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  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. The 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
As of 8 June 2022, over 530 000 000 people worldwide have been diagnosed with COVID-19, with over 6.3 million deaths according to the WHO dashboard. A new variant, Omicron, that emerged in late November 2021 is now the dominant strain across the world and has contributed to the ongoing surge in several countries. Vaccination is having a substantial impact on case numbers and hospitalizations in a number of high-income countries, but limitations in global access to vaccines mean that many populations remain vulnerable . Even in vaccinated individuals, uncertainties remain about duration of protection and efficacy of current vaccines against Omicron and other emerging SARS-CoV-2 variants. Taken together, there remains a need for more effective treatments for COVID-19. The COVID-19 pandemic -and the explosion of both research and misinformation -has highlighted the need for trustworthy, accessible and regularly updated living guidelines to place emerging findings into context and provide clear recommendations for clinical practice.

# Clinical characterization in children:
The clinical manifestations of COVID-19 are similar in children and adults, but generally milder with varying frequency of symptoms. Although severe cases of COVID-19 in children, including fatal cases, have been reported, most children appear to have asymptomatic, mild, or moderate disease and recover within 1 to 2 weeks of disease onset . The clinical findings overlap with those of multiple other clinical syndromes (e.g., pneumonia, bronchiolitis, gastroenteritis and common febrile illnesses with fever or chills and cough being the most common reported symptoms . Relatively few cases of infants confirmed with COVID-19 have been reported; additional clinical findings include feeding difficulty and fever without an obvious source .
As in adults, children with underlying medical conditions are at risk for severe disease, and chronic pulmonary disease (including asthma), obesity, neurologic and developmental conditions, cardiovascular disease and immunosuppression conditions are the most frequently reported risk factors. Elevated inflammatory markers (e.g. CRP, procalcitonin, interleukin 6, ferritin, D-dimer) at admission or during hospitalization; dyspnoea, tachypnoea, and/or hypoxia at admission; and gastrointestinal symptoms at admission have been associated with severe disease in children . In addition, a rare but serious multisystem inflammatory syndrome in children and adolescents (MIS-C). leading to multiorgan failure and shock has been reported . Clinical features of MIS-C may be similar to those of Kawasaki disease, Kawasaki disease shock syndrome, and toxic shock syndrome. They include persistent fever, hypotension, gastrointestinal symptoms, rash, myocarditis, and laboratory findings associated with increased inflammation but respiratory symptoms may be lacking .
Clinical characterization in pregnant women : The results of a living systematic review (as of 27 April 2021) show that pregnant and recently pregnant women with COVID-19 appear to be less likely to be symptomatic (0.66, 95% CI 0.52-0.86; 15 studies, 2 017 808 women), or manifest common symptoms such as fever, dyspnoea, cough and myalgia, compared with non-pregnant women of reproductive age. These findings are largely influenced by studies of pregnant women who were managed in hospitals for any reason, with limited data on women during early pregnancy or postpartum. Pregnant or recently pregnant women with severe COVID-19 are at higher odds of requiring admission to an ICU (OR=2.61, 95% CI 1.84-3.71; 10 studies, 2 027 360 women), invasive ventilation (OR=2.41, 95% CI 2.13-2.71; 8 studies, 1 889 174 women). Older maternal age, high body mass index (BMI), non-white ethnicity, any pre-existing comorbidities, including chronic hypertension and diabetes, and pregnancy specific complications such as gestational diabetes and pre-eclampsia associated with serious complications (severe Covid-19, admission to intensive care unit, invasive ventilation and maternal death). Complications related to COVID-19 did not seem to be increased in women presenting in the third trimester compared with earlier trimester of pregnancy or in multiparous compared with primiparous women, but the existing sample sizes for these comparisons are not large.
Post COVID-19 condition: WHO released A clinical case definition of post COVID-19 condition by a Delphi consensus also known as "Long COVID-19." To harmonize coding, the Classification and Terminologies unit at the WHO created ICD-10 and ICD-11 codes for "post COVID-19 condition". Having a single name and definition for post COVID-19 condition is important as it allows physicians, patients, epidemiologists, ministers of health, policy-makers, and governments to be aligned in their understanding and informed to make policy decisions. It also allows researchers to aggregate data in a consistent and reliable manner and to conduct interventional studies using common enrolment criteria, case report forms, and core outcome sets.
Recognition and evidence regarding post COVID-19 condition is emerging. A recent meta-analysis of 10 cohort studies suggests the following factors may be associated with post COVID-19 condition: female gender, poor pre-pandemic mental health, poor general health, asthma, or being overweight or obese; and that non-white ethnic minority may be protective. A cohort study found that neurological and psychological diagnosis were more common in those who had "severe" COVID-19, which was defined as being hospitalized, needing intensive care treatment, and having encephalopathy. Three meta-analysis suggest the following symptoms to be more common: fatigue, dyspnea, cough, sleep disturbances, anxiety, depression, cognitive impairment, and difficulty concentrating . Of these, fatigue and concentration problems were noted to last beyond 12 weeks.
Variants of concern and severity of disease: At present, there are five variants of concern (VoC) recognized by WHO: Alpha, Beta, Gamma, Delta and Omicron (Coronavirus disease -Answers). VoCs seem to be more transmissible with Omicron currently outcompeting the other variants   . However, it is complex to determine whether a VoC causes more severe disease or higher mortality, as many other factors may also impact mortality. In a WHO-led analysis using data provided by country-level collaborators from South Africa Omicron was observed to cause less severe disease as well as have a lower risk of mortality. Similar reports of lower severity for Omicron have emerged from United States, United Kingdom, Denmark, Portugal and Canada. However, caution must be exercised in interpreting these reports due to the incomplete adjustment for the impact of confounding variables such as vaccination and prior infection. Additionally, in the WHO analysis, nearly a third of the hospitalized Omicron patients developed severe disease and 15% died, numbers which are not insignificant. Omicron with its enhanced transmissibility has and continues to overwhelm health care systems globally and international efforts to bring the pandemic to an end must continue with enhanced urgency. Among vulnerable populations, i.e. patients at the extremes of age, in populations with high comorbid burden, in frail patients and among the unvaccinated, COVID-19 (all VoCs) continues to contribute to substantial morbidity and mortality.

# Guideline development and implementation
What triggered this version of the guideline?
The current version of the WHO living guideline addresses the use of advanced non-invasive respiratory support options for patients with severe and critical COVID-19 with acute hypoxaemic respiratory failure not requiring emergent intubation. It follows the availability of data from five RCTs  .

# Who made this guideline?
For these new recommendations, the WHO selected additional Guideline Development Group (GDG) members with expertise on the subject matter. The GDG for this update was made up of 20 individuals, of whom 19 were content experts (clinicians, methodologists, scientists) and one was a patient partner. The methods chair (methodological expertise) and two clinical chairs (content expertise) guided the GDG discussions. See link here for short bios of GDG members.
WHO selected GDG members to ensure global geographical representation, gender balance, and appropriate technical and clinical expertise, thus not all of the standing GDG members participated in this current update. The technical unit collected and managed declarations of interests (DOIs) and found no GDG member to have a conflict of interest. In addition to 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. Web searches also did not identify any conflicts.

# 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. 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).
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;
For the fourth (v4), fifth (v5), and current versions (v6) of the guideline, new recommendations were developed according to standards and methods for trustworthy guidelines, making use of an innovative process to achieve efficiency in dynamic updating of recommendations. The methods are aligned with the WHO Handbook for guideline development.

# Related guidelines
This living WHO guideline for the clinical management of COVID-19 is related to the Living Guideline for therapeutics and COVID- 19 also published in the BMJ  and available in MAGICapp.
This guideline aims to be trustworthy and living; dynamically updated and globally disseminated once new evidence warrants a change in recommendations for COVID-19. The aim is to produce at least two updates per year, maintaining standards for trustworthy guidelines.
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.
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 February 2021, 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.
Clinical management of COVID-19 patients: living guideline -World Health Organization (WHO)
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 previously published Clinical management of severe acute respiratory infection when Middle East respiratory syndrome coronavirus (MERS-CoV) infection is suspected: interim guidance.
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 Guideline Development Group (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 in rapid systematic reviews. 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).
Step 2: Convening the GDG WHO selected GDG members to ensure global geographical representation, gender balance, and appropriate technical and clinical expertise, and patient representatives. 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
The pre-selected expert GDG (see Acknowledgements) convened on March 17 2022 to address advanced non-invasive respiratory support interventions i.e. HFNO, CPAP and NIV. The meeting involved a review of the basics of GRADE methodology including formulating population, intervention, comparator, outcome (PICO) questions and subgroups of interests, and prioritization of patientimportant outcomes (see step 4 below). For the new GDG members, an additional preparatory session on methodological issues and orientation to the WHO guideline development process was conducted on 16 March 2022 ahead of the main GDG meeting. The GDG subsequently reviewed analyses, including pre-specified subgroup analyses presented in summary of findings tables, considered an individual patient perspective and feasibility issues specific to this intervention, and formulated recommendations.
Step 3: Evidence synthesis The WHO Clinical Management Unit with support of the Quality Assurance of Norms and Standards (QNS) unit, commissioned an independent systematic review to examine the benefits and harms of the intervention. The systematic review team included librarian, methodologists, and clinicians and had experience in GRADE methodology and rating certainty of evidence (see Acknowledgements).
The technical unit collected and managed declarations of interests (DOIs) and found no systematic review team members to have a conflict of interest.
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 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 or 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 . 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 this recommendation 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  ;
- values and preferences of patients ;
- resources and other considerations (including considerations of feasibility, applicability, equity) ;
- 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.
Step 5: External and internal review The WHO guideline was then reviewed by pre-specified external reviewers (see Acknowledgements) and then approved by the WHO Publication and Guideline Review Committees. 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 2.1).
Clinical management of COVID-19 patients: living guideline -World Health Organization (WHO) 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.
- Most patients would be reluctant to use a medication/intervention for which the evidence left high uncertainty regarding effects on outcomes they consider important. This was particularly so when evidence suggested treatment effects, if they do exist, are small, and the possibility of important harm remains. - In an alternative situation with larger benefits and less uncertainty regarding both benefits and harms, more patients would be inclined to choose the intervention.
In addition to taking an individual patient perspective, the GDG also considered a population perspective in which feasibility, acceptability, equity and cost were important considerations.
Specific deliberations on values and preferences and associated feasibility and resource related considerations are presented for each recommendation.
For these new recommendations (see Section 11) the majority of GDG members inferred that most well-informed patients, and their families, would, despite the low certainty of evidence, want to receive non-invasive advanced respiratory support options, as compared with standard oxygen therapy. 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.

# Selecting and rating the importance of outcomes
GDG members prioritized outcomes from the perspective of patients with severe/critical COVID-19. SD: standard deviation. Note: 7 to 9 -critical; 4 to 6 -important; 1 to 3 -of limited importance.
Clinical management of COVID-19 patients: living guideline -World Health Organization (WHO)

# Baseline risk estimates
The evidence summaries that informed the guideline recommendations report the anticipated absolute effects of non-invasive advanced respiratory support options compared with standard oxygen therapy across all patient-important outcomes. The absolute effects of treatment are informed by the prognosis (i.e., baseline risk estimates) combined with the relative estimates of effects (e.g., RR, OR) obtained from the meta-analysis.

# Values and preferences
We had insufficient information to provide the GDG with an evidence-based description of patient experiences or values and preferences regarding treatment decisions. The GDG, therefore, relied on their own judgments of what well-informed patients would value after carefully balancing the benefits, harms, and burdens of treatment. Judgments on values and preferences were crucially informed through the experiences of former COVID-19 patients, represented in the GDG.
The GDG agreed that the following values and preferences would be typical of well-informed patients:
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). 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 non-invasive) 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).
Clinical management of COVID-19 patients: living guideline -World Health Organization (WHO)

# 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.

# COVID-19 care pathway (see Annex 1)
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 s/he is screened, based on a standardized case definition, including assessment of symptoms, and meets criteria for a suspect case.
- Suspect cases may be referred to as "persons or patients under investigation" (PUIs) in some contexts.

# UNDER REVEW
This section is under review and will be updated in the next iteration of the guidelines. 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.

# 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. 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).

# 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: 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.
- Screening can be performed in areas such as the emergency unit, outpatient department/primary care clinic, in the community by a community health worker or by telemedicine. In the context of this outbreak, this should be done at a distance (> 1 m). Use a simple set of questions based on the WHO case definition (see Table 6.1). This is best done by establishing screening protocols at all health access points and during contact tracing activities. Older people and those immunosuppressed may present with atypical symptoms such as fatigue, reduced alertness, reduced mobility, diarrhoea, loss of appetite, delirium and absence of fever . Thus, screening questions may need to be adjusted for certain settings and guided by epidemiologic considerations.

# Persons with symptoms (see

# 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.

# 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

# 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 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 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 patients: 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 popula ions
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. Presenting signs and symptoms of COVID-19 vary.
Most persons experience fever (83-99%), cough (59-82%), fatigue (44-70%), anorexia (40-84%), shortness of breath (31-40%), myalgias (11-35%). Other non-specific symptoms, such as sore throat, nasal congestion, headache, diarrhoea, nausea and vomiting, have also been reported . Loss of smell (anosmia) or loss of taste (ageusia) preceding the onset of respiratory symptoms has also been reported.
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.
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 .
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.
Children might not have reported fever or cough as frequently as adults.

# 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. 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. For COVID-19 patients with severe or critical disease, also collect blood cultures, ideally prior to initiation of antimicrobial therapy.
If blood cultures cannot be taken timely before the administration of antimicrobial therapies, indicate the details of administered antibiotics on the laboratory request. .

# 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 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 patients: living guideline -World Health Organization (WHO)

# Management of moderate COVID-19: pneumonia treatment
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.
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

# Clinical Question/ PICO Population:
Patients treated at home with confirmed or suspected COVID-19 disease
SpO2 < 92% (Pulse oximetry use at home)
SpO2  92% (Pulse oximetry use at home)

# Very low
Due to serious risk of bias, Due to serious imprecision 3

# SpO2 <92% possibly increases the risk of ARDS

# Septic shock
Relative risk 6.6 (CI 95% 1.3 -32.9) Based on data from 77 participants in 1 studies.

# Very low
Due to serious risk of bias, Due to serious imprecision 4 SpO2 <92% possibly increases the risk of septic shock
Based on data from participants in 2 studies.
Two small single arm (no comparator group) studies that offered home monitoring to patients discharged from emergency department. 3/20 (150 per 1000) and 6/52 (115 per 1000) of patients using home SpO2 monitors required hospitalization.

# 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
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.
- The same review showed that 8.2% of the patients (95%CI 6. This recommendation is currently under review and will be updated in the next iteration of the guidelines.

# 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.
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.

# Conditional recommendation for

# We suggest awake prone positioning of severely ill patients hospitalized with COVID-19 requiring supplemental oxygen (includes high flow nasal oxygen) or non-invasive ventilation (conditional, low certainty evidence).
In light of the uncertain benefits of awake prone positioning, a high level of vigilance should be maintained, and patients should be monitored closely for signs of clinical deterioration.
Monitoring of patients and training of providers in caring for patients who are awake and prone is an important part of implementation, as part of multi-faceted training for acute care management, which includes medical device training.
As for duration, some suggest regimens that target being in awake prone position for 8-12 hours/day, broken into shorter periods over the day.
Further RCTs are recommended to better define benefits and harms, as well as specific populations of interest.

# Evidence To Decision
Uncertain benefits or harms
There have been no randomized controlled trials (RCTs) completed for awake prone positioning for patients with COVID-19 requiring supplemental oxygen or non-invasive ventilation. Observational studies of awake prone position in patients with COVID-19 suggest benefits on patient-important outcomes of mortality and the need for intubation COVID-19 (very low certainty). Evidence from RCTs of prone positioning for intubated, critically ill patients with ARDS (non-COVID-19) have demonstrated benefits in mortality. The effect on less important outcomes is uncertain.
The harms of awake prone positioning are possibly patient discomfort and pain (very low certainty). The indirect evidence on harms of prone positioning from the randomized evidence on sedated, intubated patients are pressure sores, nerve injury, and haemodynamic instability, which were not considered relevant for this less severely ill population.

# Benefits and harms
For patient-important outcomes of mortality and the need for mechanical ventilation, the panel considered the direct evidence to be of very low certainty. For the patient-important outcomes of mortality, indirect evidence from intubated, sedated patients with ARDS was downgraded for indirectness, from high to low, with key considerations including the different physiology of critical disease, data from a non-COVID-19 period, and the different sedation strategies employed.

# Certainty of the Evidence
Applying the agreed values and preferences, the GDG inferred that almost all well-informed patients would want to undergo prone positioning if awake, requiring oxygen or non-invasive respiratory support, given the lack of harm from the observational studies and panel experience. The panel did not expect there would be much variation in values and preferences between patients when it came to this intervention. Patient discomfort for prone position could limit time spent in individual circumstances.
No substantial variability expected

# Values and preferences

# Important considerations
Patients who are able to follow instructions can self-prone, without assistance from health care workers. Proning patients who require assistance is associated with human resource requirements regarding training, particularly with monitoring of respiratory status. The panel felt that that this intervention should be feasible in all settings, but implementation requires dedicated training and monitoring.

# Resources and other considerations
Clinical management of COVID-19 patients: 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, the panel emphasized the low certainty evidence of reduction in mortality, downgraded from higher certainty evidence in critically ill patients with ARDS. It also noted the limited harm with the experience thus far with awake prone positioning across different resource settings.

# Subgroup analyses
The panel commented on the need for data in specific populations, namely paediatrics, older people, and pregnant women in the first two trimesters.

# Very low
Due to serious risk of bias, Due to very serious imprecision 1 There are no comparative data assessing the effect of awake proning in COVID-19 patients with regards to mortality.
Based on data from 450 participants in 25 studies.
25 single arm (no comparator group) studies that enrolled a total of 450 participants. 130/450 (289 per 1000) patients positioned prone while receiving oxygen supplementation or NIV required intubation.

# Very low
Due to serious risk of bias, Due to very serious imprecision 2
There are no comparative data assessing the effect of awake proning in COVID-19 patients with regards to intubation rates.

# Adverse effect (pain or discomfort)
Based on data from 151 participants in 6 studies.
6 single arm (no comparator group) studies that enrolled a total of 151 participants. 29/151 (192 per 1000) patients positioned prone while receiving oxygen supplementation or NIV reported pain or discomfort.

# Very low
Due to serious risk of bias, Due to very serious imprecision 3 There are no comparative data assessing the effect of awake proning in COVID-19 patients with regards to adverse events.

# Use cautious fluid management in patients with COVID-19 without tissue hypoperfusion and fluid responsiveness.
Remark: 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. This applies to both children and adults.

# Assessment and recognition
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.
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.
Clinical management of COVID-19 patients: living guideline -World Health Organization (WHO)

# 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.

# 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.
-  2.  3. #tab=tab_1

# Info Box

# 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.
Clinical management of COVID-19 patients: living guideline -World Health Organization (WHO)

# Advanced non-invasive respiratory support
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

# Resources and other considerations
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.
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.
A specific consideration for HFNO is that these devices may require a higher oxygen flow compared with other noninvasive respiratory support devices. Appropriate calculations of oxygen needs should be made at the facility level when expanding 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    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). 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.
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. . 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.
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

# 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.
For infection prevention precautions related to the use of these respiratory support devices, please refer to Section 5 on IPC. See also Research needs.

# Evidence To Decision
(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.

# 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

# Certainty of the Evidence

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

# Intervention: CPAP

# Comparator: SOT
The meta-analysis for the comparison of CPAP vs SOT was informed by the results of one trial which enrolled 742 participants (direct PICO, i.e. COVID-19 patients with AHRF) by 3 RCTs which enrolled a total of 168 patients (Helmet CPAP vs SOT; indirect PICO, i.e. non-COVID patients with ARDS)  and by one additional trial that enrolled 123 patients (face mask CPAP vs SOT; indirect PICO, i.e. non-COVID patients with ARDS). The trial that informed the direct PICO was 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.
For patien with severe or critical COVID-19, the GRADE Summary of Findings

# Very low
Due to serious indirectness and very serious imprecision 1 We are very uncertain of the impact of helmet CPAP on mortality IMV
The meta-analysis for the comparison of CPAP vs SOT was informed by the results of one trial which enrolled 742 participants (direct PICO, i.e. COVID-19 patients with AHRF) by 3 RCTs which enrolled a total of 168 patients (helmet CPAP vs SOT; indirect PICO, i.e. non-COVID patients with ARDS)  and by one additional trial that enrolled 123 patients (face mask CPAP vs SOT; indirect PICO, i.e. non-COVID patients with ARDS). The trial that informed the direct PICO was 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.
For patients with severe or critical COVID-19, the GRADE Summary of Findings table shows the relative and absolute effects of CPAP compared with SOT for the outcomes of interest, with certainty ratings, informed by the meta-analysis.
Not all trials reported on all outcomes.
Note: for RECOVERY-RS (direct PICO-COVID-19 patients with AHRF), the denominator number of patients varied by outcome.

# Outcome Timeframe

# Study results and measurements

# Face mask CPAP

# Certainty of the Evidence
(Quality of evidence)
Plain language summary 1. Inconsistency: no serious. Indirectness: no serious. Imprecision: extremely serious. Data from one study, wide confidence intervals that include important large benefit and harm (rated down by three). Publication bias: no serious.
- Inconsistency: no serious. Indirectness: no serious. Imprecision: extremely serious. Data from one study, wide confidence intervals that include important large benefit and harm (rated down by three). Publication bias: no serious.

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

# 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

# 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.
For infection prevention precautions related to the use of these respiratory support devices, please refer to Section 5 on IPC. See also Research needs.
Resources: Evidence To Decision confidence intervals that include important large benefit and harm (rated down by three). Publication bias: no serious. 4. Inconsistency: no serious. Indirectness: no serious. Imprecision: extremely serious. Data from one study, wide confidence intervals that include important large benefit and harm (rated down by three levels). Publication bias: no serious.

# Conditional recommendation for
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.
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:

# Certainty of the Evidence
Clinical management of COVID-19 patients: living guideline -World Health Organization (WHO)
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
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.
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); 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.
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 patients: living guideline -World Health Organization (WHO)
- 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). 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
The meta-analysis for the comparison of face mask NIV vs SOT was informed by 11 RCTs that enrolled 1254 participants (indirect PICO, i.e. non COVID patients with ARDS). All RCTs were published and trials either explicitly excluded pregnant women or children or did not mention them in their methods or results sections.
For patients with severe or critical COVID-19, the GRADE Summary of Findings table shows the relative and absolute effects of face mask NIV vs SOT for the outcomes of interest, with certainty ratings, informed by the meta-analysis.
Not all trials reported on all outcomes.
The meta-analysis for the comparison of face mask NIV vs HFNO was informed by 3 RCTs that enrolled 316 participants (indirect PICO, i.e. non COVID patients with ARDS). All trials were published and either explicitly excluded pregnant women and children or did not mention their inclusion in the methods and results section.
For patients with severe or critical COVID-19, the GRADE Summary of Findings table shows the relative and absolute effects of face mask NIV compared with HFNO for the outcomes of interest, with certainty ratings, informed by the meta-analysis.
Not all trials reported all outcomes.

# Study results and measurements
Face mask NIV

# Certainty of the Evidence
(Quality of evidence)
Plain language summary 1. Inconsistency: no serious. The magnitude of statistical heterogeneity was moderately high, with I^2: 51%. Indirectness: serious. Differences between the population of interest and those studied (one of two RCTs 100% in interstitial lung disease patients, the other 100% with community-acquired pneumonia). Imprecision: very serious. Number of patients is far less than would be required to meet the optimal information size. Publication bias: no serious.
- Risk of Bias: serious. Two of three trials have unclear sequence generation and concealment of allocation during randomization process (one is a research abstract with incomplete data). Inconsistency: no serious. Indirectness: serious. Differences between the population of interest and those studied (one of three RCTs 100% in interstitial lung disease patients, one reports 100% with community-acquired pneumonia, and a third reports mixed acute respiratory failure and community-acquired pneumonia). Imprecision: serious. Wide confidence interval contains important benefit and harm. Publication bias: no serious.

# 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). 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.
Due to very serious imprecision 4 Helmet NIV may decrease hospital LOS

# ICU LOS
No studies were found that looked at ICU LOS Clinical management of COVID-19 patients: living guideline -World Health Organization (WHO) 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 . 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 and is also suggested for patients with sepsis-induced respiratory failure who do not meet ARDS criteria. 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. 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.
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 . 2. 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. The main effect is to shorten the duration of ventilation. A sample protocol for implementation of this recommendation is available.
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.. In younger children, maximal PEEP pressures are 15 cmH2O. Although high driving pressure (plateau pressure  PEEP) may more accurately predict increased mortality in ARDS compared with high tidal volume or plateau pressure ; data from RCTs of ventilation strategies that target driving pressure are not currently available. (30-40 cmH2O), progressive incremental increases in PEEP with constant driving pressure, or high driving pressure; considerations of benefits vs risks are similar. Higher PEEP and RMs were both conditionally recommended in a clinical practice guideline. For PEEP, the guideline considered an individual patient data meta-analysis  of three RCTs. However, a subsequent RCT of high PEEP and prolonged high-pressure RMs showed harm, suggesting that the protocol in this RCT should be avoided. Monitoring of patients to identify those who respond to the initial application of higher PEEP or a different RM protocol and stopping these interventions in non-responders are suggested.

# Remarks: 1. 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 available to guide PEEP titration based on the FiO2 required to maintain SpO2

# A related intervention of recruitment manoeuvres (RMs) is delivered as episodic periods of high CPAP
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 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. 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
In patients with excessive secretions, or difficulty clearing secretions, consider application of airway clearance techniques. These should be performed only if deemed medically appropriate  and appropriate IPC measures are in place.
- Active cycle of breathing techniques and positioning techniques can be used to optimize oxygenation . 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. These techniques are only indicated for patients with mucous hypersecretion and difficulties clearing secretions, and for patients with co-existing respiratory or neuromuscular comorbidities.. 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.

# All interventions inducing cough for airway clearance are potentially aerosol-generating procedures, and airborne precautions should be in place (see Section 5 on IPC) ; and single-patient-use disposable options are recommended (such as positive expiratory pressure device). 3. Consider use respiratory muscle training in patients recovering from critical illness with suspected respiratory muscle weakness

# In settings with access to expertise in ECMO, consider referral of patients who have refractory hypoxaemia (e.g. including a ratio of partial pressure of arterial oxygen  to the fraction of inspired oxygen  of  6 hours) despite lung protective ventilation.

# 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). However, ECMO was associated with a reduced risk of the composite outcome that consisted of mortality and crossover to ECMO treatment and a post-hoc Bayesian analysis of this RCT showed that ECMO is very likely to reduce mortality across a range of prior assumptions. In patients with MERS, ECMO vs conventional treatment was associated with reduced mortality in a cohort study. 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 . In children, ECMO can also be considered in those with severe ARDS, although high-quality evidence for benefit is lacking.
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.. The

# 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

# 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  and children . Alternate fluid regimens are suggested when caring for adults and children in resource-limited settings .
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.

# 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.. 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.. 5. Clinical trials conducted in resource-limited settings comparing aggressive versus conservative fluid regimens suggest higher mortality in patients treated with aggressive fluid regimens . Refer to the WHO-ICRC Basic emergency care (Shock module) for an initial approach and management of shock in resource-limited settings.

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

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

# 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.

# 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 . 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.

# 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.
- 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  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. 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.

# 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.

# 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 ; other information available at ), preventing VAP treating sepsis (reviewed in ), preventing central venous catheter infection and preventing pressure ulcers (). For some bundles, observational data have shown variable association between the bundle components and patient important outcomes. 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 prevent VAP treat sepsis (), and prevent central venous catheter infection  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

# 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  .
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).
Clinical management of COVID-19 patients: living guideline -World Health Organization (WHO)

# 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.
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 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 Very low

# Certainty of the Evidence Justification
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.
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    or other guidelines  and are generally limited to feasible recommendations based on high-quality evidence. Recent publications have encouraged best practices to continue during the COVID-19 outbreak. See the WHO Clinical care for severe acute respiratory infection toolkit: COVID-19 adaptation for practical tools to assist implementation. - 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

# 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.
Clinical management of COVID-19 patients: living guideline -World Health Organization (WHO)
Adverse effects of medications 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 . 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 Clinical management of COVID-19 patients: living guideline -World Health Organization (WHO)

# Multisystem 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 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.

# 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.
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 and the WHO Paediatric emergency triage, assessment and treatment: care of critically ill children.
- 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 patients: living guideline -World Health Organization (WHO)

# Subgroup analysis
Subgroup analyses were not conducted.
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.
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.
Clinical management of COVID-19 patients: 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.

# 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
Comparator 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))
11 fewer per 1000 ( CI 95% 15 fewer -14 more

# 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 (

# 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

# 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.
- 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.
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.
- 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.
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.
- 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.
- 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. 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.

# 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

# 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 haemodynamic 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 ventilation 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
2 fewer per 1000 ( CI 95% 4 fewer -21 more

# 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

# 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 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.
- 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.
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.
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.
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.
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.
- 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.
- 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.

# Fever persisting 2 days after initiation of treatment
Odds ratio 1.3 (CI 95% 0.55 -3.23) Based on data from 195 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 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

# Comparator: 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))
1 fewer per 1000 ( CI 95% 4 fewer -11 more

# 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
Odds ratio 1.95 (CI 95% 0.83 -4.6) Based on data from 212 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 steroids alone compared with IVIG alone on clinical improvement 2 days after initiation of treatment

# Fever persisting 2 days after initiation of treatment

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

# 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.
- 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.
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.
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.
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.
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. Imprecision: serious. Downgraded for imprecision due to wide confidence intervals around the absolute effects which also crossed the line of no effect.
- 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. 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 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 and 15.5% (95% CI 10.5%-22%; n=10559) had coinfection at ICU admission.
- The same review showed that 8.2% of the patients (95%CI 6.3-10.7%; n=30805) developed secondary bacterial infections while in the hospital while 41.9% (95%CI 29.5-55.4; n=8377) of the patients admitted to ICU developed secondary infections. Hence, estimates suggest that the likelihood of bacterial coinfection in patients with COVID-19 on presentation to hospital is low and empiric antibiotic therapy should not be given as standard of care at hospital admission, unless bacterial infections is strongly suspected, and COVID-19 diagnosis is not confirmed. In patients admitted to ICU, the frequency of bacterial secondary infections is high, therefore empiric antibiotic therapy should be considered in this population.
- Biomarkers of infection in blood, such as C-reactive protein (CRP) and procalcitonin (PCT) are elevated in patients with severe COVID-19 and therefore cannot reliably be used to indicate bacterial coinfection. 4. For patients with severe disease, early and appropriate empiric antimicrobial therapy  can be administered and should be based on the clinical diagnosis (community-acquired pneumonia, health care-associated pneumonia  or sepsis), local epidemiology, and susceptibility data, and national treatment guidelines. Choose antibiotics with the least ecologic impact based on data and guidance from your own institution, region or country (e.g. of the Access group of the AWaRe classification). The AWaRe classification categorizes antibiotics into three different groups (Access, Watch and Reserve) based on their indication for common infectious syndromes, their spectrum of activity, and their potential for increasing antibiotic resistance. The AWaRe classification is a tool for antibiotic stewardship at local, national and global levels with the aim of optimizing antibiotic use and reducing antibiotic resistance 5. Empiric antibiotic therapy should be de-escalated on the basis of microbiology results and clinical judgment. Regularly review the possibility of switching of intravenous to oral route of administration and provide targeted treatment based on microbiologic results. 6. Duration of empiric antibiotic treatment should be as short as possible; generally, 5 days is sufficient for bacterial community-acquired pneumonia.
- An increase in antibiotic use during the pandemic may cause adverse reactions such as Clostridioides difficile infections, with clinical disease ranging from diarrhoea and fever to colitis. Antibiotic stewardship programmes should be put into place or continue among COVID-19 patients.
Clinical management of COVID-19 patients: living guideline -World Health Organization (WHO)

# 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 and will be based on local factors and endemic or other emerging infections . 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.

# 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.
- 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.
In a WHO-led study looking at outcomes for patients living with HIV and infected with the SARS-CoV2 virus, HIV increased the odds of severe presentation by 15% and the hazards for death by 38%. 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.
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.
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. 2. Maintain awareness for concurrent underlying neurological conditions such as stroke  or non-convulsive status epilepticus  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. 4. 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. 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. 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. 6. 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. 7. 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.
Clinical management of COVID-19 patients: living guideline -World Health Organization (WHO)

# 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. Moreover, there may be potential for longer term neurological consequences such as cognitive impairment  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. 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.
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.
- 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.
- This recommendation is consistent with the Inter-Agency Standing Committee briefing note about mental health and psychosocial aspects of COVID-19 and guidance on basic psychosocial skills for COVID- 19  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) .
Clinical management of COVID-19 patients: living guideline -World Health Organization (WHO)

# 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).

# 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. 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. Intensive care unitacquired weakness is ubiquitous in ARDS survivors, as it is in critically ill COVID-19 patients who required prolonged sedation and recovery may be incomplete at 5 years after ICU discharge. 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. For ARDS survivors, a reduced exercise capacity persists in the context of relatively preserved pulmonary function at 1 year. 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.
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. 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.
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. PTSD has also been described after SARS-CoV-1 infection .
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. Not returning to usual health within 2-3 weeks of testing was reported by approximately one third of symptomatic adults in an outpatient setting. 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.
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. 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. Telehealth may play a role in the acute and subacute phases, in which face-to-face rehabilitation is costly, risky, and impractical. Consider strategies for communication with and engagement of families during physical distancing. 2. Early mobilization is recommended for all patients with severe risk of functional limitations, resulting from frailty or ICU-acquired weakness. . 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. 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. 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  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.
Prior to hospital discharge, COVID-19 patients should be screened for rehabilitation needs in order to facilitate onward referral. 3. 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. An example of a rapid exercise test to assess desaturation on exertion is the 1-minute sit-to-stand test. 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. 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.

# 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).
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. 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. 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.
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  (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.

# 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.
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. Refer to the WHO policy brief Preventing and managing COVID-19 across long-term care services  and WHO guidance Integrated care for older people (ICOPE)  for person-centred and coordinated model of care.
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. 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.

# Description of codes ICD -10
- 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.

# 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 Table 26.1 and 26.2 for details.

# Clinical research during the COVID-19 pandemic
A living mapping and systematic review of COVID-19 studies are available. For more information about the WHO research roadmap see . Adolescent Illness (IMAI), BEC teaches a systematic approach to the initial assessment and management of time-sensitive conditions where early intervention saves lives.  protocols for the management of common and serious or potentially life-threatening conditions at district hospitals. The target audience includes doctors, clinical officers, health officers and senior nurse practitioners. It has been designed to be applicable in both high and low HIV prevalence settings. / Pocket book of hospital care for children: guidelines for the management of common childhood illnesses (second edition) (2013) For use by doctors, nurses, and other health workers caring for children at first-level referral hospitals with basic laboratory facilities and essential medicines. These guidelines focus on the management of the major causes of childhood mortality in most developing countries, including pneumonia, and also cover common procedures, patient monitoring, and supportive care on the wards. /

# Oxygen therapy for children (2016)
A bedside manual for health workers to guide the provision of oxygen therapy for children. The manual focuses on the availability and clinical use of oxygen therapy in children in health facilities to guide health workers, biomedical engineers and administrators. It addresses detection of hypoxaemia, use of pulse oximetry, clinical use of oxygen, delivery systems, and monitoring of patients on oxygen therapy. The manual also addresses the practical use of pulse oximetry, and oxygen concentrators and cylinders. /

# Technical specifications for oxygen concentrators (2015)
Provides an overview of oxygen concentrators and technical specifications to aid in selection, procurement, and quality assurance. It highlights the minimum performance requirements and technical characteristics for oxygen concentrators and related equipment that are suitable for the use in health facilities. /

# WHO-UNICEF technical specifications and guidance for oxygen therapy devices (2019)
The purpose of this document is to increase access to quality products to ensure the supply of oxygen, especially in low-and middleincome countries and low-resource settings within countries from all income groups. It aims to support ministries of health to ensure that oxygen supply is available, as well as to raise awareness of the importance of appropriate selection, procurement, maintenance, and use of medical devices, both capital equipment and single-use devices. 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  Five randomized controlled trials (RCTs) of non-invasive ventilation strategies in hospitalized patients with severe or critical COVID-19 and acute hypoxaemic respiratory failure not requiring emergent intubation were identified. This evidence was collected using the included study lists of three relevant systematic reviews, four rapid reviews, and a top-up search of bibliographic databases for more recent RCTs (with alerts until December 2021). This evidence was collected using the included study lists of four systematic reviews (SRs). 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.