), and by 5 RCTs which enrolled a total of 1425 participants (indirect PICO, i.e. non-COVID-19 ARDS patients) (237). All the RCTs for the direct PICO were published. None of the trials evaluating the direct PICO included pregnant women or children. For the trials evaluating the indirect PICO, pregnant women and children were either excluded or there was no specific mention of their inclusion in methods or results sections of the trial (237).
For patients with severe or critical COVID-19, the GRADE Summary of Findings table shows the relative and absolute effects of HFNO compared with SOT for the outcomes of interest, with certainty ratings, informed by the metaanalysis.
Not all trials reported on all outcomes.
The meta-analysis for the comparison of HFNO vs SOT was informed by 4 RCTs (74)(230)(75) (233), which enrolled a total of 1053 participants (direct PICO, i.e. COVID-19 patients with AHRF) and by 5 RCTs which enrolled a total of 1425 participants (indirect PICO, i.e. non-COVID ARDS patients) (237). All the RCTs for the direct PICO were published. None of the trials evaluating the direct PICO included pregnant women or children. For the trials evaluating the indirect PICO, pregnant women and children were either excluded or there was no specific mention of their inclusion in methods or in the results sections (237).
For patients with severe or critical COVID-19, the GRADE Summary of Findings table shows the relative and absolute effects of HFNO compared with SOT for the outcomes of interest, with certainty ratings, informed by the metaanalysis.
Not all trials reported on all outcomes.

# Outcome Timeframe

# Study results and measurements

# Very low
Due to extremely serious inconsistency 5 We are very uncertain of the impact of HFNO on ICU LOS Clinical management of COVID-19: living guideline -World Health Organization (WHO)

# Practical Info
There is no specific recommendation as to the initial pressure to be used for CPAP, leaving to local clinical decision-making and patient-specific factors. Based on clinical experience of the GDG, there is a suggestion to start with a pressure of 5-10 cm H2O, titrated to patient comfort and work of breathing, with FiO2 titrated to achieve the target oxygen saturation when using facemask or oral-nasal mask. For use of helmet interfaces, additional information can be found in recent publications (355).
For infection prevention precautions related to the use of these respiratory support devices, please refer to Chapter 5 on IPC. See also Research needs.
-  2.  3. #tab=tab_1
Evidence To Decision 5. Inconsistency: very serious. The magnitude of statistical heterogeneity was high, with I^2: 85%, the direction of the effect is not consistent between the included studies. One RCT suggested large benefit while one RCT suggested large harm (rated down by three). Indirectness: no serious. Imprecision: no serious. Publication bias: no serious.

# Attached Images

# Conditional recommendation for
In hospitalized patients with severe or critical COVID-19 and AHRF not needing emergent intubation, we suggest CPAP, rather than standard oxygen therapy (conditional recommendation).
The GDG chose not to make a recommendation regarding optimal interface for CPAP, whether helmet or face mask, given the lack of direct data available for the comparison. The choice between interface should be guided by clinician experience, availability, and patient comfort.
The GDG chose not to make a recommendation regarding HFNO versus CPAP due to the uncertainty of the data. Clinicians should choose between the three on the basis of considerations such as availability of devices and the local supply of oxygen, their personal comfort and experience with the relevant devices, and patient-specific considerations (such as claustrophobia that some patients experience with CPAP/NIV masks, and nasal discomfort that some patients experience with HFNO).
Given the likely similar direction of benefit, the GDG chose to extend this recommendation to the paediatric age range (despite the absence of data), while emphasizing the need for more research in this population.
In patients with severe or critical COVID-19 and AHRF not requiring emergent intubation, CPAP, in comparison with standard oxygen therapy, may decrease mortality (direct PICO, low certainty evidence), probably decreases the need for invasive mechanical ventilation (direct PICO, moderate certainty evidence), may decrease hospital length-of-stay (direct PICO, low certainty evidence), and may have little or no impact on ICU length-of-stay (direct PICO, low certainty evidence).
Based on overall clinical experience with the device and its use among critically ill patients, the GDG was of the opinion that benefits are likely to supersede any potential harms.

# Benefits and harms
When moving from evidence to the conditional recommendation for patients hospitalized for COVID-19 with acute hypoxaemic respiratory failure not requiring emergent intubation, the panel noted the low certainty of evidence for the important outcomes of mortality, but the moderate certainty for reduction in the need for invasive mechanical ventilation. The panel incorporated indirect evidence from patients without COVID-19, but acknowledged the largely very low certainty in that evidence.

# Choosing between devices:
For the direct comparison of CPAP with high-flow nasal oxygen, the GDG noted the very low certainty evidence for the important outcome of mortality. The low certainty in the available evidence that CPAP, when compared with high-flow nasal oxygen, decreases the requirement for invasive mechanical ventilation also influenced the decision-making, and the panel felt that more evidence was required to make a recommendation for this comparison.
The panel integrated the available evidence on the risk to health care workers due to infection transmission with the use of CPAP. There is currently insufficient evidence to inform recommendations for the outcome of health care worker transmission.

# Research Needs
Further research is needed about:
- The optimal choice of interface while delivering CPAP (helmet vs face mask, etc); - Between-device comparisons such as between HFNO and CPAP;
- The impact of varying levels of positive pressure provided by these devices on evolving lung injury in patients with ARDS;
- The risks of aerosol generation and risk of transmission to health care workers based on choice of respiratory support

# Comparisons with SOT:
In the direct population of patients with severe or critical COVID-19 experiencing acute hypoxaemic respiratory failure but not requiring emergent intubation, for the outcome of mortality, there is low-certainty evidence due to very serious imprecision. For the outcome of need for invasive mechanical ventilation, there is moderate certainty evidence due to serious imprecision. For the outcomes of ICU and hospital length-of-stay, there is low certainty evidence, due to very serious imprecision.
In the indirect population of patients with non-COVID-19 ARDS, there were studies evaluating both helmet CPAP and face mask CPAP, compared with standard oxygen therapy, largely with very low certainty evidence due to extremely serious imprecision.

# Comparison between devices or interfaces:
One trial in patients with COVID-19 and AHRF for the comparison of CPAP and HFNO provided very low certainty evidence for the outcome of mortality due to extremely serious imprecision. For the outcomes of need for invasive mechanical ventilation, hospital and ICU length of stay, the certainty of the evidence is low due to very serious imprecision.

# Certainty of the Evidence
Applying the agreed upon values and preferences, the GDG inferred that most well-informed patients with AHRF not requiring emergent intubation would choose to receive CPAP rather than standard oxygen therapy.

# Values and preferences
Studies of HFNO, CPAP, and NIV were conducted in high-resource settings with ICUs, health care workers experienced in these interventions, and resources for patient monitoring and rescue in case of clinical deterioration. The GDG emphasized that implementation of any non-invasive respiratory support intervention requires consideration of the local context of oxygen supply, training of health care providers, additional equipment for patient monitoring, considerations around maintenance of equipment, cost, and organization of service delivery. Availability of these additional resources has traditionally been restricted to areas within hospitals that provide intensive care. The GDG believed that the availability of these additional resources should be expanded to facilitate safe delivery of non-invasive respiratory support interventions globally.

# Resources and other considerations
Clinical management of COVID-19: living guideline -World Health Organization (WHO) device; - Staffing requirements and skills in deploying these devices in resource-limited settings as well as on cost and oxygen requirements from the use of these devices; - Specific populations such as children and pregnant women.

# Very low
Due to serious indirectness and very serious imprecision 1 We are very uncertain of the impact of helmet CPAP on mortality IMV

# Very low
Due to extremely serious imprecision 1 We are very uncertain of the impact of face mask CPAP on mortality IMV

# Very low
Due to extremely serious imprecision 3 We are very uncertain of the impact of face mask CPAP on hospital LOS ICU LOS

# Very low
Due to extremely serious imprecision 4 We are very uncertain of the impact of face mask CPAP on ICU LOS Clinical management of COVID-19: living guideline -World Health Organization (WHO)

# Practical Info
There is no specific recommendation for the initial settings to be used for non-invasive ventilation, with local experience and patient-specific factors informing decisions and manufacturer instructions. Based on clinical experience of the GDG, there is a suggestion to start with an expiratory positive airway pressure of 5-10 cmH2O, an inspiratory positive airway pressure to achieve a tidal volume of ~6 ml/kg, titration of both settings to patient comfort and work of breathing, and titration of FiO2 to achieve the target oxygen saturation when using facemask or oral-nasal mask. For use of helmet interfaces, additional information can be found in recent publications (235).
For infection prevention precautions related to the use of these respiratory support devices, please refer to Chapter 5 on IPC. See also Research needs.
Resources: In hospitalized patients with severe or critical COVID-19 and AHRF not needing emergent intubation, we suggest non-invasive ventilation, rather than standard oxygen therapy (conditional recommendation).
The GDG chose not to make a recommendation regarding optimal interface for NIV, whether helmet or face mask, given the limited data. The choice between interface should be guided by clinician experience, availability, and patient comfort.
The GDG chose not to make a recommendation regarding HFNO versus CPAP versus NIV due to the uncertainty of the data. Clinicians should choose on the basis of considerations such as availability of devices and the supply of oxygen, their personal comfort and experience, and patient-specific considerations (such as claustrophobia that some patients experience with CPAP/NIV masks, and nasal discomfort that some patients experience with HFNO).
Given the likely similar direction of benefit, the GDG elected to extend this recommendation to the paediatric age range (despite the absence of randomized trial data), while emphasizing the need for more research in this population.

# Evidence To Decision Justification
When moving from evidence to the conditional recommendation for patients hospitalized for COVID-19 with acute hypoxaemic respiratory failure and not requiring emergent intubation, the panel emphasized the moderate certainty of evidence from indirect comparisons in patients without COVID-19 for the important outcomes of mortality and need for invasive mechanical ventilation.
In patients with non-COVID-19 ARDS, face mask NIV probably reduces mortality (indirect PICO, moderate certainty) and need for invasive mechanical ventilation when compared to standard oxygen therapy. Based on overall clinical experience with the device and its use among critically ill patients, the GDG was of the opinion that benefits are likely to supersede any potential harms.

# Benefits and harms

# Comparisons with SOT:
No trials enrolling patients with COVID-19 are available. In the indirect population of hospitalized patients with ARDS not due to COVID-19 and not needing emergent intubation, moderate certainty evidence (due to serious indirectness) suggests that face mask NIV probably reduces mortality compared with SOT, and moderate-certainty evidence (due to serious inconsistency) suggests that NIV probably reduces the need for invasive mechanical ventilation. Very low-certainty evidence (due to serious inconsistency, serious imprecision, and serious indirectness) suggests impact of NIV on hospital and ICU length of stay is uncertain

# Comparisons between devices or interfaces:
Trials in patients with COVID-19 and AHRF provided very low certainty evidence for the comparison between helmet NIV and HFNO for outcomes of mortality, hospital length of stay, ICU length of stay due to extremely serious imprecision; whereas there is low certainty evidence for outcome of need for invasive ventilation due to very serious imprecision, and low certainty evidence for the outcome of device-related comfort due to serious risk of bias and serious imprecision.
Trials in patients with non-COVID-19 ARDS provided very low certainty evidence for the comparison between face mask NIV and HFNO for the outcomes of mortality and need for invasive ventilation due to serious indirectness, serious risk of bias and serious and very serious imprecision. For the outcome of ICU length of stay, the certainty of evidence is low due to very serious imprecision.
Trials in patients with non-COVID-19 ARDS provided low certainty evidence for the comparison between helmet NIV and face mask NIV for the outcomes of mortality, need for invasive mechanical ventilation and hospital length of stay due to very serious imprecision.

# Certainty of the Evidence
Applying the agreed upon values and preferences, the GDG inferred that most well-informed patients with AHRF not requiring emergent intubation would choose to receive NIV rather than standard oxygen therapy.

# Values and preferences
Studies of HFNO, CPAP, and NIV were conducted in high-resource settings with ICUs, health care workers experienced in these interventions, and resources for patient monitoring and rescue in case of clinical deterioration. The GDG emphasized that implementation of any non-invasive respiratory support intervention requires consideration of the local context of oxygen supply, training of health care providers, additional equipment for patient monitoring, considerations around maintenance of equipment, cost, and organization of service delivery. Availability of these additional resources has traditionally been restricted to areas within hospitals that provide intensive care. The GDG believed that the availability of these additional resources should be expanded to facilitate safe delivery of non-invasive respiratory support interventions globally.

# Resources and other considerations
Clinical management of COVID-19: living guideline -World Health Organization (WHO)
The GDG integrated the available evidence on the risk to health care workers due to infection transmission with the use of noninvasive ventilation. There is currently insufficient evidence to inform recommendations for the outcome of health care worker transmission.
The GDG chose not to make recommendations among non-invasive respiratory support devices because of the very low or low certainty of evidence and variable contextual factors of oxygen supply, staff training, and patient monitoring that would weigh more heavily in utilization decisions, compared with evidence of clinical effectiveness.

# Research Needs
Further research is needed about:
- The optimal choice of interface while delivering CPAP (helmet vs face mask, etc); - Between-device comparisons such as between HFNO and CPAP;
- The impact of varying levels of positive pressure provided by these devices on evolving lung injury in patients with ARDS;
- The risks of aerosol generation and risk of transmission to health care workers based on choice of respiratory support device; - Staffing requirements and skills in deploying these devices in resource-limited settings as well as on cost and oxygen requirements from the use of these devices; - Specific populations such as children and pregnant women.

# Clinical Question/ PICO Population:
Hospitalized patients with severe or critical COVID-19 and AHRF not needing emergent intubation

# Comparator: HFNO
The meta-analysis for the comparison for Helmet NIV vs HFNO was informed by the results of one trial which enrolled 110 patients (direct PICO, i.e. COVID-19 patients with AHRF) (235). The trial was published and did not include children or pregnant women.
For patients with severe or critical COVID-19, the GRADE Summary of Findings table shows the relative and absolute effects of Helmet NIV vs HFNO for the outcomes of interest, with certainty ratings, informed by the meta-analysis.

# Very low
Due to extremely serious imprecision 4 We are very uncertain of the impact of helmet NIV on hospital LOS ICU LOS

# Very low
Due to extremely serious imprecision 5 We are very uncertain of the impact of helmet NIV on ICU LOS Device-related discomfort

# Very low
Due to serious indirectness and very serious imprecision 1 We are very uncertain of the impact of face mask NIV on mortality IMV
The meta-analysis for the comparison of helmet NIV vs face mask NIV was informed by one trial that enrolled 83 participants (indirect PICO, i.e. non COVID patients with ARDS) (237). The trial was published and did not include pregnant women or children.
For patients with severe or critical COVID-19, the GRADE Summary of Findings table shows the relative and absolute effects of helmet NIV compared with face mask NIV for the outcomes of interest, with certainty ratings, informed by the meta-analysis.

# Implementation tools
Additional educational modules and implementation tools for health workers:
WHO COVID-19 essential supplies forecasting tool (COVID-ESFT) assists governments, partners, and other stakeholders to forecast the necessary volume of personal protective equipment, diagnostic test equipment, consumable medical supplies, biomedical equipment for case management, and essential drugs for supportive care and treatment of COVID-19.
WHO Clinical care for severe acute respiratory infection toolkit: COVID-19 adaptation provides algorithms and practical tools for clinicians working in acute care hospitals managing adult and paediatric patients with acute respiratory infection, including severe pneumonia, acute respiratory distress syndrome, sepsis and septic shock. This includes information on screening, testing, monitoring and treatments.
WHO Openwho.org clinical management course series hosts a full course series on COVID-19 which covers a holistic pathway of care for a patient, from screening and triage to rehabilitation, testing and treatments and palliative care.
WHO Priority medical device list for the COVID-19 response and associated technical specifications describes the technical and performance characteristics of medical devices used to manage patients with COVID-19, and also includes related standards for accessories and consumables. It is intended for policy-makers and planning officers in ministries of health, procurement and regulatory agencies, intergovernmental and international agencies as well as the medical device industry. For more information see WHO website on Health products and policy standards.

# Invasive ventilation and ARDS management
We recommend that endotracheal intubation be performed by a trained and experienced provider using airborne precautions.
Patients with ARDS, especially young children or those who are obese or pregnant, may desaturate quickly during intubation. Preoxygenation with 100% FiO2 for 5 minutes, and use of a face mask with reservoir bag is preferred. When possible, avoid bag-valve mask ventilation to reduce exposure to aerosols. Rapid sequence intubation is appropriate after an airway assessment that identifies no signs of difficult intubation (239)(241) (76). However, as with all critically ill patients, anticipate and prepare for anatomically and physiologically difficult airway.
We recommend implementation of mechanical ventilation using lower tidal volumes (4-8 mL/kg predicted body weight and lower inspiratory pressures (plateau pressure < 30 cmH2O).

# Remark for adults:
The implementation of mechanical ventilation using lower tidal volumes and lower inspiratory pressures is a strong recommendation from a clinical guideline for patients with ARDS (70), and is also suggested for patients with sepsis-induced respiratory failure who do not meet ARDS criteria (70). The initial target tidal volume is 6 mL/kg PBW; tidal volume up to 8 mL/kg PBW is allowed if undesirable side-effects occur (e.g. dyssynchrony, pH < 7.15). Permissive hypercapnia is permitted. Ventilator protocols are available (244). The use of deep sedation may be required to control respiratory drive and achieve tidal volume targets.

# Remark for children:
In children, a lower level of plateau pressure (< 28 cmH2O) is targeted, and a lower target of pH is permitted (7.15-7.30). Tidal volumes should be adapted to disease severity: 3-6 mL/kg PBW in the case of poor respiratory system compliance, and 5-8 mL/kg PBW with better preserved compliance (246).
In adult patients with severe ARDS (PaO2/FiO2 < 150) prone ventilation for 12-16 hours per day is recommended.
- Application of prone ventilation is recommended for adult patients, preferably for 16 hours per day, and may be considered for paediatric patients with severe ARDS but requires sufficient human resources and expertise to be performed safely; protocols (including videos) are available (41) (42).
- There is little evidence on prone positioning in pregnant women with ARDS; this could be considered in early pregnancy. Pregnant women in the third trimester may benefit from being placed in the lateral decubitus position.
Use a conservative fluid management strategy for ARDS patients without tissue hypoperfusion and fluid responsiveness.

# Remarks for adults and children:
This has also been recommended in another international guideline (70). The main effect is to shorten the duration of ventilation. A sample protocol for implementation of this recommendation is available (146).
In patients with moderate or severe ARDS, a trial of higher positive end-expiratory pressure (PEEP) instead of lower PEEP is suggested and requires consideration of benefits versus risks. In COVID-19, we suggest the individualization of PEEP where during titration the patient is monitored for effects (beneficial or harmful) and driving pressure.
- PEEP titration requires consideration of benefits (reducing atelectrauma and improving alveolar recruitment) vs risks (endinspiratory overdistension leading to lung injury and higher pulmonary vascular resistance). Tables are (44).
In patients with moderate-severe ARDS (PaO2/FiO2 < 150), neuromuscular blockade by continuous infusion should not be routinely used.
A trial found that this strategy improved survival in adult patients with moderate-severe ARDS (PaO2/FiO2 < 150) without causing significant weakness (255), but results of a recent larger trial found that use of neuromuscular blockade with high PEEP strategy was not associated with a survival benefit when compared with a light sedation strategy without neuromuscular blockade (256).
Intermittent or continuous neuromuscular blockade may still be considered in patients with ARDS, both adults and children, in certain situations: ventilator dyssynchrony despite sedation, such that tidal volume limitation cannot be reliably achieved; or refractory hypoxaemia or hypercapnia.
Avoid disconnecting the patient from the ventilator, which results in loss of PEEP, atelectasis and increased risk of infection of health care workers.

# Remarks: 1. Use in-line catheters for airway suctioning and clamp endotracheal tube when disconnection is required (for example, transfer to a transport ventilator). 2. Manual hyperinflation should be avoided and ventilator hyperinflation used instead, if indicated (221).
In patients with excessive secretions, or difficulty clearing secretions, consider application of airway clearance techniques. These should be performed only if deemed medically appropriate (221) and appropriate IPC measures are in place.
- Active cycle of breathing techniques and positioning techniques can be used to optimize oxygenation (257) (81). Techniques for airway clearance and secretion management include positioning with gravity-assisted drainage, active cycle of breathing techniques, positive expiratory pressure therapy, and assisted or stimulated cough manoeuvres (81). These techniques are only indicated for patients with mucous hypersecretion and difficulties clearing secretions, and for patients with co-existing respiratory or neuromuscular comorbidities (81) (81). 4. Especially for critically ill patients, the early involvement of the multidisciplinary rehabilitation team is paramount to improve shortand long-term outcomes. This may include physiotherapists, occupational therapists, speech and language therapists, mental health and psychosocial providers, dieticians and in complex cases, physical and rehabilitation medicine doctors. However, rehabilitation workforce composition may vary by context and availability in different parts of the world.

# Remarks for adults:
An RCT of ECMO for adult patients with ARDS was stopped early and found no statistically significant difference in the primary outcome of 60-day mortality between ECMO and standard medical management (including prone positioning and neuromuscular blockade) (156). However, ECMO was associated with a reduced risk of the composite outcome that consisted of mortality and crossover to ECMO treatment (156), and a post-hoc Bayesian analysis of this RCT showed that ECMO is very likely to reduce mortality across a range of prior assumptions (157). In patients with MERS, ECMO vs conventional treatment was associated with reduced mortality in a cohort study (158). ECMO is a resource-intensive therapy and should be offered only in expert centres with a sufficient case volume to maintain expertise and staff volume and capacity to apply the IPC measures required (159) (46). In children, ECMO can also be considered in those with severe ARDS, although high-quality evidence for benefit is lacking (246).

# Management of critical COVID-19: septic shock
The mortality in hospitalized and critically ill patients has varied substantially in different case series throughout the pandemic. The following recommendations are aligned with current international standards for management of all-cause sepsis (70).
Recognize septic shock in adults when infection is suspected or confirmed AND vasopressors are needed to maintain mean arterial pressure (MAP)  65 mmHg AND lactate is  2 mmol/L, in the absence of hypovolaemia (see Table 6.
Recognize septic shock in children with any hypotension (SBP  2 SD below normal for age) or two or more of the following: altered mental status; bradycardia or tachycardia (HR  160 bpm in infants and HR  150 bpm in children); prolonged capillary refill (> 2 sec) or feeble pulses; tachypnoea; mottled or cold skin or petechial or purpuric rash; increased lactate; oliguria; hyperthermia or hypothermia (see Table 6.3).
- In the absence of a lactate measurement, use blood pressure (i.e. MAP) and clinical signs of perfusion to define shock. 2. Standard care includes early recognition and the following treatments to be done immediately, within 1 hour of recognition: antimicrobial therapy, and initiation of fluid bolus and vasopressors for hypotension (70). The use of central venous and arterial catheters should be based on resource availability and individual patient needs. Detailed guidelines from the Surviving Sepsis Campaign and WHO are available for the management of septic shock in adults (70) and children (83) (182). Alternate fluid regimens are suggested when caring for adults and children in resource-limited settings (262) (263).
In resuscitation for septic shock in adults, give 250-500 mL crystalloid fluid as rapid bolus in first 15-30 minutes.
In resuscitation for septic shock in children, give 10-20 mL/kg crystalloid fluid as a bolus in the first 30-60 minutes.
Fluid resuscitation may lead to volume overload, including respiratory failure, particularly with ARDS. If there is no response to fluid loading or signs of volume overload appear (e.g. jugular venous distension, crackles on lung auscultation, pulmonary oedema on imaging, or hepatomegaly), then reduce or discontinue fluid administration. This step is particularly important in patients with hypoxaemic respiratory failure.
- Crystalloids include normal saline and Ringer's lactate. 2. Determine the need for additional fluid boluses (250-500 mL in adults; 10-20 mL/kg in children) based on clinical response and improvement of perfusion targets and reassess for signs of fluid overload after each bolus. Perfusion targets include MAP (> 65 mmHg or age-appropriate targets in children), urine output (> 0.5 mL/kg/hr in adults; 1 mL/kg/hr in children), and improvement of skin mottling and extremity perfusion, capillary refill, heart rate, level of consciousness, and lactate. (70). These indices include passive leg raise, fluid challenges with serial stroke volume measurements, or variations in systolic pressure, pulse pressure, inferior vena cava size, or stroke volume in response to changes in intrathoracic pressure during mechanical ventilation. 4. In pregnant women, compression of the inferior vena cava can cause a decrease in venous return and cardiac preload and may result in hypotension. For this reason, pregnant women with sepsis and or septic shock may need to be placed in the lateral decubitus position to offload the inferior vena cava (84). 5. Clinical trials conducted in resource-limited settings comparing aggressive versus conservative fluid regimens suggest higher mortality in patients treated with aggressive fluid regimens (262) (263). Refer to the WHO-ICRC Basic emergency care (Shock module) for an initial approach and management of shock in resource-limited settings (159).

# Consider dynamic indices of volume responsiveness to guide volume administration beyond initial resuscitation based on local resources and experience

# Do not use hypotonic crystalloids, starches or gelatins for resuscitation.
Starches are associated with an increased risk of death and acute kidney injury compared with crystalloids. The effects of gelatins are less clear, but they are more expensive than crystalloids (70) (264). Hypotonic (vs isotonic) solutions are less effective at increasing intravascular volume. Surviving Sepsis guidelines also suggest albumin for resuscitation when patients require substantial amounts of crystalloids, but this conditional recommendation is based on low-quality evidence (70).
In adults, administer vasopressors when shock persists during or after fluid resuscitation. The initial blood pressure target is MAP  65 mmHg in adults and improvement of markers of perfusion.
In children, administer vasopressors if signs of fluid overload are apparent or the following persist after two fluid boluses:
- signs of shock such as altered mental state;
- bradycardia or tachycardia (HR  160 bpm in infants and HR  150 bpm in children); - prolonged capillary refill (> 2 seconds) or feeble pulses;
- tachypnoea; mottled or cool skin or petechial or purpuric rash; increased lactate; oliguria persists after two repeat boluses;
- or age-appropriate blood pressure targets are not achieved (182).
- Vasopressors (i.e. norepinephrine, epinephrine, vasopressin and dopamine) are most safely given through a central venous catheter at a strictly controlled rate, but it is also possible to safely administer them via peripheral vein (166) and intraosseous needle. Monitor blood pressure frequently and titrate the vasopressor to the minimum dose necessary to maintain perfusion and prevent side-effects. A recent study suggests that in adults 65 years or older a MAP 60-65 mmHg target is equivalent to  65 mmHg (167). 2. Norepinephrine is considered the first-line treatment in adult patients; epinephrine or vasopressin can be added to achieve the MAP target. Because of the risk of tachyarrhythmia, reserve dopamine for selected patients with low risk of tachyarrhythmia or those with bradycardia. 3. In children, epinephrine is considered the first-line treatment, while norepinephrine can be added if shock persists despite optimal dose of epinephrine (182).

# If central venous catheters are not available, vasopressors can be given through a peripheral IV, but use a large vein and closely monitor for signs of extravasation and local tissue necrosis. If extravasation occurs, stop infusion. Vasopressors can also be administered through intraosseous needles.
If signs of poor perfusion and cardiac dysfunction persist despite achieving MAP target with fluids and vasopressors, consider an inotrope such as dobutamine.
No RCTs have compared dobutamine with placebo for clinical outcomes.
Clinical management of COVID-19: living guideline -World Health Organization (WHO)

# Prevention of complications in hospitalized and critically ill patients with COVID-19 Practical Info
The GDG made a conditional recommendation in favour of care bundles for critically ill patients with COVID-19. Existing care bundles for critically ill patients include those for reducing delirium and improving cognition and sleep (reviewed in (85); other information available at ), preventing VAP (267), treating sepsis (reviewed in ), preventing central venous catheter infection (86), and preventing pressure ulcers (). For some bundles, observational data have shown variable association between the bundle components and patient important outcomes (268). Even in currently accepted care bundles, the components may change as the evidence base evolves. Hospitals and ICUs should choose bundles for which adherence is likely to be high.
Monitor multiple RCTs in process in patients with COVID-19.

# Evidence To Decision

# Conditional recommendation for
For patients with COVID-19 who are critically ill, with or without invasive mechanical ventilation, we suggest the use of existing care bundles (defined as three or more evidence informed practices delivered together and consistently to improve care; (see Evidence to decision for examples), chosen locally by the hospital or ICU and adapted as necessary for local circumstances (conditional recommendation, very low certainty).

# Some benefits
Indirect evidence in patients without COVID-19 suggest that some care bundles may improve patient-important outcomes, such as mortality, but the effects vary depending on the specific bundle, and the population targeted. The certainty of evidence is generally low to very low. Examples of care bundles in the critically ill can be found in the practical info tab and in the Cochrane Collaboration review of the literature published in the Web Annex. The effect on other outcomes is uncertain.
Potential harms of bundles include the administrative burden of initial implementation, ongoing training, and monitoring of performance (very low certainty).

# Benefits and harms
The evidence review consisted of a rapid review by the Cochrane Collaboration, supplemented by references provided by GDG members. The Cochrane review found very low certainty evidence in support of a mortality reduction with implementation of care bundles in critically ill patients. Supplementary references provided low to very low certainty evidence for important effects on mortality with bundles to reduce delirium (85), prevent VAP (267), treat sepsis (), and prevent central venous catheter infection (86) and pressure ulcers (). All evidence reviewed was indirect, from non-COVID-19 populations.

# Very low

# Certainty of the Evidence
Applying the agreed values and preferences, the GDG inferred that the majority of well-informed patients would want to receive care bundles, locally adapted as necessary and applicable to their situation, given the low to very low certainty evidence suggesting a reduction in mortality and very low certainty of harm.

# No substantial variability expected

# Values and preferences

# Important considerations

# Resources and other considerations Justification
When moving from evidence to the conditional recommendation in favour of care bundles for critically ill patients with COVID-19, the panel emphasized the low to very low certainty evidence of reduction in mortality and possible administrative burdens for implementation. The GDG recognized that hospital or ICUs may select among existing care bundles and adapt them to local circumstances as required, based on contextual factors of resource considerations and feasibility. The GDG judged that considerations of accessibility and impact on health equity would not alter the recommendation. The GDG was not aware of ongoing studies of care bundles in the critically ill COVID-19 population.

# Subgroup analyses
The panel did not find any evidence bearing on the question of subgroup effects across patients with different levels of disease severity or between children and adults. In other words, the conditional recommendation is applicable across all these subgroups.

# Special populations
None of the reviewed studies of care bundles enrolled children, and therefore the applicability of this recommendation to children is uncertain. However, the panel thought that the implementation of relevant care bundles for children with COVID-19 would have similar effects to care bundles in adults. Similarly, the panel concluded that the recommendation applies to pregnant women.
Care bundles may contain practices that require adaptation to implement in all settings, depending on their contents. For example, early mobilization and rehabilitation as part of a care bundle to reduce delirium may require additional training, and central line insertion may require multiple sterile towels or a sterile gown placed on the patient, if large sterile drapes are not available.

# Clinical Question/ PICO Population:
Patients with COVID-19 and ARDS or viral pneumonia who are critically ill in ICU, with or without invasive ventilation. Populations of children (defined <18 years) and adult patients (18 years)
Existing validated care bundles, chosen locally by the hospital or ICU, adapted to local circumstances, and felt to be appropriate for patients with COVID-19 as specified above. A care bundle is defined as three or more evidence informed practices delivered together and consistently to improve care.
Not using existing care bundles
This section is currently under review and will be updated in the next iteration of the guidelines.

# Practical Info
Therapeutic dosing of anticoagulation refers to the dose used for treatment of acute venous thromboembolism; intermediate dosing is commonly interpreted as twice the standard thromboprophylaxis dose. The GDG made a conditional recommendation in favour of standard thromboprophylaxis dosing of anticoagulation in patients with COVID-19 who do not have an established indication for higher dose anticoagulation.
Patients on standard thromboprophylaxis dosing of anticoagulation do not require monitoring, except for platelet count monitoring after 5-7 days if unfractionated heparin is used. Dosing should be adjusted according to body weight/BMI and renal function according to local protocols. For example, if renal failure is present, patient should receive unfractionated heparin or reduced dose of low molecular weight heparin.

# Attached Images

# Administrative burden
Based on data from 0 participants in 0 studies.

# Very low
Care bundles may be associated with an appreciable administrative burden.

# Impingement on physician autonomy
Based on data from 0 participants in 0 studies.

# Very low
Care bundles may be associated with an impingement of physician autonomy.
Coagulopathy is common in patients with severe COVID-19, and both venous and arterial thromboembolism have been reported (29)(30)(269)(270) (271).
Monitor patients with COVID-19, for signs or symptoms suggestive of thromboembolism, such as stroke, deep venous thrombosis, pulmonary embolism or acute coronary syndrome. If these are clinically suspected, proceed immediately with appropriate diagnostic and management pathways.

# Conditional recommendation for
In hospitalized patients with COVID-19, without an established indication for higher dose anticoagulation, we suggest administering standard thromboprophylaxis dosing of anticoagulation rather than therapeutic or intermediate dosing (conditional recommendation, very low certainty).
In review Suggested dosing of standard thromboprophylaxis is as follows:
Enoxaparin 40 mg by subcutaneous injection every 24h:
- Prophylactic dosages (non-weight adjusted) in low body weight (women < 45 kg, men < 57 kg) may lead to a higher risk of bleeding. Careful clinical observation is advised.
- If BMI > 40 kg/m 2 or weight > 120 kg: enoxaparin 40 mg by subcutaneous injection every 12h.
Unfractionated heparin (UFH) 5000 units by subcutaneous injection every 8 or 12h:
- If BMI > 40 kg/m 2 or weight > 120 kg: 7500 units q12h or 5000 units every 8h.
Tinzaparin 4500 units/day if BMI  40 kg/m 2 or weight > 120 kg.
- Dalteparin 5000 units/day BMI  40 kg/m 2 or weight > 120 kg.
- Fondaparinux 2.5 mg by subcutaneous injection every 24h.
Exoxaparin and unfractionated heparin are both on the WHO Model List of Essential Medicines; enoxaparin has the advantage of daily dosing. The suggested duration of standard thromboprophylaxis is until hospital discharge.
If therapeutic dosing is prescribed, clinicians should be aware of the increased risk of bleeding, including major bleeding requiring transfusion (e.g. gastrointestinal) or clinically significant bleeding even if transfusion is not required (e.g. intracranial). These increased risks may also occur with intermediate dosing of anticoagulants, especially in the presence of other risk factors for bleeding. Heparin-induced thrombocytopenia associated with thrombosis is also a risk of unfractionated heparin and, less commonly, low molecular weight heparin.
Potential agents for therapeutic and intermediate intensity anticoagulation include low molecular weight heparin, unfractionated heparin, direct oral anticoagulants, or fondaparinux. Factors influencing the choice of agent include availability of laboratory monitoring (needed for unfractionated heparin), requirement for rapid reversibility (favours unfractionated heparin), presence of severe renal dysfunction (favours unfractionated heparin), interaction with other drugs used to treat COVID-19 (especially direct oral anticoagulants), convenience (least with unfractionated heparin, most with direct oral anticoagulants), and suspicion of heparininduced thrombocytopenia (favours fondaparinux or direct oral anticoagulants).

# Evidence To Decision
Therapeutic or intermediate dosing of anticoagulation, compared with prophylactic dosing of anticoagulation, possibly reduces mortality (very low certainty) and pulmonary embolism and probably increases the risk of major bleeding (moderate certainty for therapeutic anticoagulation; low certainty for intermediate dosing of anticoagulation). The effects on other outcomes are uncertain.
The absolute reductions in risks of mortality and pulmonary embolism, and the absolute increase in risk of major bleeding, are likely to be higher in patients with severe or critical illness due to COVID-19, who may have a higher baseline risk of these outcomes compared with patients with mild or moderate illness.

# Important harms

# Benefits and harms
For reduction in mortality and pulmonary embolism, the panel considered the evidence in favour of therapeutic or intermediate dosing of anticoagulation to be of very low certainty, due to serious imprecision (confidence intervals included both important benefit and important harm) and risk of bias (confounding in observational studies; no randomized trials). For avoidance of major bleeding, the panel considered the evidence in favour of standard thromboprohylaxis dosing, compared with therapeutic anticoagulation, to be of moderate certainty. This judgment was based on low-certainty evidence in observational studies in COVID-19 that was upgraded to moderate certainty based on a large body of supportive indirect Very low

# Certainty of the Evidence
Clinical management of COVID-19: living guideline -World Health Organization (WHO)
When moving from evidence to the conditional recommendation in favour of standard thromboprophylaxis anticoagulation for patients with moderate, severe, and critical COVID-19, the panel emphasized the very low certainty evidence of reduction in mortality or pulmonary embolism with higher anticoagulant dosing. The panel recognized that the evidence supporting an increased risk of major bleeding was dominated by studies of therapeutic anticoagulation rather than intermediate dosing. The GDG panellists anticipated variability in patient values and preferences, and judged that other contextual factors, such as resource considerations, accessibility, feasibility and impact on health equity would not alter the recommendation. The panel acknowledged that ongoing randomized trials are expected to add substantially to the evidence base over the next several months.

# Subgroup analyses
The panel did not find any evidence bearing on the question of subgroup effects across patients with different levels of disease severity, between children and adults, by different anticoagulant regimens (including agent, dose and duration), and therefore did not make any subgroup recommendations. In other words, the conditional recommendation is applicable across all these subgroups.

# Special populations
None of the studies enrolled children, and therefore the applicability of this recommendation to children is uncertain. However, the panel did not think that children with COVID-19 would respond any differently to therapeutic or intermediate intensity anticoagulation. One observational study enrolled pregnant women, with very low certainty evidence in this population for a possible reduction in mortality. The panel thought that pregnant women would have a similar risk of increased bleeding as nonpregnant individuals. Therefore, the panel concluded that the recommendation applies to pregnant women. Safe anticoagulants for the fetus in pregnancy include unfractionated heparin and low molecular weight heparin, which do not cross the placental barrier.
evidence at low risk of bias (randomized trials of therapeutic anticoagulation for other indications). For the comparison of standard thromboprophylaxis dosing compared with intermediate dosing of anticoagulation, the evidence for avoidance of major bleeding was rated as low certainty.
The panel acknowledged that reporting of ongoing randomized trials of therapeutic and intermediate dosing of anticoagulation, compared with standard thromboprophylaxis dosing, over the next several months were highly likely to upgrade the certainty of evidence and may lead to changes in recommendations.
The majority of GDG members inferred that most well-informed patients would not want to receive therapeutic or intermediate dosing of anticoagulation given the very low certainty evidence suggesting a possible reduction in mortality and pulmonary embolism and the low certainty (for intermediate dosing of anticoagulation) or moderate certainty (for therapeutic anticoagulation) of increased risk of major bleeding. A minority of GDG members believed that some well-informed patients would choose to receive intermediate dosing of anticoagulation, given the very low certainty evidence suggesting a possible reduction in mortality and pulmonary embolism and the low certainty of increased risk of major bleeding.

# Substantial variability is expected or uncertain

# Values and preferences

# Important considerations
Unfractionated heparin sodium and low molecular weight heparins such as enoxaparin are relatively inexpensive and are listed on the WHO Model List of Essential Medicines; but availability is variable. Shortages may reduce the availability of low molecular weight heparins in some settings. In low-resource settings, management of bleeding complications in patients receiving anticoagulant dosing higher than that used for standard thromboprophylaxis may be challenging due to limited coagulation testing and transfusion capacity.

# Resources and other considerations
Clinical Question/ PICO   (88), and are generally limited to feasible recommendations based on highquality evidence. Recent publications have encouraged best practices to continue during the COVID-19 outbreak (273). See the WHO Clinical care for severe acute respiratory infection toolkit: COVID-19 adaptation for practical tools to assist implementation (161). - Do not prescribe antibiotics to suspected or confirmed COVID-19 patients with low suspicion of a bacterial infection, to avoid more short-term side-effects of antibiotics in patients and negative long-term consequences of increased antimicrobial resistance

# Adverse effects of medications

# Careful consideration should be given to the numerous, clinically significant side-effects of medications that may be used in the context of COVID-19, as well as drug-drug interactions between medications, both of which may affect COVID-19 symptomatology (including effects on respiratory, cardiac, immune and mental and neurological function). Both pharmacokinetic and pharmacodynamic effects should be considered.
- The risk of relevant side-effects and drug-drug interactions relating to COVID-19 symptomatology include sedation, cardiotoxicity via QTc-prolongation and respiratory suppression, and these may be dose-dependent (i.e. increase with escalating doses). For this reason, care should be taken that minimum effective doses of medications with dose-dependent negative effects are used and for the shortest durations possible.

# Use medications that carry the least risk possible for drug-drug interactions with other medications the person may be receiving.
Psychotropic medications with sedative proprieties, such as benzodiazepines, can worsen respiratory function. Some, psychotropic medications have QTc-prolonging activity (such as some antipsychotics and some antidepressants). Use medications that carry the least risk possible for side-effects that may worsen COVID-19 symptomatology, including sedation, respiratory or cardiac function, risk of fever or other immunological abnormalities, or coagulation abnormalities.

# Multi-system inflammatory syndrome in children (MIS-C) with COVID-19
This section outlines what information the GDG requested and used in making their recommendations for corticosteroids in hospitalized children with COVID-19 aged 0 to 18 years, who meet standardized clinical definition for MIS-C (see Annex 5 for standardized definitions).

# Prioritized outcomes
For the previous recommendations, the GDG members prioritized outcomes (rating from 9  to 1  with severe and critical COVID-19, taking a patient perspective (Table 2.1). For these new recommendations on MIS-C, the GDG concluded that the values and preferences of children and adolescents with MIS-C may differ from those used in previous recommendations. A new targeted outcomes prioritization exercise was conducted (Table 14.1). These new prioritized outcomes were used to update the metaanalysis.

# Values and preferences
For these new recommendations for MIS-C, the majority of GDG members inferred that most well-informed patients, and their families, would, despite the high uncertainty of important benefit, want to receive some therapeutic agent in addition to supportive care for MIS-C, compared with no specific therapeutic agent. In doing so, patients would be placing a high value on uncertain benefit and a low value on avoiding any mild adverse effects associated with treatment.

# Evidence summary
The GDG's recommendations for corticosteroid use in hospitalized children who meet the standard clinical definition for MIS-C were informed by the results of systematic review and meta-analysis of the literature that pooled data from 3 studies, n = 885 (89)(90) (275). In Annexes 3 and 4, the systematic search criteria and table of trial characteristics can be found, respectively. From these studies, for the three comparisons: a) adding corticosteroids to IVIG compared to IVIG alone; b) corticosteroids compared to IVIG; and c) adding corticosteroids to IVIG compared to corticosteroids alone and for all prioritized outcomes including death, need for invasive mechanical ventilation two days after initiation of treatment, need for hemodynamic support two days after initiation of treatment, coronary artery dilation, acute left ventricular dysfunction 2 days after initiation of treatment, and reduction in fever 2 days after initiation of treatment, the evidence was of very low certainty.
The evidence was summarized in the summary of findings tables and presented to the GDG addressing the pre-specified PICOs and prioritized outcomes: corticosteroids + IVIG vs IVIG alone; corticosteroids alone vs IVIG alone; and corticosteroids + IVIG vs corticosteroids alone (see Research Evidence tab) below). For all three PICOs, very low certainty evidence was ascertained for all outcomes.

# Subgroup analysis
Subgroup analyses were not conducted.

# Practical Info

# Practical info
There are slightly different case definitions for MIS-C (Annex 5). This guideline is applicable for any standard case definition of MIS-C. Case definitions will continue to be updated as new data emerge. Based on accessibility to corticosteroids being much wider than accessibility to IVIG, the panel suggested that most patients will receive corticosteroids before they receive IVIG, even in patients where both are prescribed.
Route: Systemic corticosteroids can be given orally or intravenously. All studies examined intravenous administration.

# Dose and duration:
In the three studies included in the meta-analysis, intravenous methylprednisilone was used at varying doses; one study did not report a dose. The other two reported ranges between 0.8-2.0 mg/kg/day for 5 days; or higher bolus doses of 10-30 mg/kg/day for 3 days. Both lower and higher dose options can be considered. See Annex 4 for study details.
Monitoring: It would be prudent to monitor for known complications associated with corticosteroid use, such as hyperglycemia and behavioural changes.
Supportive care: Most emphatically, the GDG emphasized the importance of high-quality supportive care to improve the outcomes of these children, apart from specific therapies. Please see the WHO Pocket Book of Hospital Care for Children for syndromic management guidance of severely ill children, including the importance of recognizing other conditions such leading to shock, sepsis and severe infections; as well as guidance from other organizations on supportive management of Kawasaki disease (83).
The GDG emphasized the need for further randomized clinical trials in this population with these agents. The panel acknowledged that results of ongoing randomized trials of therapeutic interventions for MIS-C over the next several months were highly likely to upgrade the certainty of evidence and may lead to changes in recommendations. Enrolment of patients into randomized trials should be prioritized.

# Evidence To Decision
Conditional recommendation for - In hospitalized children aged 0-18 who meet a standard case definition for MIS-C, we suggest using corticosteroids in addition to supportive care (rather than either IVIG plus supportive care, or supportive care alone) (conditional recommendation, very low certainty). - In hospitalized children aged 0-18 who meet both a standard case definition for MIS-C and diagnostic criteria for Kawasaki disease, we suggest using corticosteroids in addition to standard of care for Kawasaki disease (conditional recommendation, very low certainty).
Supportive care/standard of care: The GDG emphasized the importance of optimized supportive care for children meeting the standardized case definition of MIS-C. Thus, the interpretation of these results, should consider that supportive care is the current standard of care on which these interventions are additive. See WHO Pocket Book of Hospital Care for Children (83), and the WHO Paediatric emergency triage, assessment and treatment: care of critically ill children (219).
- The effects of corticosteroids in addition to IVIG, compared with IVIG alone plus supportive care, or supportive care alone, all prioritized outcomes, including death during hospitalization, need for mechanical ventilation, coronary artery abnormalities, and cardiac dysfunction are very uncertain (very low certainty, direct evidence). - The effects of corticosteroids alone, compared with IVIG plus supportive care, or supportive care alone on all prioritized outcomes, including death during hospitalization, need for mechanical ventilation, coronary artery abnormalities,

# Benefits and harms
Clinical management of COVID-19: living guideline -World Health Organization (WHO)
When moving from evidence to the conditional recommendations for children hospitalized with MIS-C, the panel emphasized the very low certainty evidence of reduction in mortality and the need for haemodynamic support and mechanical ventilation with the use of corticosteroids. The panel also acknowledged that some children will simultaneously meet diagnostic criteria for Kawasaki disease, and the standard of care in many parts of the world is to use IVIG, where available, in that population. The panel emphasized the practical difficulty in differentiating the two populations, leading to the emphasis on IVIG in care pathways, despite the lack of supporting direct evidence. In the absence of randomized evidence showing IVIG to be harmful, the panel expressed concern about not providing IVIG, where available, to children who meet diagnostic criteria of both Kawasaki disease and MIS-C. The panel acknowledged that ongoing randomized trials are expected to add substantially to the evidence base over the next several months.

# Subgroup analyses
Given the available evidence, the panel did not find any evidence bearing on the question of subgroup effects across patients with different levels of disease severity, and therefore did not make any subgroup recommendations. In other words, the conditional recommendations are applicable across all patient subgroups. In particular, there are insufficient data to support different recommendations in the younger age ranges (given the predilection for younger age ranges in Kawasaki disease). Analyses based on dose of corticosteroid or IVIG administered were unable to be performed, given the limitations of the studies.
and cardiac dysfunction are very uncertain (very low certainty, direct evidence). - The effects of corticosteroids in addition to IVIG compared to corticosteroids alone on all prioritized outcomes including death during hospitalization, need for mechanical ventilation, and other prioritized outcomes are very uncertain (very low certainty, direct evidence).
Based on the clinical experience of the GDG of other conditions, the possible harms of steroids were deemed to be of lesser importance than the possible benefits. However, the GDG did emphasize that for appropriate evaluation and management for undifferentiated children presenting with shock, consider other serious infections based on epidemiologic considerations (i.e., malaria, HIV, etc). Possible harms of IVIG, based on the clinical experience of the panel of other conditions, include fluid overload due to the volume of IVIG preparations. The GDG acknowledged the care of Kawasaki disease, a clinically similar condition which can be difficult to distinguish from MIS-C, includes IVIG (83).
For all outcomes in the three pre-specified PICOs, the GDG considered the evidence to be of very low certainty, due to risk of bias from observational designs and due to serious imprecision (confidence intervals included both important benefit and important harm). The evidence for corticosteroids and IVIG is from observational studies that compare the combination of these agents against them individually.

# Very low

# Certainty of the Evidence

# Variability expected
The majority of GDG members inferred that most well-informed patients, and their families, would, despite the high uncertainty of important benefit, want to receive some therapeutic agent in addition to supportive care for MIS-C, compared with no specific therapeutic agent. In doing so, patients would be placing a high value on uncertain benefit and a low value on avoiding any mild adverse effects associated with treatment.

# Values and preferences

# Important considerations
Corticosteroids are widely available in all regions of the world and methylprednisolone is on the WHO Model List of Essential Medicines. IVIG has important resource considerations, including higher cost, and is not readily available across all care settings and regions.

# Resources and other considerations

# Special populations
There was no special population where the panel inferred different applicability of these recommendations.

# Clinical Question/ PICO Population:
Children aged 0-19 years meeting any standard case definition of MIS-C in hospitals in high-income countries (HIC) and low-and middle-income countries (LMIC)
IVIG plus steroids as the initial treatment

# Comparator: IVIG alone as the initial treatment

# Study results and measurements

# IVIG alone as the initial treatment

# IVIG plus steroids as the initial treatment
Certainty of the Evidence (Quality of evidence)

# Plain language summary

# Death during hospitalization
Odds ratio 0.32 (CI 95% 0.05 -1.86) Based on data from 334 participants in 1 studies. 1 (Observational (nonrandomized))

# Very low
Due to very serious risk of bias and serious imprecision 2
The evidence is very uncertain about the effect of adding steroids to IVIG on death during hospitalization

# Ventilation support 2 days after initiation of treatment
Odds ratio 0.52 (CI 95% 0.1 -2.76) Based on data from 429 participants in 2 studies. 3 (Observational (nonrandomized))

# Very low
Due to very serious risk of bias, serious inconsistency, and serious imprecision 4 The evidence is very uncertain about the effect of adding steroids to IVIG on the need for ventilation support 2 days after initiation of treatment

# Haemodynamic support 2 days after initiation of treatment
Odds ratio 0.52 (CI 95% 0.32 -0.83) Based on data from 551 participants in 3 studies. 5 (Observational (nonrandomized))

# Very low
Due to very serious risk of bias 6 The evidence is very uncertain about the effect of adding steroids to IVIG results in a reduction in the need for haemodynamic support 2 days after initiation of treatment

# Coronary artery dilatation at discharge
Odds ratio 0.46 (CI 95% 0.05 -4.22) Based on data from 224 participants in 1 studies. 7 (Observational (nonrandomized))

# Very low
Due to very serious risk of bias and serious imprecision 8 The evidence is very uncertain about the effect of adding steroids to IVIG on coronary artery dilatation at discharge

# Acute left ventricular dysfunction 2 days after initiation of treatment
Odds ratio 0.55 (CI 95% 0.18 -1.67) Based on data from 543 participants in 3 studies. 9 (Observational (nonrandomized))

# Very low
Due to very serious risk of bias and serious imprecision 10 The evidence is very uncertain about the effect of adding steroids to IVIG on acute left ventricular dysfunction 2 days after initiation of treatment Clinical management of COVID-19: living guideline -World Health Organization (WHO)

# Outcome Timeframe

# Study results and measurements

# IVIG alone as the initial treatment

# IVIG plus steroids as the initial treatment
Certainty of the Evidence (Quality of evidence)
Plain language summary 1. Systematic reviewwith included studies:. Baseline/comparator: Control arm of reference used for intervention. 2. Risk of Bias: very serious. Downgraded two levels for serious risk of confounding and selection bias in all studies which substantially lowered confidence in the certainty of the estimate of effect.. Imprecision: serious. Downgraded for imprecision due to wide confidence intervals around the absolute effects which also crossed the line of no effect.. 3. Systematic reviewwith included studies:. Baseline/comparator: Control arm of reference used for intervention. 4. Risk of Bias: very serious. Downgraded two levels for serious risk of confounding and selection bias in all studies which substantially lowered confidence in the certainty of the estimate of effect.. Inconsistency: serious. Downgraded for inconsistency as I squared > 50% or p value represented presence of statistical heterogeneity. Random effects model for pooling ORs was used. Imprecision: serious. Downgraded for imprecision due to wide confidence intervals around the absolute effects which also crossed the line of no effect.. 5. Systematic reviewwith included studies:. Baseline/comparator: Control arm of reference used for intervention. 6. Risk of Bias: very serious. Downgraded two levels for serious risk of confounding and selection bias in all studies which substantially lowered confidence in the certainty of the estimate of effect.. 7. Systematic reviewwith included studies:. Baseline/comparator: Control arm of reference used for intervention. 8. Risk of Bias: very serious. Downgraded two levels for serious risk of confounding and selection bias in all studies which substantially lowered confidence in the certainty of the estimate of effect.. Imprecision: serious. Downgraded for imprecision due to wide confidence intervals around the absolute effects which also crossed the line of no effect.. 9. Systematic reviewwith included studies:. Baseline/comparator: Control arm of reference used for intervention. 10. Risk of Bias: very serious. Downgraded two levels for serious risk of confounding and selection bias in all studies which substantially lowered confidence in the certainty of the estimate of effect.. Imprecision: serious. Downgraded for imprecision due to wide confidence intervals around the absolute effects which also crossed the line of no effect.. 11. Systematic reviewwith included studies:. Baseline/comparator: Control arm of reference used for intervention. 12. Risk of Bias: very serious. Downgraded two levels for serious risk of confounding and selection bias in all studies which substantially lowered confidence in the certainty of the estimate of effect.. Imprecision: serious. Downgraded for imprecision due to wide confidence intervals around the absolute effects which also crossed the line of no effect.. 13. Systematic reviewwith included studies:. Baseline/comparator: Control arm of reference used for intervention.
- Risk of Bias: very serious. Downgraded two levels for serious risk of confounding and selection bias in all studies which substantially lowered confidence in the certainty of the estimate of effect..

# Attached Images

# Clinical improvement 2 days after initiation of treatment
Odds ratio 1.09 (CI 95% 0.53 -2.23) Based on data from 304 participants in 1 studies. 11

# Very low
Due to very serious risk of bias and serious imprecision 12 The evidence is very uncertain about the effect of adding steroids to IVIG on clinical improvement 2 days after initiation of treatment

# Fever persisting 2 days after initiation of treatment
Odds ratio 0.69 (CI 95% 0.5 -0.95) Based on data from 661 participants in 3 studies. 13

# Very low
Due to very serious risk of bias 14 The evidence is very uncertain about the effect of adding steroids to IVIG results in a reduction in fever 2 days after initiation of treatment Clinical management of COVID-19: living guideline -World Health Organization (WHO)

# Clinical Question/ PICO Population:
Children aged 0-19 years meeting any standard case definition of MIS-C in hospitals in high-income countries (HIC) and low-and middle-income countries (LMIC)
IVIG plus steroids as the initial treatment

# Comparator: Steroids alone as the initial treatment

# Study results and measurements

# Steroids alone as the initial treatment

# IVIG plus steroids as the initial treatment
Certainty of the Evidence (Quality of evidence)

# Plain language summary

# Death during hospitalization
Based on data from 233 participants in 1 studies. 1 (Observational (nonrandomized)) 0 per 1000

# Very low
Due to very serious risk of bias and serious imprecision 2
The evidence is very uncertain about the effect of adding IVIG to steroids on death during hospitalization

# Ventilation support 2 days after initiation of treatment
Odds ratio 3.7 (CI 95% 0.88 -16.67) Based on data from 234 participants in 1 studies. 3 (Observational (nonrandomized))
168 more per 1000 ( CI 95% 7 fewer -971 more

# Very low
Due to very serious risk of bias and serious imprecision 4 The evidence is very uncertain about the effect of adding IVIG to steroids on the need for ventilation support 2 days after initiation of treatment

# Haemodynamic support 2 days after initiation of treatment
Odds ratio 1.75 (CI 95% 0.64 -4.76) Based on data from 238 participants in 1 studies. 5 (Observational (nonrandomized))

# Very low
Due to very serious risk of bias and serious imprecision 6 The evidence is very uncertain about the effect of adding IVIG to steroids on the need for haemodynamic support 2 days after initiation of treatment

# Coronary artery dilatation at discharge
Odds ratio 0.61 (CI 95% 0.06 -5.88) Based on data from 159 participants in 1 studies. 7 (Observational (nonrandomized))

# Very low
Due to very serious risk of bias and serious imprecision 8 The evidence is very uncertain about the effect of adding IVIG to steroids on coronary artery dilatation at discharge

# Acute left ventricular dysfunction 2 days after initiation of treatment
Odds ratio 2.08 (CI 95% 0.56 -7.69) Based on data from 238 participants in 1 studies. 9 (Observational (nonrandomized))

# Very low
Due to very serious risk of bias and serious imprecision 10 The evidence is very uncertain about the effect of adding IVIG to steroids on acute left ventricular dysfunction 2 days after initiation of treatment

# Clinical improvement 2 days after initiation of treatment
Odds ratio 0.56 (CI 95% 0.24 -1.32) Based on data from 212 participants in 1 studies. 11 (Observational (nonrandomized))

# Very low
Due to very serious risk of bias and serious imprecision 12 The evidence is very uncertain about the effect of adding IVIG to steroids on clinical improvement 2 days after initiation of treatment Clinical management of COVID-19: living guideline -World Health Organization (WHO)

# Outcome Timeframe

# Study results and measurements

# Steroids alone as the initial treatment

# IVIG plus steroids as the initial treatment
Certainty of the Evidence (Quality of evidence)
Plain language summary 1. Systematic reviewwith included studies:. Adjusted relative risk not available.. Baseline/comparator: Control arm of reference used for intervention. 2. Risk of Bias: very serious. Downgraded two levels for serious risk of confounding and selection bias in all studies which substantially lowered confidence in the certainty of the estimate of effect.. Imprecision: serious. Downgraded for imprecision due to wide confidence intervals around the absolute effects which also crossed the line of no effect.. 3. Systematic reviewwith included studies:. Baseline/comparator: Control arm of reference used for intervention. 4. Risk of Bias: very serious. Downgraded two levels for serious risk of confounding and selection bias in all studies which substantially lowered confidence in the certainty of the estimate of effect.. Imprecision: serious. Downgraded for imprecision due to wide confidence intervals around the absolute effects which also crossed the line of no effect.. 5. Systematic reviewwith included studies:. Baseline/comparator: Control arm of reference used for intervention. 6. Risk of Bias: very serious. Downgraded two levels for serious risk of confounding and selection bias in all studies which substantially lowered confidence in the certainty of the estimate of effect.. Imprecision: serious. Downgraded for imprecision due to wide confidence intervals around the absolute effects which also crossed the line of no effect.. 7. Systematic reviewwith included studies:. Baseline/comparator: Control arm of reference used for intervention. 8. Risk of Bias: very serious. Downgraded two levels for serious risk of confounding and selection bias in all studies which substantially lowered confidence in the certainty of the estimate of effect.. Imprecision: serious. Downgraded for imprecision due to wide confidence intervals around the absolute effects which also crossed the line of no effect.. 9. Systematic reviewwith included studies:. Baseline/comparator: Control arm of reference used for intervention. 10. Risk of Bias: very serious. Downgraded two levels for serious risk of confounding and selection bias in all studies which substantially lowered confidence in the certainty of the estimate of effect.. Imprecision: serious. Downgraded for imprecision due to wide confidence intervals around the absolute effects which also crossed the line of no effect.. 11. Systematic reviewwith included studies:. Baseline/comparator: Control arm of reference used for intervention. 12. Risk of Bias: very serious. Downgraded two levels for serious risk of confounding and selection bias in all studies which substantially lowered confidence in the certainty of the estimate of effect.. Imprecision: serious. Downgraded for imprecision due to wide confidence intervals around the absolute effects which also crossed the line of no effect.. 13. Systematic reviewwith included studies:. Baseline/comparator: Control arm of reference used for intervention. 14. Risk of Bias: very serious. Downgraded two levels for serious risk of confounding and selection bias in all studies which substantially lowered confidence in the certainty of the estimate of effect.. Imprecision: serious. Downgraded for imprecision due to wide confidence intervals around the absolute effects which also crossed the line of no effect..

# Attached Images
( CI 95% 310 fewer -129 more

# Fever persisting 2 days after initiation of treatment

# Very low
Due to very serious risk of bias and serious imprecision 14 The evidence is very uncertain about the effect of adding IVIG to steroids on fever persisting two days after initiation of treatment

# Clinical Question/ PICO Population:
Children aged 0-19 years meeting any standard case definition of MIS-C in hospitals in high-income countries (HIC) and low-and middle-income countries (LMIC)
Steroids alone as the initial treatment

# IVIG alone as the initial treatment

# Study results and measurements

# IVIG alone as the initial treatment

# Steroids alone as the initial treatment
Certainty of the Evidence (Quality of evidence)

# Plain language summary

# Death during hospitalization
Based on data from 239 participants in 1 studies. 1 (Observational (nonrandomized))
per 1000 0 per 1000

# Very low
Due to very serious risk of bias and serious imprecision 2
The evidence is very uncertain about the effect of steroids alone compared with IVIG alone on death during hospitalization

# Ventilation support 2 days after initiation of treatment
Odds ratio 0.31 (CI 95% 0.07 -1.43) Based on data from 237 participants in 1 studies. 3 (Observational (nonrandomized))

# Very low
Due to very serious risk of bias and serious imprecision 4 The evidence is very uncertain about the effect of steroids alone compared with IVIG alone on the need for ventilation support 2 days after initiation of treatment

# Haemodynamic support 2 days after initiation of treatment
Odds ratio 0.43 (CI 95% 0.15 -1.22) Based on data from 241 participants in 1 studies. 5 (Observational (nonrandomized))

# Very low
Due to very serious risk of bias and serious imprecision 6 The evidence is very uncertain about the effect of steroids alone compared with IVIG alone on the need for haemodynamic support 2 days after initiation of treatment

# Coronary artery dilatation at discharge
Odds ratio 0.75 (CI 95% 0.18 -3.22) Based on data from 171 participants in 1 studies. 7 (Observational (nonrandomized))

# Very low
Due to very serious risk of bias and serious imprecision 8 The evidence is very uncertain about the effect of steroids alone compared with IVIG alone on coronary artery dilatation at discharge

# Acute left ventricular dysfunction 2 days after initiation of treatment
Odds ratio 0.69 (CI 95% 0.18 -2.62) Based on data from 243 participants in 1 studies. 9 (Observational (nonrandomized))

# Very low
Due to very serious risk of bias and serious imprecision 10 The evidence is very uncertain about the effect of steroids alone compared with IVIG alone on acute left ventricular dysfunction 2 days after initiation of treatment

# Clinical improvement 2 days after initiation of treatment

# Very low
Due to very serious risk of bias and serious imprecision 12 The evidence is very uncertain about the effect of steroids alone compared with IVIG alone on clinical improvement 2 days after initiation of treatment Clinical management of COVID-19: living guideline -World Health Organization (WHO)

# Outcome Timeframe

# Study results and measurements

# IVIG alone as the initial treatment

# Steroids alone as the initial treatment
Certainty of the Evidence (Quality of evidence)
Plain language summary 1. Systematic reviewwith included studies:. Adjusted relative risk not available.. Baseline/comparator: Control arm of reference used for intervention.
- Risk of Bias: very serious. Downgraded two levels for serious risk of confounding and selection bias in all studies which substantially lowered confidence in the certainty of the estimate of effect.. Imprecision: serious. Downgraded for imprecision due to wide confidence intervals around the absolute effects which also crossed the line of no effect.. 3. Systematic reviewwith included studies:. Baseline/comparator: Control arm of reference used for intervention. 4. Risk of Bias: very serious. Downgraded two levels for serious risk of confounding and selection bias in all studies which substantially lowered confidence in the certainty of the estimate of effect.. Imprecision: serious. Downgraded for imprecision due to wide confidence intervals around the absolute effects which also crossed the line of no effect.. 5. Systematic reviewwith included studies:. Baseline/comparator: Control arm of reference used for intervention. 6. Risk of Bias: very serious. Downgraded two levels for serious risk of confounding and selection bias in all studies which substantially lowered confidence in the certainty of the estimate of effect.. Imprecision: serious. Downgraded for imprecision due to wide confidence intervals around the absolute effects which also crossed the line of no effect.. 7. Systematic reviewwith included studies:. Baseline/comparator: Control arm of reference used for intervention. 8. Risk of Bias: very serious. Downgraded two levels for serious risk of confounding and selection bias in all studies which substantially lowered confidence in the certainty of the estimate of effect.. Imprecision: serious. Downgraded for imprecision due to wide confidence intervals around the absolute effects which also crossed the line of no effect.. 9. Systematic reviewwith included studies:. Baseline/comparator: Control arm of reference used for intervention. 10. Risk of Bias: very serious. Downgraded two levels for serious risk of confounding and selection bias in all studies which substantially lowered confidence in the certainty of the estimate of effect.. Imprecision: serious. Downgraded for imprecision due to wide confidence intervals around the absolute effects which also crossed the line of no effect.. 11. Systematic reviewwith included studies:. Baseline/comparator: Control arm of reference used for intervention. 12. Risk of Bias: very serious. Downgraded two levels for serious risk of confounding and selection bias in all studies which substantially lowered confidence in the certainty of the estimate of effect.. Imprecision: serious. Downgraded for imprecision due to wide confidence intervals around the absolute effects which also crossed the line of no effect.. 13. Systematic reviewwith included studies:. Baseline/comparator: Control arm of reference used for intervention. 14. Risk of Bias: very serious. Downgraded two levels for serious risk of confounding and selection bias in all studies which substantially lowered confidence in the certainty of the estimate of effect.. Imprecision: serious. Downgraded for imprecision due to wide confidence intervals around the absolute effects which also crossed the line of no effect..

# Attached Images

# Fever persisting 2 days after initiation of treatment
Odds ratio 0.51 (CI 95% 0.21 -1.2) Based on data from 208 participants in 1 studies. 13

# Very low
Due to very serious risk of bias and serious imprecision 14 The evidence is very uncertain about the effect of steroids alone compared with IVIG alone on fever persisting 2 days after initiation of treatment Clinical management of COVID-19: living guideline -World Health Organization (WHO)

# Therapeutics and COVID-19

# Info Box
For the most up to date clinical practice guideline on therapeutics and COVID-19 see WHO website and BMJ website and MAGICapp.

# Treatment of other acute and chronic infections in patients with COVID-19
The prevalence of acute coinfections or secondary infections coinciding with COVID-19 has not been adequately described but appears to be low (198), and will be based on local factors and endemic or other emerging infections (65)(210)(212) (274). Antibiotic overuse increases the risk of emergence and transmission of multidrug-resistant bacteria. Infections with multidrug-resistant bacteria are more difficult to treat, and associated with increased morbidity and mortality.

# UNDER REVIEW
This section is currently under review and will be updated in the next iteration of the guidelines.
We recommend for patients with suspected or confirmed mild COVID-19, against the use of antibiotic therapy or prophylaxis.
We recommend for patients with suspected or confirmed moderate COVID-19, that antibiotics should not be prescribed unless severe bacterial infections are laboratory confirmed or are clinically suspected.
- Evidence from a living rapid review and meta-analysis of bacterial co-infection in patients who were assessed for bacterial infection presenting with

# Treatment of other coinfections may be based on a laboratory-confirmed diagnosis or epidemiological and clinical criteria.
- In malaria endemic areas, when a malaria RDT is also positive, antimalarials should be initiated as soon as possible as per local protocol (148).
- When there is ongoing suspected or confirmed local circulation of seasonal influenza, empiric therapy with a neuraminidase inhibitor (i.e. oseltamivir) should be considered for patients with severe disease or at risk for severe influenza, and given as soon as possible.
- If TB coinfection is suspected or confirmed, then follow local TB treatment protocols (153).
In a WHO-led study looking at outcomes for patients living with HIV and infected with the SARS-CoV-2 virus, HIV increased the odds of severe presentation by 15% and the hazards for death by 38% (278). The use of antiretroviral therapy reduced the risk of poor outcomes; however, HIV infection remained a risk factor for severity and mortality regardless of ART and viral load suppression status (278).
Facility-based HIV testing services should continue and those newly diagnosed should start antiretroviral therapy as soon as possible. For people living with HIV already on treatment, continuity of antiretroviral therapy and prophylaxis for coinfections is essential, with multi-month prescribing.

# Management of neurological and mental manifestations associated with COVID-19
People with COVID-19 are at increased risk for neurological, neuropsychiatric, and mental manifestations (see Chapter 1. Background). Neuropsychiatric manifestations such as delirium/encephalopathy and neurological manifestations such as stroke may be presenting features without respiratory symptoms (see Table 6.1). In addition to acute neurological manifestations, Guillain-Barre syndrome, acute disseminated encephalomyelitis, and acute haemorrhagic leukoencephalitis-like presentations may occur weeks after the acute stage of infection (34). Moreover, there may be potential for longer term neurological consequences such as cognitive impairment (279) and/or post-intensive care syndrome (PICS). Further research is needed in order to fully characterize these complications.
Anxiety and depressive symptoms constitute common reactions for people in the context of COVID-19 diagnosis, especially for those who may be hospitalized, due to concerns for one's own health or the health of others, the need for physical isolation (which can lead to social isolation), potential risk of death, concerns over the risk of infecting others, and concerns over leaving family members alone who may need care. Stressors particular to COVID-19 include: fear of falling ill and dying, fear of being socially excluded/placed in quarantine, loss of livelihood and loss of loved ones, and feelings of helplessness, boredom and loneliness due to being isolated. These stressors may trigger new symptoms or exacerbate underlying mental or neurological conditions. Pre-existing mental, neurological or substance use disorders increase the risk of becoming severely ill or of death, or of having long-term complications due to COVID-19 (280)(281)(92)(282)( 283) (284). People with COVID-19 are also at higher risk for sleep problems owing to acute stress responses, as well as additional reasons for those who are hospitalized such as environmental factors, invasive medical procedures (e.g. mechanical ventilation) and the frequent combination of multiple medications possibly disrupting sleep patterns (285).
We recommend, in patients with COVID-19, that measures to prevent delirium, an acute neuropsychiatric emergency, be implemented; and patients be evaluated using standardized protocols, for the development of delirium. If detected, then immediate evaluation by a clinician is recommended to address any underlying cause of delirium and treat appropriately.
- Manage any underlying cause of delirium by monitoring oxygenation and fluid status, correcting metabolic or endocrine abnormalities, addressing coinfections, minimizing the use of medications that may cause or worsen delirium, treating withdrawal from substances, understanding and minimizing the effects of any harmful drug-drug interactions and maintaining normal sleep cycles as much as possible (286). 2. Maintain awareness for concurrent underlying neurological conditions such as stroke (287) or non-convulsive status epilepticus (288) which can be masked by delirium.

# In patients receiving invasive ventilation, minimize continuous or intermittent sedation, targeting specific titration endpoints (light sedation unless contraindicated) or with daily interruption of continuous sedative infusions, to reduce delirium (286).
- In patients experiencing agitation (defined as marked restlessness or excessive motor activity, often accompanied by anxiety), use calming communication strategies and attempt to reorient the person. Acute pain due to physical illness or air hunger should be considered as triggers for agitation and need to be addressed immediately. If the person continues to be agitated despite the strategies described above and is experiencing severe distress, it may be necessary to use psychotropic medications (289). 5. When using antipsychotic medications for agitation, consider side-effects that may worsen symptomatology, including sedation, respiratory or cardiac function, risk of fever or other immunological abnormalities, or coagulation abnormalities and any potential drug-drug interactions between these and other medications. Use minimum effective doses of antipsychotic medications at the lowest frequency and for the shortest duration possible, with doses adjusted according to age, medical co-morbidities and degree of distress (289). For severe agitation, low doses of haloperidol (administered orally or by intramuscular injection) can be considered, while carefully monitoring for adverse effects such as QT prolongation and extrapyramidal symptoms (289).

# If haloperidol is contraindicated due to the patient's clinical condition (e.g. prolonged QT interval, recent myocardial infarction, Parkinson's Disease, Lewy-Body dementia, etc.), other antipsychotic medications with safer cardiovascular profiles may be used after careful consideration of other risks (such as respiratory suppression or sedation) and drug-drug interactions (94).
- If the patient remains severely agitated despite the strategies described above, benzodiazepines can be added, with preference given to those with shorter half-lives and lower risk of drug-drug interactions (such as lorazepam); lowest doses should be used and for the shortest duration possible. The intravenous route should be avoided (94).
Patients presenting with rapidly developing neurological symptoms suggestive of stroke should be evaluated as soon as possible and standard stroke protocols should be followed including systemic thrombolysis and/or intraarterial thrombectomy, if indicated. Signs and symptoms of stroke can include weakness of limbs or face, sensory loss, speech difficulties, impairment of vision, ataxia, confusion, or decreased consciousness. Standard IPC measures must be followed during the clinical evaluation, neuroimaging or procedures for patients with stroke.
Remark: Strokes can be missed in severely sick or unresponsive ICU patients and a low threshold for further evaluation (including neuroimaging) is recommended for acute neurological worsening.

# We recommend providing basic mental health and psychosocial support (MHPSS) for all persons with suspected or confirmed COVID-19 by asking them about their needs and concerns, and addressing them (290).
Remarks: 1. Basic psychosocial support skills are essential for management of all patients and they represent an integral part of the care to be provided for different groups, including children, older adults, pregnant women and others affected by COVID-19 (200). 2. This recommendation is consistent with the Inter-Agency Standing Committee briefing note about mental health and psychosocial aspects of and guidance on basic psychosocial skills for COVID-19 responders (200), and WHO recommendations on providing access to support based on psychological first aid principles to people in acute distress exposed recently to a traumatic event (201).

# Ask people about their needs and concerns around diagnosis, prognosis, and other social, family or work-related issues. Listen carefully, try to understand what is most important to the person at this moment, and help them work out what their priorities are and link them with relevant resources and services. 4. Give accurate information on the person's condition and treatment plans in easily understood and non-technical language, as lack of information can be a major source of stress. Help people address urgent needs and concerns, and help with decision-making, as necessary.
Help connect people with loved ones and social support, including through phone or internet as appropriate. 5. MHPSS and follow up should continue after the person is discharged from hospital to ensure their symptoms are not worsening and they are continuing to do well. This can be provided through telehealth, where available and appropriate. 6. Given the stress that COVID-19 may create at individual and family levels, the high prevalence of common mental health conditions among women in the antenatal and postpartum period, and the acceptability of programmes aimed at them, interventions for MHPSS targeted to mothers need to be more widely implemented. Prevention services should be available in addition to services that treat mental health conditions.

# Parents and caregivers who may need to be separated from their children, and children who may need to be separated from their primary caregivers, should have access to appropriately trained health or non-health workers for MHPSS. MHPSS should be appropriately adapted for the needs of children, taking into consideration their social and emotional development, learning and behaviour (290).

# We recommend prompt identification and assessment for anxiety and depressive symptoms in the context of COVID-19 and to initiate psychosocial support strategies and first-line interventions, for the management of new anxiety and depressive symptoms.
- For people who are experiencing symptoms of anxiety, basic psychological skills such as psychological first aid stress management, and brief psychological interventions based on the principles of cognitive behavioural therapy should be considered (201) (202). 2. For relieving anxiety causing severe distress that is not responsive to psychosocial support strategies, benzodiazepines can be considered, specifically in the hospital setting. Benzodiazepines should only be used with extreme caution with preference for those with shorter half-lives and lower risk of drug-drug interactions (such as lorazepam). Lowest doses should be used and for the shortest duration possible; high doses and longer term use should be avoided. Benzodiazepines carry the risks of confusion and respiratory suppression, may worsen traumatic stress reactions, can produce tolerance and dependence, and are known to be prescribed indiscriminately in many emergencies (289). (203). Consider using remote mental health support (i.e. telephone therapy) when access to regular services is disrupted. 4. If a person's anxiety or depressive symptoms persist beyond recovery from COVID-19 and/or discharge from the hospital, then an underlying anxiety or depressive disorder may be suspected, and a mental health professional should be consulted and these conditions should be managed appropriately. Refer to the mhGAP Intervention Guide for mental, neurological and substance use disorders in nonspecialized health settings (204). 5. It is important to ask about thoughts or acts of self-harm, particularly during COVID-19, due to risk factors for self-harm and suicide such as sense of isolation, loss of a loved one, job, or financial loss and hopelessness. Remove possible means of self-harm, activate psychosocial support, follow up with the person, and consult a mental health professional as necessary. Refer to the mhGAP Intervention Guide for mental, neurological and substance use disorders in non-specialized health settings (204). 6. To ensure comprehensive care and based on the initial assessment, following discharge, link the person to employment, education, social services (including housing) and other relevant sectors (204).

# For people who are experiencing symptoms of depression, brief psychological interventions based on the principles of cognitive behavioural therapy, problem-solving treatment and relaxation training can be considered

# Cognitive-behavioural therapy with a trauma focus, eye movement desensitization and reprocessing or stress management should be considered for adults with post-traumatic stress disorder (PTSD) (57).
We recommend psychosocial support strategies as the first-line interventions for management of sleep problems in the context of acute stress.

# Remarks: 1. Sleep hygiene advice (including avoiding the use of psychostimulants such as caffeine, nicotine or alcohol), and stress management (including relaxation techniques and mindfulness practices) are effective in reducing sleep problems and may be offered. Psychological interventions based on the principles of cognitive behavioural therapy may also be considered. 2. For people who are hospitalized for COVID-19, additional causes of insomnia may include environmental factors (e.g. excessive light
and noise at night), anxiety, persistent cough, delirium, agitation, pain or air hunger. Identifying and promptly addressing underlying causes should be prioritized before using any pharmacological sleep aids.

# Noncommunicable diseases and COVID-19
Pre-existing NCDs, including cardiovascular disease, diabetes, chronic respiratory disease, hypertension, obesity and cancer, have been identified as independent risk factors for death (see Table 6.1).

# We recommend when caring for patients with suspected and confirmed COVID-19 that have underlying NCDs to continue or modify previous medical therapy according to the patient's clinical condition.
Antihypertensive drugs should not routinely be stopped in patients with COVID-19, but therapy may need to be adjusted based on general considerations for patients with acute illness, with particular reference to maintaining normal blood pressure and renal function. (296). To date, there are no studies that can conclusively substantiate these theories, and it is generally advised to continue these medications unless there are other reasons to stop these (e.g. hyperkalaemia, hypotension or acute deterioration in renal function) (97) (297).

# Remark: SARS-CoV-2 uses the ACE 2 receptor for entry into cells. It has been suggested that antihypertensive drugs that exert their effect by inhibiting ACE or blocking the ACE 2 receptor may either aggravate or ameliorate the clinical course of patients with COVID-19

# Rehabilitation for patients with COVID-19
At the outset of the pandemic, the rehabilitation needs for patients recovering from COVID-19 were based on evidence from the critical care population and long-term sequelae in SARS-CoV-1 survivors (298)( 299 (308). Postintensive care syndrome (PICS) refers to a range of impairments including physical deconditioning, and cognitive and mental health impairments. The COVID-19 patients who are at higher risk of ICU admission are also those at higher risk to develop PICS, i.e. older persons with underlying diseases such as diabetes, hypertension, increased frailty and other chronic disorders (309). Intensive care unitacquired weakness is ubiquitous in ARDS survivors, as it is in critically ill COVID-19 patients who required prolonged sedation (100), and recovery may be incomplete at 5 years after ICU discharge (310). Some studies suggest that cognitive impairment ranges from 70-100% at hospital discharge, 46-80% at 1 year, and 20% at 5 years. Mood disorders including depression and PTSD are also sustained and prevalent (310). For ARDS survivors, a reduced exercise capacity persists in the context of relatively preserved pulmonary function at 1 year (311). In SARS-CoV-1 survivors, pulmonary function at 1-year is reported to be normal in 63%, mildly reduced in 32% and moderately impaired in 5%, with abnormalities characterized by restrictive patterns and reduced carbon monoxide diffusing capacity (312).
The following symptoms have been reported 4-8 weeks after discharge from the hospital in both ICU admitted COVID-19 patients and non-ICU admitted COVID-19 patients: new illness-related fatigue, breathlessness, PTSD symptoms, pain, voice change, cough, dysphagia, anxiety, depression, and problems with concentration, memory and continence. Patients admitted to ICU had greater prevalence of symptoms in almost all reported symptom domains than COVID-19 patients not admitted to ICU (313). More than half of all COVID-19 patients who had been hospitalized, regardless of their clinical management, reported persistence of fatigue at 60 days since the onset of symptoms (313) (314).
With progression of the pandemic and the follow up of patients who have not been critically ill, new evidence is emerging about COVID-19 related persistent symptoms, which have parallels with other coronavirus diseases. Some patients with SARS-CoV-1 infection went on to develop a long-term illness with widespread pain, fatigue, depression and sleep disturbance (315) (205). PTSD has also been described after SARS-CoV-1 infection (205) (205).
Early findings report, most commonly reported ongoing symptoms (regardless of hospitalization status) are fatigue, muscle ache, shortness of breath and headache at a follow up of 4 months (316). Not returning to usual health within 2-3 weeks of testing was reported by approximately one third of symptomatic adults in an outpatient setting (317). A study reported that at 3 months after the onset of symptoms, one third of non-hospitalized patients were to some degree dependent on others for personal care (318).
In addition, several complications from COVID-19 have been reported in different clinical domains, resulting from a thrombotic event (such as ischaemic stroke and ischaemic heart disease), direct invasion (such as myocarditis, myositis, and meningitis) or an immunemediated reaction (such as Guillain-Barre syndrome). While many of these complications are amenable for rehabilitation, they are not addressed in this chapter. Clinicians and rehabilitation professionals can refer to existing clinical practice guidelines for the appropriate management of these sequelae.

# In hospitalized patients, during the acute phase of illness, rehabilitation professionals may provide interventions that relieve respiratory distress, prevent complications and support communication.
- Decision on when to start rehabilitation should be determined by a multidisciplinary team taking into account the patient's medical status (319). Ensure that appropriate IPC is available at designated rehabilitation areas caring for patients with COVID-19 that remain infectious. Make optimal use of digital and/or written information for the instruction of patients (81). Telehealth may play a role in the acute and subacute phases, in which face-to-face rehabilitation is costly, risky, and impractical (320). Consider strategies for communication with and engagement of families during physical distancing (102). 2. Early mobilization is recommended for all patients with severe risk of functional limitations, resulting from frailty or ICU-acquired weakness (221). In ICU, early mobilization should be part of a bundle of care (See Chapter 12 and 13 on management of critical COVID-19 for new recommendation on bundles), and appropriate levels of activity would be based on the Richmond Agitation-Sedation Scale (81). Monitor oxygen saturation levels closely as desaturation may occur. To identify every next level of mobility the ICU mobility scale can be used.

# See Chapter 11 (Management of critical COVID-19: ARDS) for examples of respiratory interventions that may be considered. 4. Communication challenges may result from voice and speech disorders that are often linked with intubation or a cognitive impairment.
Augmented communication strategies may assist, and where available, refer for speech and language therapy. 5. COVID-19 patients with dysphagia are at risk of aspiration. Dysphagia is common post-extubation and the presumed aspiration prevalence for the general critical care population is 10-25% at ICU discharge (298). Referral to an appropriately trained health professional such as a speech and language therapist, for additional breathing exercises, vocal exercises, and eating and drinking exercises where available (104). 6. Patients with COVID-19 have demonstrated improved mobility at hospital discharge and higher probability of discharging home with increased frequency and longer mean duration of physical therapy visits (321). Some reports have found that early aerobic exercises may not be well tolerated and result in rapid desaturation in COVID-19 inpatients. Exercise training may have to start with gradual functional exercises, using no or minimal equipment (81) including an active range of motion exercises, balance exercises, and walking with or without a walking aid. When (assisted) exercises are well tolerated while lying supine, the rehabilitation professional may proceed with exercises while sitting, and then standing (81).
Prior to hospital discharge, COVID-19 patients should be screened for rehabilitation needs in order to facilitate onward referral.
- Hospitalized COVID-19 patients may have ongoing rehabilitation needs which prevent safe discharge or require continued rehabilitation services. These needs can be based on physical deconditioning, and respiratory, swallow, cognitive and mental health impairments. Consider the context of the person's individual situation, including social support and home environment when making decisions about a course of intervention or support needs.

# When indicated from screening, further assessment of rehabilitation needs can be based on a basic set of measures that cover potentially affected functioning domains. This includes, but is not limited to: respiratory function (such as respiratory rate and SpO2), mobility (such as ICU mobility scale), muscle strength (such as Medical Research Council sumscore), balance (such as Berg balance scale), dysphagia (such as fluid and food trials), and activities of daily living (ADL) (such as Barthel index). Additional tests might be helpful based on a first screening for mental and cognitive impairment (such as Montreal Cognitive Assessment, Hospital Anxiety and Depression Scale, PTSD Checklist-5).
- When the patient is ready for discharge, evaluate the need of an assistive device (such as a mobility aid) and oxygen requirements at rest and during exertion. Oxygen desaturation on exertion may happen during the recovery phase, even during physical exercise of moderate activity, and is unrelated to the oxygen saturation at rest and the degree of dyspnoea (322). An example of a rapid exercise test to assess desaturation on exertion is the 1-minute sit-to-stand test (63). 4. Where continued rehabilitation needs are identified, refer for inpatient, outpatient or community-based follow up as indicated and according to the type and severity of rehabilitation needs. When a patient does not require inpatient rehabilitation but would benefit from rehabilitation follow up post-discharge, refer to outpatient or community-based services according to local service availability. Consider which options have the least barriers to attendance/service utilization and, where available and appropriate, refer to services delivered through telehealth (320) particularly where IPC measures prevent in-person consultations. 5. Information, including documentation, should be communicated between hospitals and to other hospital-based or community rehabilitation services and primary care services (319). 6. Ensure patients are provided with education and information resources for self-management management of COVID-19 symptoms, especially when barriers to accessing rehabilitation follow up are anticipated (patient leaflet / support-for-rehabilitation-self-management-after-covid-19-related-illness).
Patients with COVID-19, should be provided with education and support for the self-management of breathlessness and resumption of activities, both in a hospitalized and a non-hospitalized setting caring for COVID-19.
- Education about control of breathing can support COVID-19 patients to those recovering from respiratory illness, especially those troubled by breathlessness. Patients may be advised to adopt positions, such as high side lying and forward lean sitting, and breathing techniques, such as pursed lip breathing and square box breathing, that help to manage breathlessness. Adequate walking pace regulation is recommended to reduce breathlessness and to prevent desaturation on exertion. Severe shortness of breath that is not relieved by positioning and breathing techniques requires medical investigation. 2. All rehabilitating patients should be educated about resuming everyday activities conservatively at an appropriate pace that is safe and manageable for energy levels within the limits of current symptoms and should not be pushed for post-exertional fatigue. A gradual increase in exercise should be based on symptoms. 3. For patients with COVID-19 that also have underlying cardiovascular or pulmonary conditions, resumption of exercise should be done after consultation with appropriate health professionals (239)(108) (65). COVID-19 patients with confirmed cardiac involvement need a cardiac evaluation before resuming exercise. 4. Resuming sports gradually should also be guided by appropriate health professionals, an example is provided for return-to-play guideline for myocarditis (239)(108) (65).
For patients who have been discharged from the hospital or patients who have been managed at home and experience persistent symptoms and/or limitations in functioning, screen for physical, cognitive and mental impairments, and manage accordingly.
- Patients with COVID-19, regardless of the disease severity, might present with persistent symptoms and a functional decline which may not be obviously apparent (such as a cognitive impairment). Consult with family members or caregivers about health-related premorbid functional difficulties and compare with their current presentation. 2. Screening may include a full history, evaluation of pre-existing health conditions, observation of the patient performing functional tasks, and a symptom-based questionnaire or easily administered screening tool (324) (324). 4. Late deterioration of COVID-19 may still occur and late onset inflammatory, thromboembolic and autonomic complications including pulmonary embolism, heart attack, heart failure and stroke have been reported. Rehabilitation or health staff should be alerted and referred to specialist, as part of multidisciplinary, coordinated care pathway.

# Provide individualized rehabilitation programmes from subacute to long term according to patient needs. The prescription and provision of rehabilitation programmes should be guided by persistent symptoms and functional limitations.
- COVID-19 related impairments, such as fatigue, muscle weakness and cognitive impairment, might impact the performance of ADLs. As patients regain strength and fitness, autonomy in ADLs will improve, but some will need to accept additional support from a caregiver for a time. Provide ADL training and consider home modifications (such as grab bars in the shower and toilet, handrails along stairs) and the provision of an assistive product (such as a mobility aid, shower chair, over-toilet frame), as needed. 2. The training principles of comprehensive pulmonary rehabilitation programmes apply for COVID-19 patients with persistent fatigue, reduced exercise capacity and breathlessness (257)(322) (325). COVID-19 population needs patient-tailored supervised programmes that are flexible to adapt for patients with gas exchange abnormalities (257)(322)(325)(326) guided by baseline oxygen needs at rest and during exercise. 3. Patients with physical deconditioning and muscle weakness should start with exercises that support recovery in daily functioning. Start with active range of motion exercises, and when tolerated, proceed with progressive muscle strengthening, typically offered with resistance training. Return to physical exercise should always be guided by symptoms (108). 4. For patients having difficulties with memory, concentration and problem solving, education should be provided, and advice on strategies to help establish expectations (including from family members) and to alleviate stress and anxiety. Cognitive restorative rehabilitation may support with cognitive exercises (such as memory exercises, puzzles, games, reading) and compensation tools such as prompts (e.g. lists and notes) and breaking down activities. Encourage participation in daily activities that are meaningful for the patient. 5. For patients with anxiety, depression and PTSD, basic mental health and psychosocial support by appropriately trained health or nonhealth workers should be provided. See Chapter 17 on neurologic and mental manifestations (324)(327)(112). 6. For patients with persistent pain, a multidisciplinary approach is recommended in order to provide pain management according to the principles of the biopsychosocial model.

# Caring for women with COVID-19 during and after pregnancy
The results of a living systematic review (as of 27 April 2021) (39) show that the odds of stillbirth (OR= 1.81, 95% CI 1.38 to 2.37; 25 studies, 423 477 women) and neonatal death (OR= 2.35, 95% CI 1.16 to 4.76; 21 studies, 12 416) were higher in babies born to women with Covid-19 versus those without Covid-19. Although the overall number of neonatal deaths was small (only sixteen events in the Covid-19 group), pregnant women with COVID-19 are more likely to experience any type of preterm birth (OR=1.57, 95% CI 1.36-1.81; 48 studies, 449 040 women) compared with pregnant women without the disease. Overall, 25% (95% CI 21% to 30%; 97 studies, 17 687 women) of neonates were admitted to the neonatal intensive care unit, and had higher odds of NICU admission (OR= 2.18, 95% CI 1.46 to 3.26; 29 studies, 197 196 neonates) In another living systematic review (as of 3 August 2021) (328) SARS-CoV-2 positivity rates were found to be low in babies born to mothers with SARS-CoV-2 infection (1.8%, 95% CI 1.2% to 2.5%; 140 studies, 14 271 babies); the rates are lower (1%) when limited to babies with antenatal or intrapartum exposure to the virus. Evidence was found for confirmed mother-to-child transmission through in utero, intrapartum, and early postnatal exposure; but the overall risk is likely to be low. Severity of maternal Covid-19 (OR=2.36, 95% CI 1.28 to 4.36; 22 studies, 2842 mother-baby dyads) and maternal admission to an intensive care unit (3.46, 95% C 1.74 to 6.91; 19 studies, 2851 mother-baby dyads) seem to be associated with SARSCoV-2 positivity in offspring, and not trimester of maternal infection, gestation at birth, mode of delivery, breastfeeding, or mother-baby dyad separation at birth. This section builds on existing recommendations from WHO on pregnancy and infectious diseases and provides additional remarks for the management of pregnant and recently pregnant women.
We recommend all pregnant women with history of contact with a person with confirmed COVID-19 be carefully monitored.
Pregnant or recently pregnant women with suspected or confirmed mild or moderate COVID-19 may not require acute care in hospital, unless there is concern for rapid deterioration or an inability to promptly return to hospital; but isolation to contain virus transmission is recommended, and can be done at a health facility, community facility or at home, according to established COVID-19 care pathways.
Pregnant or recently pregnant women with severe or critical COVID-19 require acute care in the hospital, as there is concern for rapid deterioration that may warrant supportive care for severe respiratory morbidity; and/or interventions to improve maternal and fetal survival.
Remarks: Pregnant and recently pregnant women with suspected, or confirmed COVID-19, should have access to womancentered, respectful skilled care, including midwifery, obstetric, fetal medicine and neonatal care, as well as mental health and psychosocial support, with readiness to care for maternal and neonatal complications.
- Woman-centred, respectful, skilled care refers to care organized for and provided to all women in a manner that maintains their dignity, privacy and confidentiality, ensures freedom from harm and mistreatment, and enables informed choice. During labour and childbirth this includes a companion of choice, pain relief, mobility during labour and birth position of choice. 2. Screen birth companions using the standardized case definition. If the companion has suspected or confirmed COVID-19, arrange for an alternative, healthy birth companion in consultation with the woman. Emphasize to any and all companions the importance of IPC measures during labour, childbirth and the woman's and newborn's postnatal stay in the health facility, including appropriate training on and use of PPE and movement restriction in the health care facility.

# Mode of birth should be individualized, based on obstetric indications and the woman's preferences. WHO recommends that induction of labour and caesarean section should only be undertaken when medically justified and based on maternal and fetal condition. COVID-19 positive status alone is not an indication for caesarean section. See WHO recommendations for induction of labour (332).
Remarks: 3. Delayed umbilical cord clamping (not earlier than 1 minute after birth) is recommended for improved maternal and infant health and nutrition outcomes. The risk of transmission of COVID-19 through blood is likely to be minimal. There is no evidence that delaying cord clamping increases the possibility of viral transmission from the mother to the newborn. The proven benefits of a 1-3 minute delay, at least, in clamping the cord outweigh the theoretical, and unproven, harms. 4. Individualized decisions should be taken about postponing planned (elective) induction or caesarean section in pregnant women with suspected or confirmed mild.
Pregnant and recently pregnant women who have recovered from COVID-19 and been released from the COVID-19 care pathway, should be enabled and encouraged to receive routine antenatal, postpartum, or postabortion care, as appropriate. Additional care should be provided if there are any complications.
- All pregnant women with or recovering from COVID-19 should be provided with counselling and information related to the potential risk of adverse pregnancy outcomes. 2. Women's choices and rights to sexual and reproductive health care should be respected regardless of COVID-19 status, including access to contraception and quality abortion care (331).

# Feeding and caring for infants and young children of mothers with COVID-19
Relatively few cases have been reported of infants confirmed with COVID-19; those that have been reported experienced mild illness. Of 115 mother-child pairs from 17 articles where the mother is confirmed to be infected with COVID-19, 13 children had COVID-19 (4 breastfed, 5 formula-fed, 2 mix-fed, 2 unreported feeding practice). Twenty mothers had breastmilk samples tested for the presence of SARS-CoV-2 RNA particles by RT-PCR; 7 of them had children with COVID-19 (2 breastfed,1 formula fed, 2 mix-fed, 2 unreported). Of the 20 with breastmilk tested, 18 had negative results and 2 had positive results. One of the two mothers whose breastmilk sample was positive for SARS-CoV-2, had a mix-fed child who was not infected with COVID-19; the other one had a child with COVID-19 (feeding practice was not reported) (115)(334)(335)(336)(337)(338)(339)(340)(341) (342).
Breastfeeding protects against morbidity and death in the post-neonatal period and throughout infancy and childhood. The protective effect is particularly strong against infectious diseases that are prevented through both direct transfer of antibodies and other antiinfective factors and long-lasting transfer of immunological competence and memory. See WHO Essential newborn care and breastfeeding (343). Therefore, standard infant feeding guidelines should be followed with appropriate precautions for IPC.
Recommendations on the care and feeding of infants whose mothers have suspected or confirmed COVID-19 promote the health and well-being of the mother and infant. Such recommendations must consider not only the risks of infection of the infant with the COVID-19 virus, but also the risks of serious morbidity and mortality associated with not breastfeeding or the inappropriate use of breastmilk substitutes as well as the protective effects of skin-to-skin contact and kangaroo mother care. In light of the current evidence, WHO has concluded that mothers with suspected or confirmed COVID-19 should not be separated from their infants. Mother-infant contact and holding enhances thermoregulation and other physiological outcomes, significantly reduces mortality and morbidity, and improves child and parental attachment. Overall, the recommendation to keep mothers and their children together is based on several important benefits that outweigh the potential (and likely mild) harms of COVID-19 transmission to the child.
We recommend that mothers with suspected or confirmed COVID-19 should be encouraged to initiate and continue breastfeeding. From the available evidence, mothers should be counselled that the benefits of breastfeeding substantially outweigh the potential risks of transmission.
- WHO recognizes that the recommendation for an infected mother to be in close contact with her baby may appear to contradict other IPC measures that include isolation of persons infected with COVID-19 virus (165). However, the balance of risks is significantly different for infants than for adults. In infants, the risk of COVID-19 infection is low, the infection is typically mild or asymptomatic, and the consequences of not breastfeeding or separation of mother and child can be significant. At this point it appears that COVID-19 in infants and children represents a much lower risk to survival and health than the other infections and conditions that breastfeeding is protective against. This protection is especially important when health and other community services are themselves under pressure. In contrast, the risks associated with COVID-19 in adults are much higher and more severe. Improved communication is needed to address the uncertainties and confusion among programme managers, health workers and communities on this issue. 2. See Table 21.1 below for recommendations when mother with COVID-19 is caring for infant.
Info Box Mothers should not be separated from their infants unless the mother is too sick to care for her baby. If the mother is unable to care for the infant another competent family caregiver should be identified.
Mother and infant should be enabled to remain together while rooming-in throughout the day and night and practise skin-to-skin contact, including kangaroo mother care, especially immediately after birth and during establishment of breastfeeding, whether they or their infants have suspected or confirmed COVID-19 virus infection.
Neonates born to mothers with suspected or confirmed COVID-19 should be breastfed within 1 hour of birth. Mothers should apply appropriate IPC.
Early and uninterrupted skin-to-skin contact between mothers and infants should be facilitated and encouraged as soon as possible after birth, while applying necessary measures for IPC. This applies also to infants who are born preterm or low birth weight.
If the newborn or infant is ill and requires specialist care (such as neonatal unit), arrangements should be made to allow the mother free access to the unit, with appropriate IPC measures.
Earlier initiation of breastfeeding results in greater benefits. This may be relevant to mothers who give birth by caesarean section, after an anaesthetic, or those who have medical instability that precludes initiation of breastfeeding within the first hour after birth.

# During early childhood
Infants should be breastfed exclusively during the first 6 months after birth, as breastmilk provides all the nutrients and fluids they need.
From 6 months of age, breastmilk should be complemented with a variety of adequate, safe and nutrient-dense foods. Breastfeeding should continue up to 2 years of age or beyond.
Breastfeeding counselling, basic psychosocial support and practical feeding support should be provided to all pregnant women and mothers with infants and young children if they or their infants and young children have suspected or confirmed COVID-19 infection.

# If feeding is interrupted
In situations when severe illness in a mother prevents her from caring for her infant or prevents her from continuing direct breastfeeding, mothers should be encouraged and supported to express milk, and the breastmilk provided safely to the infant, while applying appropriate IPC measures.
In the event that the mother is too unwell to breastfeed or express breastmilk, explore the viability of feeding with donor human milk. If this is not possible, consider wet nursing (defined as another woman breastfeeds the child) or appropriate breastmilk substitutes, informed by feasibility, safety, sustainability, cultural context, acceptability to mother and service availability.
Mothers who are not able to initiate breastfeeding during the first hour after delivery should still be supported to breastfeed as soon as they are able. Assistance should be provided after recovery for relactation to re-establish a milk supply and continue breastfeeding.

# Practices the mother should perform during all infant and childcare
Perform frequent hand hygiene with soap and water or alcohol-based hand rub, especially before contact with her child.
Perform respiratory hygiene: sneeze or cough into a tissue and immediately dispose of the tissue. Hands should immediately be washed with soap and water or alcohol-based hand rub.
Clean and disinfect surfaces with which the mother has been in contact.
Wear a medical mask until symptom resolution and criteria for release from isolation have been met.
Additionally, breastfeeding mothers should be helped to clean her chest with soap and water if she has been coughing on it before breastfeeding. She does not need to wash her breasts prior to every breastfeed.
While mothers are recommended to wear medical masks, if the mother does not have a medical mask, she should still be encouraged to continue breastfeeding as the benefits of breastfeeding outweigh the potential risks of transmission of the virus when breastfeeding while applying other IPC measures.

# Best practices for breast-feeding
Health facilities providing maternity and newborn services should enable a mother to breastfeed for as often and for as long as she wishes. Minimizing disruption to breastfeeding will require health care practices that enable a mother to breastfeed.
All mothers should receive practical support to enable them to initiate and establish breastfeeding and manage common breastfeeding difficulties. This support should be provided by appropriately trained health care professionals and community-based lay and peer breastfeeding counsellors.
There should be no promotion of breastmilk substitutes, feeding bottles and teats, pacifiers or dummies in any part of facilities providing maternity and newborn services, or by any of the staff. Health facilities and their staff should not give feeding bottles and teats or other products that are within the scope of the International Code of Marketing of Breast-milk Substitutes and its subsequent related WHA resolutions, to infants.
If the mother is too unwell to breastfeed or express breastmilk, explore the best alternatives to breastfeeding a newborn or young infant, in priority order, as follows: 1) donor human milk should be fed if available from a human milk bank; 2) if supplies are limited, prioritize donor human milk for preterm and low birthweight newborns; 3) wet nursing may be an option depending on acceptability to mothers and families, availability of wet nurses and services to support mothers and wet nurses. COVID-19 testing of a woman who is a potential wet nurse is not required. Prioritize wet nurses for the youngest infants. In settings where HIV is prevalent, prospective wet nurses should undergo HIV counselling and rapid testing where available. In the absence of testing, if feasible, undertake HIV risk assessment. If HIV risk assessment or counselling is not possible, facilitate and support wet nursing; 4) breastmilk substitutes may be used as a last resort.

# Caring for older people with COVID-19
Older age has been reported as a risk factor for increased mortality in those affected by COVID-19. Other risk factors that have been reported are: smoking, diabetes, hypertension, cardiovascular, cancer, chronic lung disease, and functional decline (344)(345) (346). Since older people are often affected by these conditions, they are potentially at the highest risk for fatality. Furthermore, the majority of long-term care service users are older people with multiple underlying conditions and weak immune systems, which make them more susceptible to severe COVID-19 and poor outcomes (116). Refer to the WHO policy brief Preventing and managing COVID-19 across long-term care services (116) and WHO guidance Integrated care for older people (ICOPE) (347) for person-centred and coordinated model of care.
We recommend that older people be screened for COVID-19 at the first point of access to the health system, be recognized promptly if they are suspected to have COVID-19 and treated appropriately according to established COVID-19 care pathways. This should occur in all settings where older people may seek care; included but not limited to facility-based emergency units, primary care, prehospital care settings and LTCFs.
- Older patients may present with atypical symptoms (including delirium) of COVID-19, especially those with cognitive decline and dementia (118)( 119) (see Table 6.1); health workers should take this into account during the screening process.
- Provide accessible information to older people and their caregivers on clinical manifestation of COVID-19 including atypical symptoms, how to monitor symptoms, as well as when and how to seek care.
Identify if there is an advance care plan for patients with COVID-19 (such as desires for intensive care support) and respect their priorities and preferences. Tailor the care plan to be in line with patients' expressed wishes and provide the best care irrespective of treatment choice.
We recommend a review of medication prescriptions to reduce polypharmacy and prevent medicine interactions and adverse events for those being treated with COVID-19.
- Older people are at greater risk of polypharmacy, as a result of newly prescribed medications, inadequate medication reconciliation, and a lack of coordination of care, all of which increases the risk of negative health consequences. If medications are prescribed for mental and neurological manifestations of COVID-19 in older people, this should be done with extreme caution given the increased susceptibility to drug side-effects and drug interactions with other prescribed medications. 2. Over 20% of adults over 60 years have pre-existing mental or neurological conditions for which they may already be taking medications before infection (72). If a person has a previously diagnosed mental or neurological condition and is already on medications, consider how these medications (or withdrawal from them) may affect their COVID-19 symptoms. Stopping or adjusting the dosage of medications in people with COVID-19 are decisions that require careful risk-benefit analyses and when possible, consultation with a specialist is advised.
Ensure multidisciplinary collaboration among physicians, nurses, pharmacists, physiotherapists, occupational therapists, social workers, mental health and psychosocial providers, community workers and other health care professionals in the decision-making process to address multimorbidity and functional decline (347)(122) (348).
- Physiological changes with age lead to declines in physical and mental capacities such as malnutrition, cognitive decline, depressive symptoms, and those conditions interact at several levels. These interactions require an integrated approach to the screening, assessment and management of older people (347). 2. Person-centred care including geriatric, psychosocial, and palliative care by a multidisciplinary team, with a careful evaluation of baseline conditions and functions, and disease severity, followed by frequent reassessments, ensures the provision of the appropriate level of care ( 275

# Palliative care and COVID-19
Palliative care is a multifaceted, integrated approach to improving the quality of life of adults and paediatric patients and their families facing the problems associated with life-threatening illness such as COVID-19. Palliative care focuses on prevention and relief of suffering by means of early identification, assessment and treatment of physical, psychosocial and spiritual stressors. Palliative care includes but is not limited to end-of-life care (352). Palliative interventions should be integrated with curative treatment (352). Basic palliative care, including relief of dyspnoea or other symptoms and social support, should be practised by all doctors, nurses, social workers and others caring for persons affected by COVID-19, adult or child (352) (353). Refer to the WHO guide Integrating palliative care and symptom relief into responses to humanitarian emergencies and crises (352).
We recommend to identify, in all patients with COVID-19, if they have an advance care plan for COVID-19 (such as desires for intensive care support) and respect their priorities and preferences to tailor the care plan and provide the best care irrespective of treatment choice.

# Care of COVID-19 patients after acute illness
New evidence is emerging about COVID-19 related persistent symptoms, which have parallels with other coronavirus diseases (315).
The clinical characterization of mid-and long-term effects of COVID-19 remain to be clearly described and understood. In hospitalized patients, ICU and non-ICU, there are reports of new illness-related fatigue, breathlessness, PTSD symptoms, pain, voice change, cough, dysphagia, anxiety, depression, and problems with concentration, memory and continence. Patients admitted to ICU had greater prevalence of symptoms in almost all reported symptom domains than COVID-19 patients not admitted to ICU (313). As well, more than half of all COVID-19 patients who had been hospitalized, regardless of their clinical management, reported persistence of fatigue at 60 days since the onset of symptoms (313) (314).
Early findings report, most common ongoing symptoms (regardless of hospitalization status) are fatigue, muscle ache, shortness of breath and headache at a follow up of 4 months (316). Not returning to usual health within 2-3 weeks of testing was reported by approximately one third of symptomatic adults in an outpatient setting (317). A study reported that at 3 months after the onset of symptoms, one third of non-hospitalized patients were to some degree dependent on others for personal care (318). Applying the agreed values and preferences, the GDG inferred that well-informed patients would consider the possible harms associated with COVID-19 follow-up to be negligible, and that ensuring access to care is an important value to consider. To this end, WHO has developed and released a clinical case definition of post COVID-19 condition, also known as "Long COVID-19" by a Delphi consensus, 6 October 2021 to help guide patients, caregivers, and health workers on how to identify individuals who are affected by this condition.

# Evidence To Decision
No substantial variability expected

# Values and preferences
Clinical management of COVID-19: living guideline -World Health Organization (WHO)

# Justification Introduction
Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis.
Symptoms may be new onset following initial recovery from an acute COVID-19 episode, or persist from the initial illness period (WHO clinical case definition). Symptoms and impairments can present as either clusters or isolated symptoms, that limit daily activities and restrict social participation. Symptoms may be present for prolonged time frames and/or relapse over time.
This rehabilitation guidance has been developed for adults living with post COVID-19 condition and is targeting clinicians and programme planners. It has 16 topics covering both recommendations for rehabilitation programme planning and recommendations on clinical rehabilitation management. Impairment-specific topics have been selected by the GDG based on their prevalence in post COVID-19 condition and amenability to rehabilitation in other health conditions. In addition, five topics have been found essential for rehabilitation programme planning and model of care implementation.
As post COVID-19 condition can often have a multi-system impact on functioning, many of the impairment-specific topics may be interconnected and/or linked to support the rehabilitation process, reflecting the often clustered presentation of symptoms and impairments. Clinicians should take this into account to avoid duplication of interventions when developing an individualized rehabilitation care plan.

# Topic 1 Components and functions of rehabilitation care
An organizational structure is required to deliver health services and interventions within a health system. This structure relies on multiple components that are required to support the delivery of services. Components also benefit from functions as mechanisms or tools to support the operationalization of the different components.

# Important considerations
National (local), coordinated care pathways should be established that can include primary care providers (i.e. general practitioners), relevant specialists, multidisciplinary rehabilitation professionals, mental health and psychosocial providers, and social care services. Alternative delivery platforms such as home-based phone, telemedicine, or community outreach teams may be used.

# Resources and other considerations
Clinical management of COVID-19: living guideline -World Health Organization (WHO)

# Practical Info
Described components highlight the importance of interdisciplinary work and the involvement of people living with post COVID-19 condition with respect to preferred rehabilitation services and outcomes. Other components address the importance of rehabilitation needs assessment, education and guided self-management as integral parts of case management. The reported functions suggest rehabilitation care that is supported with a standardized monitoring system, including outcome measurement, which allows referrals based on patient needs and an option of home-based care that may be delivered with tele-rehabilitation services. The crux of implementing these recommendations will be the delivery of standardized training for selected staff within dedicated rehabilitation programmes.
There are currently no shared decision-making tools specifically designed for post COVID-19 condition. There is no defined core assessment for post COVID-19 condition to be used within rehabilitation care based on impact studies. Post COVID-19 condition subgrouping evidence will help define the most appropriate referral pathways and timing of follow-up.

# Evidence To Decision Justification
A Cochrane Rehabilitation systematic scoping review identified 12 articles including information on components or functions for rehabilitation care. A total of 18 components were described. The most common components were multidisciplinary rehabilitation teams, continuity and coordination of care, people-centred care and shared decision-making, case management, evidence-based care, patient education, guided self-management, integrated care and patient needs assessment. The panel agreed on the first three components to constitute the recommendation. A total of nine functions were described. The most common functions were standardized symptoms assessment, follow-up system, referral system, telehealth/virtual care and home-based care. The panel agreed on the first three functions to constitute the recommendation, and added the standardized outcome measurement. We provide a working definition for the proposed components and functions in Annex 8.
We expect that guiding people living with post COVID-19 condition through rehabilitation care based on multidisciplinary rehabilitation teams, coordinated care and shared decision-making may improve quality of life, lead to better experience and engagement with care, and increase satisfaction with access to rehabilitation. In countries with limited access to rehabilitation structures, organizing care models based on these components could represent additional cost.

# Topic 2 Red flags for safe rehabilitation
Assessment is essential to determine safe and effective rehabilitation (357). In people with post COVID-19 condition in need of rehabilitation, this includes ruling out complications resulting from COVID-19 that require further investigation and

# Conditional recommendation for
To support the delivery of rehabilitation services for post COVID-19 condition we suggest the following core components:
- Multidisciplinary rehabilitation teams; 2. Continuity and coordination of care; and 3. People-centred care and shared decision-making.
To support the operationalization of the core components, planners could implement core functions, including:
- Standardized symptoms assessment and outcome measurement; 2. Follow-up system; and 3. Referral system.
A systematic scoping review for the model of rehabilitation care (Annex 8) only identified papers that have been based on expert evidence and no GRADE certainty of evidence assessment has been applied. There is currently no evidence on impact or cost-effectiveness of components and functions underlying rehabilitation care (356). The recommendation is based on expert evidence.

# Certainty of the Evidence
Clinical management of COVID-19: living guideline -World Health Organization (WHO) management before a referral to rehabilitation in general or a specific rehabilitation intervention is undertaken (357)(358) (128).
Red flags for safe rehabilitation are those complications where commencing rehabilitation could cause an acute event or deterioration.

# Practical Info
Exertional desaturation is more likely and should be particularly considered in the post-hospital cohort (359) (360). Exertional desaturation may be suspected in the presence of dyspnoea on exertion. Exertional desaturation can be assessed with a locally available appropriate exercise test that includes measure of oxygen status (e.g. 1 minute sit to stand with pulse oximetry) (357). Drop in pulse oxygen saturation of more than 3-4% from baseline measurements (129)(131)(133) or to 94% or below, on exercise test is considered desaturation. Exercise testing for exertional desaturation should be avoided or modified (within tolerable limits for the individual) in the presence of PESE (361).
Cardiac impairment may be suspected in the presence of fast or difficulty in breathing, high resting or exertional heart rate, chest pain or palpitations (362).
Post-exertional symptom exacerbation can be assessed through history taking and reporting of symptom patterns (361) (see topic Post-exertional symptom exacerbation). Orthostatic intolerance can be investigated by measuring heart rate and blood pressure in lying and prolonged standing with an active stand test (357) (see topic Orthostatic intolerance).
Red flags for safe rehabilitation may be unclear and depend on the clinical skills of the team and availability of diagnostic investigations. Clinical teams should have access to training to screen for and identify red flags (135). Tests and investigations of red flags should be tailored to people's signs and symptoms to rule out and prevent life threatening complications (357). No one set of investigations and tests would be suitable for everyone because of the wide range of symptoms and severity.

# Evidence To Decision Justification
Exertional desaturation indicates possible new pulmonary conditions including but not limited to lung interstitial abnormality or pulmonary embolus (363)(359)(364)(365)(365)(360) (366). Exertional desaturation warrants further investigation to understand etiology, exclude and manage significant underlying pathology, before rehabilitation can be commenced safely (357). New cardiac impairment in post COVID-19 condition patients, for example myocarditis, ischaemic heart disease, left ventricular failure and arrythmia, has been reported in both previously hospitalized and non-hospitalized patients  (136). Commencing rehabilitation that increases oxygen demand, for example physical exercise training, in the presence of exertional desaturation or new cardiac impairment could precipitate an acute event.
Post-exertional symptom exacerbation and orthostatic intolerance require modifications to rehabilitation to prevent deterioration of symptoms (373)(374)(361) (see corresponding topics).

# Topic 3 Referral principles

# Strong recommendation for
In adults with post COVID-19 condition exertional desaturation and cardiac impairment following COVID-19 should be ruled out and managed before consideration of physical exercise training. While orthostatic intolerance and post-exertional symptom exacerbation (PESE) are amenable to rehabilitation, their presence will require interventions to be modified in view of these diagnoses for rehabilitation to be safe.
A systematic scoping review for the model of rehabilitation care including red flags for safe rehabilitation (Annex 8) only identified papers that have been based on expert evidence and no GRADE certainty of evidence assessment has been applied. The recommendation is based on expert evidence.

# Certainty of the Evidence
Clinical management of COVID-19: living guideline -World Health Organization (WHO)
This topic provides guidance for programme planners and health workers on who is expected to benefit from entering a rehabilitation programme for post COVID-19 condition. This recommendation builds on patient level characteristics for referral, and timing of referral is considered.

# Practical Info
The use of a tool to assess and measure the impact of post COVID-19 condition on an individual may be considered, either self-scored, or administered by a trained health worker. However, agreed post Covid-19 condition-specific measurement instruments of disability, functioning, and health are currently lacking, and challenges exist when applying patient-reported outcome measures (PROMs) developed for other conditions (375). The initial severity of COVID-19 (149), and severity or clustering of particular symptoms or impairments should not impact referral for rehabilitation.
Upon diagnosis of post COVID-19 condition (new or persistent symptoms usually at 12 weeks following a confirmed or probable SARS-CoV-2 infection), an early referral into rehabilitation based on the above referral principles is suggested.

# Conditional recommendation for
An early referral of adults with post COVID-19 condition for appropriate rehabilitation services is suggested when experiencing symptoms and impairments that may be managed effectively and that have an impact on everyday functioning, when red flags for safe rehabilitation have been considered.
A systematic scoping review for the model of rehabilitation care including referral principles (Annex 8) only identified papers that have been based on expert evidence and no GRADE certainty of evidence assessment has been applied. The recommendation is based on expert evidence.

# Certainty of the Evidence
Entrants to rehabilitation programmes should be willing and able to engage in the rehabilitation process. Referral routes may be via hospital, health centre, and community referral or self-referral (138)(141) (376).
Post COVID-19 condition affects people with varying combinations of impairments and therefore, experts value a personalized assessment to identify the impact of post COVID-19 condition upon the functioning of the individual, including activity limitations and social participation restrictions, and the development of a personalized rehabilitation programme.

# Resources and other considerations
Clinical management of COVID-19: living guideline -World Health Organization (WHO)
Referral to rehabilitation before 12 weeks may be considered based on clinical guidance.
We do not yet have sufficient evidence of expected rehabilitation outcomes in people with post COVID-19 condition and subpopulations. However, maintenance or improvement of functioning is expected in patients who are referred using this recommendation based on the available indirect evidence for interventions for rehabilitation of selected impairments.
There may be large numbers of patients referred to rehabilitation services. As outcomes and interventions are developed, it is likely that referral criteria will become more specific.

# Topic 4 Service delivery
Post COVID-19 condition is expected to pose continued burden on health care resources (391). Therefore, it is essential for health services planners including rehabilitation programme planners, to consider instituting strategies within their settings to enhance care delivery and lessen health care resource consumption or burden.

# Practical Info
SARS-CoV-2 infection prevention measures must continue to be applied during rehabilitation service delivery by both patients and health workers according to national guidance.
Self-management should be enabled and encouraged, including symptom monitoring and management at home (392) (393). However, safety considerations should be factored in by equipping the patients, family, loved ones and their care providers with knowledge and skills on self-monitoring for symptom triggers and basic identification of danger signs and symptoms that may arise whilst undergoing at-home rehabilitation (140)(385) (394).
Rehabilitation service delivery should be supported with training and psychological support of professionals. Health workers are at risk of work-related stress and burnout (395), given the uncertainty experienced around treating a novel condition, and an absence of guidelines or care pathways (396).

# Evidence To Decision Justification
A hybrid in-person and remote model is suggested that is based on patient preference and needs over time, available resources to the health system and patients, and community transmission status (140)(385)(397)(392) (396). In-person initial evaluation and follow up for post COVID-19 condition is preferred as it allows a more thorough symptom and physiological assessment.
Integrating rehabilitation into existing health services delivery is considered less involving in terms of health care organization than starting a parallel system, and is expected to be cost-effective (140)(385)(396) (398). Post COVID-19 condition rehabilitation does not or should not require high-level resources. Post COVID-19 condition rehabilitation should be integrated across all levels of health care with appropriate investment in primary care level resources and training (392)( 396) (398).
The panel does not recommend on an ideal length of rehabilitation programme; patients present differently and have varying rehabilitation needs. Currently little is known regarding the effectiveness of interventions and their respective dosages.

# Conditional recommendation for
For rehabilitation service delivery for post COVID-19 condition we suggest using a hybrid approach of in-person and remote models that is integrated across all levels of health care. It is suggested that the length of a rehabilitation programme is based on patient needs, enabling re-engagement if new onset functional decline occurs.
A systematic scoping review for the model of rehabilitation care including service delivery setting (Annex 8) only identified papers that have been based on expert evidence and no GRADE certainty of evidence assessment has been applied. The recommendation is based on expert evidence.

# Certainty of the Evidence
Clinical management of COVID-19: living guideline -World Health Organization (WHO)
Therefore, current best practice would be to consider personalizing the duration of the rehabilitation episode based on the assessment and monitoring findings. In addition, symptoms may be labile or episodic and relapses often occur; having a viable option for re-evaluation and re-engagement with rehabilitation is important (397)(392) (396).
It is expected that rehabilitation service delivery for post COVID-19 condition following a hybrid approach of in-person and remote models that is integrated across all levels of health care will result in most optimal outcomes. There is no published evidence to show that one type of service delivery setting is more or less likely to cause harm. The key safety factor is ensuring training of staff.

# Topic 5 Workforce
Workforce planning is important to ensure that appropriate health care is provided effectively and efficiently. Adequate rehabilitation workforce planning for post COVID-19 condition is essential to improve or optimize the level of functioning of people experiencing persistent symptoms following SARS-CoV-2 infection (140).

# Practical Info
Rehabilitation of people with post COVID-19 condition requires a well led, coordinated and transdisciplinary team with a range of health care professionals, which may need support from other services, community health care workers and volunteers.
A senior, experienced rehabilitation worker should be identified to comprehensively assess rehabilitation needs, and identify those occupational groups required for the rehabilitation care, support, and guidance on self-management of individual patients and their family, and to coordinate step-down processes. This person needs to be familiar with locally available resources.
For low-resource settings in which identified rehabilitation workforce is not available, we value task sharing between health care workers who have undergone training on safe rehabilitation.

# Evidence To Decision Justification
A broad range of rehabilitation workers (380) are required as the symptoms and impairments in post COVID-19 condition result in limitations in functioning in physical, cognitive, communication, and mental domains, activity limitations and participation restrictions, and reduced well-being (356). A single specialty perspective appears sub-optimal for the rehabilitation of people living with post COVID-19 condition and a transdisciplinary approach is likely the most beneficial to promote rehabilitation outcomes.
Rehabilitation workers aim to have a positive impact on the patient's everyday functioning, participation (including restrictions on employment and education), and the patients' and their carers' well-being. In the absence of natural recovery in people with post COVID-19 condition, it is anticipated that patients would benefit from rehabilitation services provided by the aforementioned workforce.

# Conditional recommendation for
A workforce for the rehabilitation of adults with post COVID-19 condition may include but is not limited to physiotherapists, occupational therapists, nurses, psychologists, speech and language therapists, physicians and social workers. Community health care workers may be required based on local needs.
A systematic scoping review for the model of rehabilitation care including workforce (Annex 8) only identified papers based on expert evidence and no GRADE certainty of evidence assessment has been applied. Limited evidence prevents identification of a core team of health care professionals providing interventions for rehabilitation of post COVID-19 condition. There is no data on the impact or cost-effectiveness of currently proposed rehabilitation workers for post COVID-19 condition. The recommendation is based on expert evidence.

# Certainty of the Evidence
Clinical management of COVID-19: living guideline -World Health Organization (WHO)

# Topic 6 Post-exertional symptom exacerbation
Post-exertional symptom exacerbation (PESE), also referred to as post-exertional malaise (PEM), is defined as the worsening of symptoms that can follow minimal cognitive, physical, emotional, or social activity, or activity that could previously be tolerated (150). Symptoms typically worsen 12 to 72 hours after activity and can last for days or even weeks, sometimes leading to a relapse (150)(152)(399) (155). PESE can contribute to the episodic nature of disability in post COVID-19 condition, often presenting as unpredictable fluctuations in symptoms and function (156) (158).

# Practical Info
Evidence-based questionnaires and screening tools (155)(400)(401)(402)(160) (403), and patient-reported outcome measures (404) (405), can be used to identify, assess, and monitor interventions for PESE.
Post-exertional symptom exacerbation may not be mentioned spontaneously by individuals, due to unfamiliarity with the concept (400). Clinicians should carefully assess for PESE in post COVID-19 condition, including PESE symptoms, triggers, duration, and change over time (403), while ruling out activity intolerance or reduced exercise tolerance which may be caused by respiratory, cardiovascular, and musculoskeletal conditions (361)(382) (406).
Activity and energy management, or pacing, should be flexible, balancing activities and rest contingent on symptoms (361).
Pacing is itself a complex and active intervention, where physical and cognitive exertion, including over exertion, can be triggers for post COVID-19 condition symptom exacerbation or relapse (388)(407)( 408) (409).
Sustained symptom stabilization may suggest positive effects of pacing, and stability (e.g. 1 month) should be achieved before attempting to modify or increase activities (361). Help patients to identify the timing to safely resume progressive and adapted physical activities. Interventions for rehabilitation based on fixed incremental increases in the time spent being physically active or graded exercise, should not be offered to people experiencing PESE (150). Careful monitoring of symptoms over time can help identify symptom improvements, potential recovery, flare-ups, or relapses.

# Evidence To Decision Justification
Interventions for rehabilitation of PESE include education about the importance of quality rest and sleep, and skills training on energy conservation techniques such as techniques for activity and energy management or pacing, techniques for building rest into routines effectively, developing an activity and energy management plan, establishing an individual activity pattern within current activity and energy limits that minimizes symptoms, and heart rate monitoring (361)(150)(410)(406)(411)(412)(413) (414). Discuss and agree self-management strategies to respond promptly to a flare-up or relapse, such as identifying possible triggers, temporarily reducing activity levels, monitoring symptoms over time, and not returning to usual activity levels until the flare-up has resolved (150).
The provision and training in the use of assistive products and environmental modifications aim to reduce activity limitations, optimize independence with daily activities impacted by PESE, and mitigate frequency of relapses (see topic Return to everyday activities and work). Patients with moderate (reduced mobility and restricted in all daily activities) or severe PESE (housebound and dependent on help for all daily activities) may benefit from walking canes or sticks, wheelchairs, and home adaptations for toileting.

# Conditional recommendation for
For the clinical rehabilitation management of PESE in adults with post COVID-19 condition we suggest using education and skills training on energy conservation techniques such as pacing approaches. The provision and training in the use of assistive products and environmental modifications may be useful for people experiencing moderate to severe PESE.
No direct evidence based on effectiveness studies for rehabilitation of PESE in post COVID-19 condition is yet available (Annex 6). Hence, no GRADE certainty of evidence assessment has been applied. Also, no Cochrane systematic review on the rehabilitation management of PESE has been identified (Annex 7, Exercise intolerance map). The recommendation is based on expert evidence and patient preferences, and is following guidance for PESE in other health conditions, which has been based on very low certainty of evidence (150).

# Certainty of the Evidence
Clinical management of COVID-19: living guideline -World Health Organization (WHO)
Currently, there is no evidence to support one intervention over the other for PESE in post COVID-19 condition.
Energy conservation techniques are considered safe (361)(410)(406)(411)(400) (415), and no evidence suggests risk of harm.

# Topic 7 Arthralgia
Arthralgia in post COVID-19 condition presents as an inflammatory type of pain in one or more joints which may be dull, sharp, stabbing, shooting, burning, throbbing or aching (and excludes chest pain from costochondritis and pain of mechanical origin such as shoulder pain from prone positioning or low back pain). Arthralgia may appear suddenly or slowly develop with worsening progression and ranges in intensity from mild to severe. It may occur after the onset of fever and respiratory symptoms with the knee, ankle, and wrist joints most frequently affected, and seems to correlate with disease severity with possibility of poly-arthralgia (416)( 417

# Practical Info
Excluding PESE before commencing exercise therapy, and careful monitoring for PESE both during and after exercise, should be considered (361).
Physical exercise training should be adapted to the patient (e.g. pregnant women, older people).

# Evidence To Decision Justification
Patient education about the nature and pattern of pain improves understanding, builds confidence, empowers knowledge, and reduces fear of movement. Skills training on self-management strategies promote active joint movement within the limits of pain to prevent chronic pain from disuse and deconditioning (422) (423).

# Conditional recommendation for
For the clinical rehabilitation management of arthralgia in adults with post COVID-19 condition we suggest using a combination of pain education, skills training on self-management strategies, prescription of short-term anti-inflammatory drugs, and in the absence of PESE physical exercise training.
No direct evidence based on effectiveness studies for rehabilitation of arthralgia in post COVID-19 condition is yet available (Annex 6). Hence, no GRADE certainty of evidence assessment has been applied. Physical exercise training has been suggested based on low to moderate quality of evidence in other health conditions (Annex 7, Arthralgia map).

# Certainty of the Evidence
Clinical management of COVID-19: living guideline -World Health Organization (WHO)

# Topic 8 Breathing impairment
Dyspnoea, also referred to as breathlessness or shortness of breath, is a subjective, distressing sensation of awareness of difficulty with breathing (432). In post COVID-19 condition, this may occur at rest or on exertion, be constant, transient, or fluctuating, and can change in nature over time (128).

# Practical Info
Breathlessness may be investigated using an exercise tolerance test suited to the person's ability, for example the oneminute sit-to-stand test (177)( 433 Psychological support including stress management could be offered to patients to address factors contributing to dyspnoea, for example anxiety (440). This should be offered regardless of pre-existing mental health conditions.
Currently, there is no evidence to support one intervention over the other in post COVID-19 condition.
The expected outcome of breathing control techniques is an improvement in breathing pattern (446)

# Certainty of the Evidence
Clinical management of COVID-19: living guideline -World Health Organization (WHO)
an improvement in the psychological well-being, increased ability to self-manage symptoms and improvement in experience of dyspnoea can be expected (440).
Restorative interventions may include education of the patient and caregiver on the condition in order to identify techniques to engage in desired tasks while managing symptoms, and cognitive exercises (e.g. Currently, there is no evidence to support one intervention over the other in post COVID-19 condition.
The panel estimates that the expected outcomes for restorative and compensatory approaches include improvement of attention, memory and executive functioning, and increased ability to perform self-care activities (e.g. bathing, dressing, grooming), instrumental activities of daily living (e.g. answering the phone, home management) and participating in work or education (e.g. online meetings, in-person tasks). Harms and adverse events are unknown or understudied.  (195).
Physical exercise training should be adapted to the patient (e.g. pregnant women, older people).

# Conditional recommendation for
For the clinical rehabilitation management of fatigue in adults with post COVID-19 condition we suggest using a combination of education, skills-training on energy conservation techniques such as pacing approaches and, in the absence of PESE, a cautious return to symptom-titrated physical exercise training. The provision and training in the use of assistive products and environmental modifications may be considered for people experiencing levels of fatigue that limit instrumental activities of daily living. Psychological support may be offered to support coping with the symptom.

# Evidence To Decision Justification
Interventions for rehabilitation may include education about fatigue and its impact on physical, cognitive, emotional, and social energy demands (412) (193), the importance of quality sleep and rest, and the often episodic and unpredictable nature of fatigue in post COVID-19 condition (156) (158). Skills training on energy conservation techniques may include techniques for activity and energy management or pacing (including the provision of an assistive product to reduce the impact of fatigue), learning individual triggers and patterns to fatigue symptoms using activity and symptom diaries, strategies for prioritizing and planning including communication of health challenges and task delegation (361)(382) (193)(199), and techniques for building quality rest into routines effectively (411) (412). People living with post COVID-19 condition find advice on pacing their activities that is given as soon as possible and practical advice on how to modify some activities helpful.
In  (474). CBT aims to support coping with fatigue and to improve functioning.

# Topic 11 Mental health
People who experience depression following COVID-19 manifest core symptoms including persistent low mood and sadness, as well as markedly diminished interest in pleasurable activities for at least two weeks. Additional symptoms of depression include sleep disturbances, changes in appetite, fatigue, experiencing beliefs of worthlessness and considering self-harm or suicide. Patients with anxiety symptoms may appear restless, have uncontrollable or racing thoughts, concentration difficulties, feelings of dread and may also experience difficulties with sleep, appetite, and irritability.
No RCT or NRSI with comparator have been identified for the rehabilitation management of fatigue. Hence, no GRADE certainty of evidence assessment has been applied (Annex 6, Fatigue PCC interventions). The recommendation is based on expert evidence and evidence for the rehabilitation management of fatigue in other conditions. There is moderate certainty for the management of fatigue with exercise therapy in other long-term conditions (466)(467)(468), however there is uncertainty how this evidence applies to people experiencing post-exertional symptom exacerbation (469) (197).
Overall, certainty of evidence is low to moderate for educational interventions and low for fatigue self-management including pacing in other conditions (197) (Annex 7, Fatigue map).

# Certainty of the Evidence

# Conditional recommendation for
For the clinical rehabilitation management of anxiety and depression in adults with post COVID-19 condition we suggest using psychological support and, in the absence of PESE, physical exercise training. In addition, mindfulness-based approaches and peer support groups may be useful to reduce distress in some people with post COVID-19 condition when managing long-term symptoms.

# Practical Info
Excluding PESE before commencing exercise therapy, and careful monitoring for PESE both during and after exercise, should be considered (361).
Physical exercise training should be adapted to the patient (e.g. pregnant women, older people).
In addition, antidepressants (e.g. amitriptyline, fluoxetine) may be considered for depression in consultation with the person and considering personal preferences, age, concurrent medical conditions, mental health conditions (e.g. bipolar disorder) and side-effects (475) (476).
Depressive symptoms can lead to reduced motivation and problem solving, thus impacting the ability for individuals to participate in the rehabilitation process. Perceived stigmatization regarding mental health treatment and disorders may further delay access to care for individuals with depression or anxiety symptoms. It is therefore important for general and more specialized health care and rehabilitation providers to be able to recognize signs of possible mental health conditions, to use effective communication skills and promote respect and dignity, and to be able to manage or refer persons presenting with mental health conditions (475).

# Evidence To Decision Justification
Psychological treatments including interpersonal therapy (IPT), CBT, and behaviour activation and problem-solving counselling, are recommended for the management of anxiety and depression (478)(479)(475) (477). There is not enough evidence to support one psychological treatment over the other in post COVID-19 condition. However, online computerized CBT has shown to effectively reduce depression and anxiety compared with treatment as usual in patients with a history of COVID-19 (480) (481). Currently, there is no evidence to support one intervention over the other in post COVID-19 condition. However, CBT and a co-intervention such as aerobic exercise may reduce depressive symptoms more than aerobic exercise alone (484).
Mindfulness-based approaches (e.g. mindfulness-based stress reduction) using a structured individual or group programme focusing on mindfulness meditation and stress reduction have demonstrated small improvements in anxiety, depression, and sleep in other chronic conditions (485).
Patients report that peer group support is helpful; they find that acknowledgment of their distress is useful and helps to alleviate their distress. Many people turn to social media and support groups (online or face to face) for support and find them to be a valuable way to share experiences, knowledge and resources with others in a similar situation. For some, this communication has helped to validate patient experiences and provided reassurance they were not alone in their struggle with long-term symptoms (486).

# Topic 12 Olfactory impairment
Post-viral olfactory dysfunction (PVOD) after SARS-CoV-2 infection is a cluster of impairments that persist after 4 weeks: loss of

# Certainty of the Evidence
Clinical management of COVID-19: living guideline -World Health Organization (WHO) olfactory function (hyposmia or anosmia), or symptomatically altered function (parosmia, phantosmia and the recently described olfactory perseveration, or "smell lock") (202) (204).

# Practical Info
Although full assessment of olfactory function with smell testing is ideal, the subjective experience of smell loss should be enough to guide institution of this intervention for rehabilitation.
The commonest delivery mechanism for the odours is via essential oils in screw-cap jars. These are simple and easily available in many countries but may present a challenge in low-resource settings. In the absence of access to these specific odorants, other locally available odorants may be substituted, although there is no evidence to support this.
The information for olfactory training can be effectively delivered via the internet as well as other media.

# Evidence To Decision Justification
Olfactory training is the repeated, deliberate attempts at smelling a set of known odours, usually twice a day over at least 3 months (488)(205) (207). The rehabilitation is self-delivered at home and requires no medical supervision or intervention. The available evidence is for training with the so-called "Hummel four" odorants (rose, clove, eucalyptus and lemon).
The expected outcome is that overall olfactory function, although variable, improves in most cases (488). The panel estimates that harms are very unlikely.

# Topic 13 Orthostatic intolerance
Orthostatic intolerance results from autonomic dysregulation and manifests in the form of blood pressure and heart rate variabilities with upright positions or standing, temperature dysregulation, excessive sweating, lightheadedness, chest pain and syncope (489)(490)(491) (209).

# Practical Info
Some people with PESE have chronotropic incompetence to the extent that it meets clinical criteria for orthostatic intolerance. Excluding PESE before commencing exercise therapy, and careful monitoring for PESE both during and after exercise, should be considered (361).

# Conditional recommendation for
For the clinical rehabilitation management of olfactory impairment in adults with post COVID-19 condition we suggest using education and skills training for olfactory training.
No direct evidence based on effectiveness studies for rehabilitation of olfactory impairment in post COVID-19 condition is yet available (Annex 6). No GRADE certainty of evidence assessment has been applied. Olfactory training has been shown to be effective in other post-viral olfactory loss, which were known to be associated with other coronaviruses (488) (205).

# Certainty of the Evidence

# Conditional recommendation for
For the clinical rehabilitation management of orthostatic intolerance in adults with post COVID-19 condition we suggest using a combination of education and skills training on self-management strategies and, in the absence of PESE, physical exercise training. Environmental modifications may be useful to support activities of daily living for people experiencing difficulties with upright positions or standing.
Autonomic dysregulation can cause symptoms that overlap with orthostatic intolerance in the absence of orthostatic haemodynamic changes and it should be considered as a potential mechanism (e.g. fatigue and PESE secondary to autonomic dysfunction without signs of orthostatic intolerance).
Physical exercise training should be adapted to the patient (e.g. pregnant women, older people). Environmental modifications should be considered to enhance safety and to avoid supine hypertension with activities of daily living (491). Patients report improvement with advice on modifying activities with aids and adjustments to the upright position (e.g. the use of a perching or shower stool to enable sitting for usually upright tasks, or long handled equipment to reduce the need to bend down) (see topic Return to everyday activities and work).

# Evidence To Decision Justification
Currently, there is no evidence to support one intervention over the other in post COVID-19 condition.
Interventions for rehabilitation aim to reduce the negative impact of orthostatic intolerance on functioning by reducing hypovolaemia, avoiding orthostatic hypotension and tachycardia (361)(490)(491)(211) (213).

# Topic 14 Swallowing impairment
Dysphagia in post COVID-19 condition is an acquired swallowing disorder that most likely results from weakness and inefficiency of the oral musculature and may have contributing symptoms of pain, exhaustion, and poor attention or memory. It most often presents with pharyngeal and laryngeal signs or symptoms, including delayed initiation of the swallow and coughing, choking, throat clearing, and voice changes (e.g. gurgly/wet voice) after the swallow. COVID-19-related dysphagia is mainly reported as post-extubation dysphagia (493)(494)( 495) (496). The existence of non-intubation dysphagia is also reported (497) but may not be as prevalent (498).

# Practical Info
Identifying disordered swallowing physiology with instrumental evaluation (e.g. flexible endoscopic evaluation of swallowing  and videofluoroscopic swallowing study will help to establish the intervention strategy, however, in lowresource settings where the instrumental evaluation may not be immediately accessible, the first step may be to apply common aspiration risk reduction strategies, including the use of positioning strategies and food/liquid modification with or
No direct evidence based on effectiveness studies for rehabilitation of orthostatic intolerance in post COVID-19 condition is yet available (Annex 6). No GRADE certainty of evidence assessment has been applied. Current level of evidence for efficacy of these interventions for orthostatic intolerance in post COVID-19 condition is based on expert opinion. The recommendation is based on expert evidence.

# Certainty of the Evidence

# Conditional recommendation for
For the clinical rehabilitation management of swallowing impairment in adults with post COVID-19 condition we suggest using a combination of education and skills training on positioning, manoeuvres and dietary modifications, and swallowing exercises.
without exercise training. Note that silent aspiration is not able to be reliably determined without instrumental evaluation and poses a threat for upper respiratory infection.
Interventions may be implemented in isolation or in combinations to control bolus flow and/or improve swallowing physiology.
Cognitive impairment (e.g., attention, memory) may impact the implementation of recommended interventions (see topic Cognitive impairment).
Diet texture and consistency modifications may follow a standardized scale (217) (218).

# Evidence To Decision Justification

# Practical Info
It is advisable that assessments and outcome measures are used both to reflect the condition and progress of patients with dysphonia receiving rehabilitation (519)(520)(521) (522).

# Evidence To Decision
There are no data from clinical trials addressing rehabilitation of dysphagia in post COVID-19 condition (Annex 6) and no GRADE certainty of evidence assessment has been applied. Large numbers of clinical studies and condition-specific systematic reviews within and across diverse patient populations support this recommendation. However, interventions for rehabilitation of dysphagia are not uniformly applied or standardized and only small-to-medium sized clinical studies support their use (499)(500)(501)(502) (Annex 7, Swallowing impairment map).

# Certainty of the Evidence

# Conditional recommendation for
For the clinical rehabilitation management of voice impairment in adults with post COVID-19 condition we suggest using education and skills training about voice rest and vocal behaviours. In addition, any combination of respiratory exercises and vocal training may be considered.
There are no data from clinical trials addressing rehabilitation for dysphonia in post COVID-19 condition (Annex 6) or

# Certainty of the Evidence
Clinical management of COVID-19: living guideline -World Health Organization (WHO)
Education and skills training regarding voice rest, hydration, and reducing laryngeal tension have been found to be effective in restoring normal phonation (236).
Respiratory exercises are essential to restore adequate respiratory muscle function to support vocalization, vocal range, intonation, and to reduce vocal strain (240).
Direct vocal training (e.g. Accent Method) and resonant vocal training may be helpful (242).
Currently, there is no evidence to support one intervention over the other in post COVID-19 condition. There is, however, a lack of evidence for respiratory muscle and vocal cord dysfunction in people with post COVID-19 condition. Hence it is suggested to prioritize the provision of education and skills training regarding voice rest, hydration, and reducing laryngeal tension.
Not addressing dysphonia is associated with secondary harm of physical impairment (e.g. vocal nodule development) and reduction in work or education participation, and employment opportunities (238) (243).
The expected outcomes from rehabilitation of COVID-19 related dysphonia include improvements in vocal stamina, voice quality, respiratory support for voicing, and well-being.

# Topic 16 Return to everyday activities and work
In post COVID-19 condition, the combined effect of impairments in multiple body functions and structures typically manifests as difficulty with standing, mobility, stamina, and cognitive demands. These impact on the ability to carry out everyday activities, including leisure time and work (524) (525). Optimizing independence in daily living and a return to work should be seen as goals of rehabilitation and health outcomes (526). Limitations in ability to engage in activities of daily living and work can lead to longterm worklessness, which is significantly and independently associated with reduced life expectancy, quality of life, and income (527).

# Practical Info
To inform an individual pacing approach, assessment of daily activities should take place in a real life context, where the burden of daily life and the impact of COVID-19 can be accurately estimated (528). In identifying 'readiness' for work, 'worklike activity' (e.g. reading duration) can be compared with work requirements.
Workplace interventions principles can also be applied by line managers, human resources personnel or union representatives (245).
Interventions in the recommendations can be applied across high-and low-resource settings as they are typically of low financial cost. Assistive product provision and environmental adaptations should consider the use of local resources in lowresource settings.

# Evidence To Decision Justification
To enable participation in daily activities, education and skills training on energy conservation techniques, including activity and energy management or pacing, is suggested (387)(532) (533). Persons are taught to apply a combination of selfmonitoring, task assessment, planned activity, and rest. In post COVID-19 condition, it has been consistently observed that too-early return to activities leads to symptom exacerbation or relapse, loss of confidence, and work loss. People with post COVID-19 condition need to be able to self-manage their energy at home before they start to work.
Consider providing and training in the use of assistive products (e.g. wheelchair, shower seat) and environmental modifications at home (e.g. perching stool or long handled equipment), to assist with activity and energy management or pacing (411)(412) (193), support mobility and activities of daily living, and maintain or improve functional independence and quality of life (150) (400). Additional environmental modifications should be considered for people with orthostatic intolerance such as handrails to prevent falls and enhance safety and head of the bed elevation of 10-20 degrees to avoid supine hypertension (491). For people with cognitive impairment environmental modifications such as maintaining a place for keys, reducing noise, and appropriate lighting may be useful.
Environmental modifications at work should address the environment, timing and duration, responsibilities, and tasks. Modifications require individualized assessment of personal capabilities matched to work requirements (529). People with post COVID-19 condition may have neurocognitive impairment, which can lead to safety issues in the workplace and require a risk assessment. Some work situations may cause harm in the presence of cardiorespiratory symptoms (530)(536).
The panel estimates there is a potential harm from not applying the suggested interventions for return to everyday activities and work in post COVID-19 condition, as a limited ability to engage in one's desired activities can negatively impact mental health, causing a cyclical and cascade effect of further negative outcomes.
Currently, there is no evidence to support one intervention over the other for a return to everyday activities and work in post COVID-19 condition.
Suggested workplace interventions have been shown to be effective in many chronic illnesses (536).
There is no direct evidence based on intervention studies for return to everyday activities and work rehabilitation in post COVID-19 condition. No GRADE certainty of evidence assessment has been applied. The stated recommendation is based on a combination of expert evidence and evidence applied from comparable health conditions and disease processes (531).

# Certainty of the Evidence
Clinical management of COVID-19: living guideline -World Health Organization (WHO)

# Ethical principles for optimum care during the COVID-19 pandemic
Ethics are central to the clinical care of COVID-19 patients in the same way that ethics pertain to all patients. Clinical care involves using clinical expertise to do what is best for patients within a relationship of care. This section provides a brief introduction to some of the ethical considerations that are important to remember in the context of COVID-19 (537)(247).
Equal moral respect: Every person is equally valuable. Treatment and care decisions should be based on medical need and not on irrelevant or discriminatory features such as ethnicity, religion, sex, age, disability or political affiliation. Patients with similar health problems or symptoms must receive equal treatment and care. Showing moral respect means involving patients and their caregivers in decision-making to the greatest extent possible, explaining options and limitations in treatment.
Duty of care: Every patient is owed the best possible care and treatment available in the circumstances. Even when resources need to be rationed during a crisis, health care professionals and frontline workers have a duty of care to promote their patients' welfare within available resources. Health care professionals and frontline workers are also owed a duty of care. In this regard, appropriate PPE for health care professionals and frontline workers should be provided to promote their safety and well-being. This is a benefit to them but also to the whole of society by ensuring that they are available to support the clinical response for as long as possible.
Non-abandonment: It follows from consideration of equal moral respect and duty of care, that no person in need of medical care should ever be neglected or abandoned. Care will extend to families and friends of patients and options to maintain communication with them should be explored. Palliative care must be accessible for all patients with respiratory failure for whom ventilatory support will be withheld or withdrawn.
Protection of the community: Appropriate IPC should be in place, respected and enforced. Such actions protect patients, health care professionals and the community. During a pandemic the focus should be on both clinical care for patients and the promotion of public health.
Confidentiality: All communications between patient and clinician must remain confidential except in the case of compelling public health concerns (e.g. contact tracing and surveillance etc.) or other accepted justifications for breach of confidentiality. Private individual information must be kept secure unless it is a justified breach.
We recommend that hospitals and health systems at local, regional, national and global level plan prepare and be ready to surge clinical care capacity (staff, structure, supplies and systems) in order to be able to provide appropriate care of all COVID-19 patients and maintain essential health services (1)(248).

# Allocation of scarce resources:
We recommend that each institution should establish a plan for what to do in situations of resource scarcity to cover the allocation or access to critical medical interventions (such as oxygen, intensive care beds and/or ventilators). Such a plan should establish a clear overall aim.
Decision-making regarding allocation: Part of planning for scarcity is ensuring that a fair system of decision-making for allocation is in place.
- Personnel familiar with the medical triage criteria and allocation protocols, who are distinct from the clinical treating team are one option. Allocation decisions should be done according to the established plan and regularly reviewed. If necessary, there should be a reallocation of a resource that was previously allocated where it is not proving beneficial. 2. For example, the aim might be to ensure the best possible use of limited resources based upon chosen medical criteria. Triage criteria should seek to balance medical utility and equity, and ease of implementation. The same criteria should be applied for all patients with similar levels of need, regardless of COVID-19 status.

# Reporting and coding during the COVID-19 pandemic (mortality and morbidity)
All coding advice is available in the official WHO languages and can be found together with more detail for classification purposes at . See  - An emergency ICD-10 code of "U07.1 COVID-19, virus identified" is assigned to a disease diagnosis of COVID-19 confirmed by laboratory testing. - An emergency ICD-10 code of "U07.2 COVID-19, virus not identified" is assigned to a clinical or epidemiological diagnosis of COVID-19 where laboratory confirmation is inconclusive or not available. - Both U07.1 and U07.2 may be used for mortality coding and tabulation as cause of death.
- The code for the confirmed diagnosis of COVID-19 is RA01.0. - The code for the clinical diagnosis (suspected or probable) of COVID-19 is RA01.1.
A set of additional categories has been agreed to be able to document or flag conditions that occur in the context of COVID-19. Both, 3-character and 4-character codes have been defined to respond to the different levels of coding depth that is in place in different countries. The categories below will not be seen in primary tabulation of the single underlying cause of death. They may be used in multiple cause of death analysis and reporting. 1. U08 Personal history of COVID-19 U08.9 Personal history of COVID-19, unspecified Note: This optional code is used to record an earlier episode of COVID-19, confirmed or probable that influences the person's health status, and the person no longer suffers of COVID-19. This code should not be used for primary mortality tabulation.
- U09 Post COVID-19 condition U09.9 Post COVID-19 condition, unspecified Note: This optional code serves to allow the establishment of a link with COVID-19. This code is not to be used in cases that still are presenting COVID-19.

# Clinical research during the COVID-19 pandemic
A living mapping and systematic review of COVID-19 studies are available (249). For more information about the WHO research roadmap see .
We recommend to collect standardized clinical data on all hospitalized patients to improve understanding of the natural history of the disease and contribute data to the WHO Global COVID-19 Clinical Data Platform (see website for details).
- Member States are invited to contribute anonymized clinical data to the WHO Global COVID-19 Clinical Data Platform; contact: COVID_ClinPlatform@who.int to get log-in credentials. This will serve to inform the public health and clinical response. 2. Four case record forms (CRFs) are now available: These can be accessed on the WHO website (251).
- Core CRF;
- Pregnancy CRF;
- Multisystem inflammatory syndrome temporally associated with COVID-19 CRF;
- Post COVID-19 condition CRF.

# Clinical characterization research protocols are also available (540).
We encourage clinicians and hospitals to enroll patients in the WHO-led Solidarity PLUS trial. For more details, please refer to: .
O2CoV2 is a WHO-led observational study in 25 low-and middle-income countries to examine baseline practices and approaches to respiratory support for patients with COVID-19. Patient enrollment completed in late 2022.
Also refer to the complete WHO R&D blueprint here: .  Countries can use this tool to collect in-depth facility inventories of biomedical equipment re-allocation, procurement and planning for COVID-19 case management. The survey assesses quantified availability and the causes for non-functioning of different sources of oxygen delivery and supply systems to the patient in order to determine priorities and re-allocation requirements in accordance with needs. Search terms "high flow oxygen" or "high-flow oxygen" or "highflow oxygen" or "high frequency oxygen" or "highfrequency oxygen" or "high flow cannula" or "high-flow cannula" or "highflow cannula" or "high frequency cannula" or "high-frequency cannula" or "high flow cannulae" or "high-flow cannulae" or "highflow cannulae" or "high frequency cannulae" or "high-frequency cannulae" or HFNC or HFOC or "HFN oxygen" or "HFN O2" or "nasal cannula" or "nasal cannulae" OR "high flow nasal" or "high-flow nasal" or "highflow nasal" or "high frequency nasal" or "high-frequency nasal" OR NIV or FNIV or "F-NIV" or HNIV or "H-NIV" OR "controlled ventilation"
OR "continuous positive airway pressure" or "continuous positive air-way pressure" or "bilevel positive airway pressure" or "bilevel positive air-way pressure" or "bi-level positive airway pressure" or "bi-level positive airway pressure" or "biphasic positive airway pressure" or "biphasic positive air-way pressure" or "bi-phasic positive airway pressure" or "bi-phasic positive air-way pressure" OR CPAP or nCPAP or BiPAP OR Vapotherm or Vapo-therm or Optiflow or Opti-flow or "transnasal insuDlation" or "trans-nasal insuDlation" or "Ambu Res-cue mask" or "Ambu Res-cue masks" or Easyfit or Performatrack or Performax or "transnasal mask" or "transnasal masks" or "trans-nasal mask" or "trans-nasal masks" OR "mechanical ventilation" or "mechanical respiration" or "artificial ventilation" or "artificial respiration" or "artificial airway" or "artificial air-way" or "artificial airways" or "artificial air-ways" OR "high frequency ventilation" or "high-frequency ventilation" OR "standard oxygen" or "standard O2" or "conventional oxygen" or "conventional O2" or "oxygen therapy" or "O2 therapy" or "oxygen inhalation therapy" or "O2 inhalation therapy" or "enriched air" OR "endotracheal tube" or "endotracheal tubes" or "endotracheal tubation" or "endotracheal tubations" or "endotracheal ventilation" or "endo-tracheal tube" or "endo-tracheal tubes" or "endo-tracheal tubation" or "endo-tracheal tubations" or "endo-tracheal ventilation" OR tracheostom OR tracheotom (tw:("high flow oxygen" or "high-flow oxygen" or "highflow oxygen" or "high frequency oxygen" or "highfrequency oxygen" or "high flow cannula" or "high-flow cannula" or "highflow cannula" or "high frequency cannula" or "high-frequency cannula" or "high flow cannulae" or "high-flow cannulae" or "highflow cannulae" or "high frequency cannulae" or "high-frequency cannulae" or HFNC or HFOC or "HFN oxygen" or "HFN O2" or "nasal cannula" or "nasal cannulae")) OR (tw:("high flow nasal" or "high-flow nasal" or "highflow nasal" or "high frequency nasal" or "high-frequency nasal")) OR (tw:(NIV or FNIV or "F-NIV" or HNIV or "H-NIV")) OR (tw:("non-invasive" and oxygenat)) OR (tw:(noninvasive and oxygenat)) OR (tw:("non-invasive" and ventilat)) OR (tw:(non-invasive and ventilat)) OR (tw:("controlled ventilation")) OR (tw:("continuous positive airway pressure" or "continuous positive air-way pressure" or "bilevel positive airway pressure" or "bilevel positive air-way pressure" or "bi-level positive airway pressure" or "bi-level positive air-way pressure" or "biphasic positive airway pressure" or "biphasic positive air-way pressure" or "bi-phasic positive airway pressure" or "bi-phasic positive air-way pressure")) OR (tw:(CPAP or nCPAP or BiPAP)) OR (tw:(Vapotherm or Vapo-therm or Optiflow or Opti-flow or "transnasal insuDlation" or "trans-nasal insuDlation" or "Ambu Res-cue mask" or "Ambu Res-cue masks" or Easyfit or Performatrack or Performax or "transnasal mask" or "transnasal masks" or "trans-nasal mask" or "trans-nasal masks")) OR (tw:("mechanical ventilation" or "mechanical respiration" or "artificial ventilation" or "artificial respiration" or "artificial airway" or "artificial air-way" or "artificial airways" or "artificial air-ways")) OR (tw:("high frequency ventilation" or "high-frequency ventilation")) OR (tw:("invasive ventilation" or IMV)) OR (tw:("airway pressure release" and ventilat)) OR (tw:(APRV)) OR (tw:("positive pressure breathing" AND inspiratory)) OR (tw:("positive pressure breathing" AND intermittent)) OR (tw:(IPPB)) OR (tw:("fluoro-carbon" AND ventilat)) OR (tw:(fluorocarbon AND ventilat)) OR (tw:("standard oxygen" or "standard O2" or "conventional oxygen" or "conventional O2" or "oxygen therapy" or "O2 therapy" or "oxygen inhalation therapy" or "O2 inhalation therapy" or "enriched air")) OR (tw:(intubat)) OR (tw:("endotracheal tube" or "endotracheal tubes" or "endotracheal tubation" or "endotracheal tubations" or "endotracheal ventilation" or "endo-tracheal tube" or "endo-tracheal tubes" or "endo-tracheal tubation" or "endo-tracheal tubations" or "endo-tracheal ventilation")) OR (tw:(tracheostom OR tracheotom)) Search terms "high flow oxygen" or "high-flow oxygen" or "highflow oxygen" or "high frequency oxygen" or "highfrequency oxygen" or "high flow cannula" or "high-flow cannula" or "highflow cannula" or "high frequency cannula" or "high-frequency cannula" or "high flow cannulae" or "high-flow cannulae" or "highflow cannulae" or "high frequency cannulae" or "high-frequency cannulae" or HFNC or HFOC or "HFN oxygen" or "HFN O2" or "nasal cannula" or "nasal cannulae" OR "high flow nasal" or "high-flow nasal" or "highflow nasal" or "high frequency nasal" or "high-frequency nasal" OR NIV or FNIV or "F-NIV" or HNIV or "H-NIV" OR "controlled ventilation"
OR "continuous positive airway pressure" or "continuous positive air-way pressure" or "bilevel positive airway pressure" or "bilevel positive air-way pressure" or "bi-level positive airway pressure" or "bi-level positive airway pressure" or "biphasic positive airway pressure" or "biphasic positive air-way pressure" or "bi-phasic positive airway pressure" or "bi-phasic positive air-way pressure" OR CPAP or nCPAP or BiPAP OR Vapotherm or Vapo-therm or Optiflow or Opti-flow or "transnasal insuDlation" or "trans-nasal insuDlation" or "Ambu Res-cue mask" or "Ambu Res-cue masks" or Easyfit or Performatrack or Performax or "transnasal mask" or "transnasal masks" or "trans-nasal mask" or "trans-nasal masks" OR "mechanical ventilation" or "mechanical respiration" or "artificial ventilation" or "artificial respiration" or "artificial airway" or "artificial air-way" or "artificial airways" or "artificial air-ways" OR "high frequency ventilation" or "high-frequency ventilation" OR "standard oxygen" or "standard O2" or "conventional oxygen" or "conventional O2" or "oxygen therapy" or "O2 therapy" or "oxygen inhalation therapy" or "O2 inhalation therapy" or "enriched air" OR "endotracheal tube" or "endotracheal tubes" or "endotracheal tubation" or "endotracheal tubations" or "endotracheal ventilation" or "endo-tracheal tube" or "endo-tracheal tubes" or "endo-tracheal tubation" or "endo-tracheal tubations" or "endo-tracheal ventilation" OR tracheostom OR tracheotom (tw:("high flow oxygen" or "high-flow oxygen" or "highflow oxygen" or "high frequency oxygen" or "highfrequency oxygen" or "high flow cannula" or "high-flow cannula" or "highflow cannula" or "high frequency cannula" or "high-frequency cannula" or "high flow cannulae" or "high-flow cannulae" or "highflow cannulae" or "high frequency cannulae" or "high-frequency cannulae" or HFNC or HFOC or "HFN oxygen" or "HFN O2" or "nasal cannula" or "nasal cannulae")) OR (tw:("high flow nasal" or "high-flow nasal" or "highflow nasal" or "high frequency nasal" or "high-frequency nasal")) OR (tw:(NIV or FNIV or "F-NIV" or HNIV or "H-NIV")) OR (tw:("non-invasive" and oxygenat)) OR (tw:(noninvasive and oxygenat)) OR (tw:("non-invasive" and ventilat)) OR (tw:(non-invasive and ventilat)) OR (tw:("controlled ventilation")) OR (tw:("continuous positive airway pressure" or "continuous positive air-way pressure" or "bilevel positive airway pressure" or "bilevel positive air-way pressure" or "bi-level positive airway pressure" or "bi-level positive air-way pressure" or "biphasic positive airway pressure" or "biphasic positive air-way pressure" or "bi-phasic positive airway pressure" or "bi-phasic positive air-way pressure")) OR (tw:(CPAP or nCPAP or BiPAP)) OR (tw:(Vapotherm or Vapo-therm or Optiflow or Opti-flow or "transnasal insuDlation" or "transnasal insuDlation" or "Ambu Res-cue mask" or "Ambu Res-cue masks" or Easyfit or Performatrack or Performax or "transnasal mask" or "transnasal masks" or "trans-nasal mask" or "trans-nasal masks")) OR (tw:("mechanical ventilation" or "mechanical respiration" or "artificial ventilation" or "artificial respiration" or "artificial airway" or "artificial air-way" or "artificial airways" or "artificial air-ways")) OR (tw:("high frequency ventilation" or "high-frequency ventilation")) OR (tw:("invasive ventilation" or IMV)) OR (tw:("airway pressure release" and ventilat)) OR (tw:(APRV)) OR (tw:("positive pressure breathing" AND inspiratory)) OR (tw:("positive pressure breathing" AND intermittent)) OR (tw:(IPPB)) OR (tw:("fluoro-carbon" AND ventilat)) OR (tw:(fluorocarbon AND ventilat)) OR (tw:("standard oxygen" or "standard O2" or "conventional oxygen" or "conventional O2" or "oxygen therapy" or "O2 therapy" or "oxygen inhalation therapy" or "O2 inhalation therapy" or "enriched air")) OR (tw:(intubat)) OR (tw:("endotracheal tube" or "endotracheal tubes" or "endotracheal tubation" or "endotracheal tubations" or "endotracheal ventilation" or "endo-tracheal tube" or "endo-tracheal tubes" or "endo-tracheal tubation" or "endo-tracheal tubations" or "endo-tracheal ventilation")) OR (tw:(tracheostom OR tracheotom))
Refined by: Controlled Clinical Trial, Year 2020-2021 504 results

# Study types
Randomized and non-randomized studies of interventions OR FNIV OR "F-NIV" OR HNIV OR "H-NIV" OR "positive airway pressure" OR ""positive air-way pressure" OR CPAP OR nCPAP OR BiPAP OR "high flow oxygen" OR "highflow oxygen" OR "high frequency oxygen" OR oxygenat OR "high flow nasal" OR "high-flow nasal" OR "highflow nasal" OR "high frequency nasal" OR "transnasal mask" OR "transnasal masks" OR "trans-nasal mask" OR "trans-nasal masks" OR IMV OR "mechanical respiration" OR "artificial respiration" OR "artificial airway" OR "artificial air-way" OR "artificial airways" OR "artificial air-ways" OR "airway pressure release" OR APRV OR "positive pressure breathing" OR "standard oxygen" OR "standard O2" OR "conventional oxygen" OR "conventional O2" OR "oxygen therapy" OR "O2 therapy" OR "oxygen inhalation therapy" OR "O2 inhalation therapy" OR "enriched air" OR intubat OR tubation OR tube OR tubes OR tracheostom OR tracheotom) OR advanced_abstract_en:(ventilat OR cannula OR HFNC OR HFOC OR "HFN oxygen" OR "HFN O2" OR NIV OR FNIV OR "F-NIV" OR HNIV OR "H-NIV" OR "positive airway pressure" OR ""positive air-way pressure" OR CPAP OR nCPAP OR BiPAP OR "high flow oxygen" OR "highflow oxygen" OR "high frequency oxygen" OR oxygenat OR "high flow nasal" OR "high-flow nasal" OR "highflow nasal" OR "high frequency nasal" OR "transnasal mask" OR "transnasal masks" OR "trans-nasal mask" OR "trans-nasal masks" OR IMV OR "mechanical respiration" OR "artificial respiration" OR "artificial airway" OR "artificial air-way" OR "artificial airways" OR "artificial air-ways" OR "airway pressure release" OR APRV OR "positive pressure breathing" OR "standard oxygen" OR "standard O2" OR "conventional oxygen" OR "conventional O2" OR "oxygen therapy" OR "O2 therapy" OR "oxygen inhalation therapy" OR "O2 inhalation therapy" OR "enriched air" OR intubat OR tubation OR tube OR tubes OR tracheostom OR tracheotom)) AND  This evidence was collected using the included study lists of four systematic reviews (SRs) (237). A top-up search of study registry databases found no additional eligible RCTs. None of the included SRs included RCTs relevant to the indirect PICO with patientreported outcomes such as comfort or satisfaction with care.