Clinical management of patients with moderate to severe COVID-19 - Interim guidance

April 2, 2020

This guidance document has been endorsed by: Canadian Critical Care Society and Association of Medical Microbiology and Infectious Disease (AMMI) Canada.

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Preamble

This guidance has been adapted for Canadian use from the WHO document entitled Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected – Interim guidance - 13 March 2020. This guidance is informed by currently available scientific evidence and expert opinion, and is subject to change as new information becomes available.

This guidance provides clinicians with interim advice on timely, effective, and safe supportive management of adult and paediatric patients with suspected or confirmed COVID-19. It is not meant to replace clinical judgment or specialist consultation, but rather to strengthen the clinical management of these patients. Best practices for triage and optimized supportive care are included.

This guidance builds on evidence-informed guidelines developed by a multidisciplinary panel of health care providers with experience in the clinical management of patients with COVID-19 and other viral infections (including SARS and MERS) as well as sepsis and acute respiratory distress syndrome (ARDS)Footnote 5Footnote 6. It should serve as a foundation to optimize supportive care to ensure the best possible chance for survival and to allow reliable comparisons of investigational interventions as part of randomized controlled trials (RCTs).

In the guidelines, these boxes are used to flag interventions:

Do – the intervention is beneficial (strong recommendation) OR the intervention is a best practice statement

Don’t – the intervention is known to be harmful.

Consider – the intervention may be beneficial in selected patients (conditional recommendation) or be careful when considering this intervention.

1.0 Background

Coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by a newly emergent coronavirus that was first recognized in Wuhan, China in December 2019. Genetic sequencing of the virus suggests that it is a betacoronavirus closely linked to the SARS virusFootnote 1.

While most people with COVID-19 develop mild or uncomplicated illness, experience in China found that approximately 14% developed severe disease requiring hospitalization and oxygen support and 5% required admission to an intensive care unit (ICU)Footnote 1. In severe cases, COVID-19 can be complicated by ARDS; sepsis and septic shock; and multiorgan failure, including acute kidney injury and cardiac injuryFootnote 2. Older age and co-morbid disease have been reported as risk factors for death, and recent multivariate analysis confirmed that older age and higher Sequential Organ Failure Assessment (SOFA) score on admission were associated with higher mortality.

There are few data on the clinical presentation of COVID-19 in specific populations, such as children and pregnant women. In children with COVID-19 the symptoms are usually less severe than adults and consist mainly of cough and temperature over 38oCFootnote 7Footnote 8. Relatively few infant COVID-19 cases have been reported; those experienced relatively mild illnessFootnote 9. There is currently no known difference between the clinical manifestations of COVID-19 infected pregnant or non-pregnant women of reproductive age; however, experience with severe viral respiratory illness from other etiologies emphasizes the need for unique appreciation of pregnancy-related critical illness.

2.0 Screening and triage

Screening and Triage

Screen and isolate all patients with suspected COVID-19 at the first point of contact with the health care system (such as the emergency department or outpatient department/clinic). Consider COVID-19 as a possible etiology in patients presenting with acute respiratory illness. Triage patients using standardized triage tools and manage initial presentations accordingly.

Remarks

Table 1 – Clinical syndromes associated with COVID-19
Syndrome Details

Mild illness

Patients with uncomplicated upper respiratory tract viral infection may have non-specific symptoms such as fever, fatigue, cough (with or without sputum production), anorexia, malaise, muscle pain, sore throat, dyspnea, nasal congestion, or headache. Patients may also present with diarrhea, abdominal pain, nausea and vomitingFootnote 3Footnote 11Footnote 13. Many are afebrile or have low-grade fever. The elderly and immunocompromised may present with atypical symptoms. Symptoms due to physiologic adaptations of pregnancy or adverse pregnancy events, e.g., dyspnea, fever, GI symptoms or fatigue, may overlap with COVID-19 symptoms.

Pneumonia

Adult with pneumonia but no signs of severe pneumonia and no need for supplemental oxygen.
Child with non-severe pneumonia who has cough or difficulty breathing plus tachypnea (in breaths per minute) : < 2 months: ≥ 60; 2–11 months: ≥ 50; 1–5 years: ≥ 40), and no signs of severe pneumonia.

Less common presentations

Both adults and children can present with nausea, vomiting, abdominal pain and/or diarrhea. This presentation is seen in about 5% of adults and is more common in children. Other non-specific or unusual presentations can also occur in the absence of initial respiratory symptoms.

Severe pneumonia

Adolescent or adult: fever or suspected respiratory infection, plus one of the following: respiratory rate > 30 breaths/min; severe respiratory distress; or SpO2 < 93% on room air (adapted from refFootnote 14).

Child with cough and/or difficulty in breathing, plus at least one of the following: central cyanosis or SpO2 < 90%; severe respiratory distress (e.g. grunting, marked chest indrawing); signs of pneumonia with: inability to breastfeed or drink, lethargy or unconsciousness, or convulsionsFootnote 15. Other signs of pneumonia may be present: fast breathing (in breaths/min) < 2 months: ≥ 60; 2–11 months: ≥ 50; 1–5 years: ≥ 40Footnote 16. While the diagnosis can be made on clinical grounds, chest imaging may identify some pulmonary complications.

Acute respiratory distress syndrome (ARDS)Footnote 17Footnote 19

Onset: within 1 week of a known clinical insult or new or worsening respiratory symptoms.

Chest imaging

(X-ray, CT scan, or lung ultrasound): bilateral opacities, not fully explained by volume overload, lobar or lung collapse, or nodules.
Origin of pulmonary infiltrates: respiratory failure not fully explained by cardiac failure or fluid overload. Need objective assessment (e.g. echocardiography) to exclude hydrostatic cause of infiltrates/edema if no risk factor present.

Oxygenation impairment in adults:Footnote 17Footnote 19

  • mild ARDS: 200 mmHg < PaO2/FiO2Footnote a ≤ 300 mmHg (with PEEP or CPAP ≥ 5 cmH2O, or non-ventilated)
  • moderate ARDS: 100 mmHg < PaO2/FiO2 ≤ 200 mmHg with PEEP ≥ 5 cmH2O, or non-ventilated)
  • severe ARDS: PaO2/FiO2 ≤ 100 mmHg with PEEP ≥ 5 cmH2O, or non-ventilated)
  • when PaO2 is not available, SpO2/FiO2 ≤ 315 suggests ARDS (including in non-ventilated patients)

Oxygenation impairment in children: Note OI = Oxygenation Index and OSI = Oxygenation Index using SpO2. Use PaO2-based metric when available. If PaO2 not available, wean FiO2 to maintain SpO2 at 92-97% to calculate OSI or SpO2/FiO2 ratio:

  • bilevel NIV or CPAP ≥ 5 cmH2O via full face mask: PaO2/FiO2 ≤ 300 mmHg or SpO2/FiO2 ≤ 264
  • mild ARDS (invasively ventilated): 4 ≤ OI < 8 or 5 ≤ OSI < 7.5
  • moderate ARDS (invasively ventilated): 8 ≤ OI < 16 or 7.5 ≤ OSI < 12.3
  • severe ARDS (invasively ventilated): OI ≥ 16 or OSI ≥ 12.3

SepsisFootnote 5Footnote 6

Adults: life-threatening organ dysfunction caused by a dysregulated host response to suspected or proven infection.Footnote b Signs of organ dysfunction include: altered mental status, difficult or fast breathing, low oxygen saturation, reduced urine output (5,20), fast heart rate, weak pulse, cold extremities or low blood pressure, skin mottling, or laboratory evidence of coagulopathy, thrombocytopenia, acidosis, high lactate or hyperbilirubinemia.

Children: suspected or proven infection and ≥ 2 age-based systemic inflammatory response syndrome criteria, of which one must be abnormal temperature or white blood cell count for age.

Septic shockFootnote 5Footnote 6

Adults: persisting hypotension despite volume resuscitation, requiring vasopressors to maintain MAP ≥ 65 mmHg and serum lactate level > 2 mmol/L.

Children: any hypotension (SBP < 5th centile or > 2 SD below normal for age) or 2 or 3 of the following: altered mental state; tachycardia or bradycardia (HR < 90 bpm or > 160 bpm in infants and HR < 70 bpm or > 150 bpm in children); prolonged capillary refill (> 2 sec) or weak pulse; tachypnea; mottled or cool skin or petechial or purpuric rash; increased lactate; oliguria; hyperthermia or hypothermiaFootnote 21. Children often have tachycardia before rapid onset of hypotension occurs.

Table 1 Footnote a

If altitude is higher than 1000m, then correction factor should be calculated as follows: PaO2/FiO2 x barometric pressure/760.

Table 1 Return to footnote a referrer

Table 1 Footnote b

The SOFA score ranges from 0 to 24 and includes points related to six organ systems: respiratory (hypoxemia defined by low PaO2/FiO2); coagulation (low platelets); liver (high bilirubin); cardiovascular (hypotension); central nervous system (low level of consciousness defined by Glasgow Coma Scale); and renal (low urine output or high creatinine). Sepsis is defined by an increase in the sepsis-related SOFA score of ≥ 2 points. Assume the baseline score is 0 if data are not availableFootnote 21.

Table 1 Return to footnote b referrer

Abbreviations: ARI acute respiratory infection; BP blood pressure; bpm beats/minute; CPAP continuous positive airway pressure; FiO2 fraction of inspired oxygen; MAP mean arterial pressure; NIV non-invasive ventilation; OI Oxygenation Index; OSI Oxygenation Index using SpO2; PaO2 partial pressure of oxygen; PEEP positive end-expiratory pressure; SBP systolic blood pressure; SD standard deviation; SIRS systemic inflammatory response syndrome; SOFA sequential organ failure assessment; SpO2 oxygen saturation.

3.0 Infection prevention and control measures

Infection prevention and control (IPC) is a critical and integral part of the clinical management of patients. Detailed national IPC guidance for COVID-19 in acute health care settings is available from the Public Health Agency of Canada (PHAC). Some provinces and territories have also issued IPC guidance for their jurisdiction.

IPC guidance documents are revised and updated as new evidence becomes available therefore refer to the guidance documents directly.

4.0 Collection of specimens for laboratory diagnosis

COVID-19 testing may be performed for surveillance and diagnostic reasons. Testing criteria recommendations are necessarily dynamic as the situation evolves in regions. All hospitalized patients who are clinically suspected of infection with COVID-19 should be tested.

Guidance on appropriate testing and specimen collection for COVID-19 is available from the Canadian Public Health Laboratory Network, and from provincial/territorial Public Health Laboratories. Testing may be prioritized to preserve limited resources.

Collect specimens for COVID-19 testing as recommended by your local or provincial public health laboratory.

Collect blood cultures for bacteria that cause pneumonia and sepsis, ideally before antimicrobial therapy. DO NOT delay antimicrobial therapy to collect blood cultures. Blood cultures should be done in children if clinically indicated.

Remarks

5.0 Management of mild COVID-19

Patients with mild disease do not require hospitalization, unless there is concern for rapid deterioration or an inability to return promptly to hospital.

Isolation is necessary to contain virus transmission. All patients cared for outside hospital should be instructed to follow public health protocols for self-isolation and return to hospital if symptoms worsen. Self-isolation protocols are available from PHAC and provincial/territorial and local public health departments.

Provide patients with mild COVID-19 information on symptomatic treatment.

Counsel patients with mild COVID-19 about the signs and symptoms of worsening disease. If they develop symptoms like difficulty breathing, pain or pressure in the chest, confusion, drowsiness, or weakness, they should seek follow-up care.

6.0 Management of severe COVID-19

6.1 Oxygen Therapy and Monitoring

Give supplemental oxygen therapy immediately to patients with COVID-19 who have severe acute respiratory infection and respiratory distress, hypoxaemia or shock, and target saturations of 90-96% SpO2 during resuscitation.

Closely monitor patients with COVID-19 for signs of clinical deterioration, such as rapidly progressive respiratory failure and sepsis and respond immediately with supportive care interventions.

Understand the patient’s co-morbid conditions to tailor the management of critical illness.

Use conservative fluid management in patients with severe acute respiratory infection when there is no evidence of shock.

6.2 Treatment of co-infections

Give empiric antimicrobials to treat all likely pathogens causing severe acute respiratory infection and sepsis as soon as possible, within 1 hour of initial patient assessment for patients with sepsis.

De-escalate empiric therapy on the basis of microbiology results and clinical judgment.

7.0 Management of critical COVID-19

7.1 Acute Respiratory Distress Syndrome (ARDS)

Recognize severe hypoxemic respiratory failure when a patient with respiratory distress is failing standard oxygen therapy and prepare to provide advanced oxygen/ventilatory support.

Endotracheal intubation should be performed by a trained and experienced provider using airborne precautions.

Recommendations for mechanically ventilated adult and paediatric patients with ARDSFootnote 5Footnote 31

Implement mechanical ventilation using lower tidal volumes (4–8 mL/kg predicted body weight [PBW]) and lower inspiratory pressures (plateau pressure < 30 cmH2O).

In adult patients with severe ARDS, prone ventilation for 12-16 hours per day is recommended.

Use a conservative fluid management strategy for ARDS patients without tissue hypoperfusion.

In patients with moderate or severe ARDS, higher PEEP instead of lower PEEP is suggested.

In patients with moderate-severe ARDS (PaO2/FiO2 < 150), neuromuscular blockade by continuous infusion should not be routinely used.

Avoid disconnecting the patient from the ventilator, which results in loss of PEEP and atelectasis.

Use in-line catheters for airway suctioning and clamp the endotracheal tube when disconnection is required (e.g., transfer to a transport ventilator).

Recommendations for adult and paediatric patients with ARDS who are treated with non-invasive or high flow oxygen systems

High-flow nasal oxygen (HFNO) and non-invasive ventilation (NIV) should be considered. Patients treated with either HFNO or NIV should be closely monitored for clinical deterioration.

Remarks

Recommendations for adult and paediatric patients with ARDS in whom a lung protective ventilation strategy fails

In settings with access to expertise in extracorporeal membrane oxygenation (ECMO), consider referral of patients who have refractory hypoxemia despite lung protective ventilation.

7.2 Septic Shock

Recognize septic shock in adults when infection is suspected or confirmed AND vasopressors are needed to maintain mean arterial pressure (MAP) ≥ 60 mmHg AND lactate is ≥ 2 mmol/L, in absence of hypovolemia.

Recognize septic shock in children with any hypotension (systolic blood pressure [SBP] < 5th centile or 2 SD below normal for age) or two or more of the following: altered mental state; bradycardia or tachycardia (HR < 90 bpm or > 160 bpm in infants and HR < 70 bpm or > 150 bpm in children); prolonged capillary refill (> 2 sec) or feeble pulses; tachypnea; mottled or cool skin or petechial or purpuric rash; increased lactate; oliguria; hyperthermia or hypothermia.

Recommendations for resuscitation strategies for adult and paediatric patients with septic shock.

In resuscitation for septic shock in adults, give 250-500 mL crystalloid fluid as a rapid bolus in the first 15-30 minutes and reassess for signs of fluid overload after each bolus.

In resuscitation for septic shock in children, give 10-20 mL/kg crystalloid fluid as a rapid bolus in the first 30-60 minutes and reassess for signs of fluid overload after each bolus.

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 edema on imaging, or hepatomegaly in children), then reduce or discontinue fluid administration. This step is particularly important in patients with hypoxemic respiratory failure.

Do not use hypotonic crystalloids, starches or gelatins for resuscitation.

In adults, administer vasopressors when shock persists during or after fluid resuscitation. The initial blood pressure target is MAP ≥ 60 mmHg in adults and improvement of markers of perfusion.

In children administer vasopressors if:

  • there are signs of shock such as altered mental state; tachycardia or bradycardia (HR < 90 bpm or > 160 bpm in infants and HR < 70 bpm or > 150 bpm in children); prolonged capillary refill (> 2 seconds) or feeble pulses; tachypnea; mottled cool skin or petechial or purpuric rash; increased lactate; persisting oliguria after 2 boluses; or
  • age-appropriate blood pressure targets are not achieved; or
  • signs of fluid overload are apparentFootnote 6.

If central venous catheters are not available, vasopressors can be given through a peripheral IV, but use a large vein and monitor closely for signs of extravasation and local tissue necrosis. If extravasation occurs, stop the infusion. Vasopressors can also be administered through intraosseous needles.

If signs of poor perfusion and cardiac dysfunction persist despite achieving the MAP target with fluids and vasopressors, consider an inotrope such as dobutamine.

7.3 Prevention of complications

Implement the interventions shown in Table 2 below to prevent complications associated with critical illness. These interventions are based on Surviving SepsisFootnote 5 and other guidelinesFootnote 52Footnote 55 and are considered to be feasible and based on high quality evidence.

Table 2 – Prevention of complications in critically ill patients
Anticipated outcome Interventions
Reduce days of invasive mechanical ventilation
  • Use weaning protocols that include daily assessment for readiness to breathe spontaneously.
  • Minimize continuous or intermittent sedation, targeting specific titration endpoints (sedation score targeted light sedation unless contraindicated) or with daily interruption of continuous sedative infusions.
Reduce incidence of ventilator-associated pneumonia
  • Oral intubation is preferable to nasal intubation in adolescents and adults.
  • Keep patient in semi-recumbent position (head of bed elevation at 30–45o)
  • Use a closed suctioning system; periodically drain and discard condensate in tubing.
  • Use a new ventilator circuit for each patient; once patient is ventilated, change circuit if it is soiled or damaged, but not routinely.
  • Change heat moisture exchanger when it malfunctions, when soiled, or every 5–7 days.
Reduce incidence of venous thromboembolism
  • Use pharmacological prophylaxis (low molecular-weight heparin [preferred] or heparin subcutaneously twice daily) in adolescents and adults without contraindications. For those with contraindications, use mechanical prophylaxis (intermittent pneumatic compression devices),
Reduce incidence of catheter-related bloodstream infection
  • Use a checklist with completion verified by a real-time observer as a reminder of each step needed for sterile insertion and as a daily reminder to remove catheter if no longer needed.
Reduce incidence of pressure ulcers
  • Turn patient every 2 hours, unless contraindicated by patient condition or use of prone positioning.
Reduce incidence of stress ulcers and gastrointestinal bleeding
  • Give early enteral nutrition (within 24–48 hours of admission).
  • Consider administering histamine-2 receptor blockers or proton-pump inhibitors in patients with risk factors for GI bleeding. Risk factors for gastrointestinal bleeding include mechanical ventilation for ≥ 48 hours, coagulopathy, renal replacement therapy, liver disease, multiple comorbidities, and higher organ failure score.
Reduce incidence of ICU-related weakness
  • Actively mobilize the patient early in the course of illness when safe to do so.

8.0 Special considerations

8.1 Caring for pregnant women with COVID-19

To date, there are limited data on clinical presentation and perinatal outcomes after COVID-19 during pregnancy or the post-partum period. There is no evidence that pregnant women present with different signs or symptoms or are at higher risk of severe illness.

Pregnant and recently pregnant women with suspected or confirmed COVID-19 should be treated with the supportive and management therapies previously described for other adults, taking into account the immunologic and physiologic adaptations occurring during and after pregnancy.

Evidence of increased severe maternal or neonatal outcomes is uncertain, and limited to infection in the third trimester, with some cases of premature rupture of membranes, fetal distress and preterm birth reported. There was one case of stillbirth and one case of neonatal death in 38 cases from China. (68,69).

Pregnant women with a suspected, probable or confirmed COVID-19 infection, including women who may need to spend time in isolation, should have access to woman-centred, respectful skilled care, including obstetric, foetal medicine and neonatal care, as well as mental health and psychosocial support, with readiness to care for maternal and neonatal complications.

All recently pregnant women with COVID-19 infection or who have recovered from COVID-19 should be provided with counselling on safe infant feeding and appropriate infection prevention measures to prevent COVID-19 transmission.

At this point, there is no evidence that pregnant women present with increased risk of severe illness. Pregnant and recently pregnant women who have recovered from COVID-19 should be encouraged to attend routine antenatal, postpartum or other obstetrical care as appropriate. Enhanced fetal surveillance is recommended for women with COVID-19 illness. The SOGC has published several resources to assist obstetricians in Canada in dealing with COVID-19.

8.2 Caring for Infants and Mothers with COVID-19 – IPC and Breastfeeding

Relatively few cases have been reported of infants confirmed with COVID-19 infection. At this time there is no clear evidence that vertical transmission may occur. Breast milk samples from the mothers after the first lactation were also all negative for the COVID-19 virusFootnote 68Footnote 69.

Infants born to mothers with suspected, probable, or confirmed COVID-19 should be fed according to standard infant feeding guidelines while providing necessary infection prevention precautions.
Symptomatic mothers who are breastfeeding should practice respiratory hygiene, including during feeding (for example, use of a mask when near a child if the mother has respiratory symptoms), perform hand hygiene before and after contact with the child, and routinely clean and disinfect surfaces with which the symptomatic mother has been in contact.

In situations when severe illness in a mother due to COVID-19 or other complications prevents her from caring for her infant or prevents her from continuing direct breastfeeding, mothers should be encouraged and supported to express milk, and safely provide breast milk to the infant, while applying appropriate IPC measures.

Mothers and infants should be allowed to remain together and to practice rooming-in if desired, especially during establishment of breastfeeding, whether they or their infants have suspected, probable or confirmed COVID-19.

Parents and caregivers who may need to be separated from their children, and children who may need to be separated from their primary caregivers, should have access to appropriately trained health or non-health workers for mental health and psychosocial support.

8.3 Caring for older persons with COVID-19

Older age and comorbid conditions such as diabetes and cardiovascular disease have been reported as risk factors for death in persons with COVID-19Footnote 4. Older persons are at highest risk for severe disease and fatality and are one of the most vulnerable populations.

For older persons with probable or suspected COVID-19, in addition to a conventional history the assessment should include an understanding of the person’s life, values, priorities and preferences for health management.

Ensure multidisciplinary collaboration (physicians, nurses, pharmacists and other health professionals) in the decision-making process to address multimorbidity and functional decline.

Early detection of inappropriate medication prescriptions is recommended to prevent adverse drug events and drug interactions in those being treated for COVID-19. Older patients are at greater risk of polypharmacy which increases the risk of negative health consequences.

Involve caregivers and family members in decision-making and goal setting throughout the management of older COVID-19 patients.

Symptom -based and palliative care should be made available as appropriate.

8.4 Managing patients with COVID-19 in remote and isolated communities

While primary health care services are available in most remote and isolated communities, they have limited capacity to provide acute care and may lack appropriate medical equipment, supplies and services (e.g., ventilators, access to specialists) to treat patients with severe illness. In many remote and isolated communities, a nurse-led health care team can provide emergency resuscitation and stabilization, emergency ambulatory care and out-patient non-urgent services. Access to physician services is available remotely via telehealth or teleconference, but much variation exists from community to community regarding the availability and frequency of physicians. Severely ill patients requiring complex emergency medical care are evacuated to a secondary or tertiary hospital or facility.

Treatment considerations for these remote and isolated settings include the following measures:

9.0 Specific and adjunctive COVID-19 treatments and clinical research

There is no current evidence to recommend any specific anti-COVID-19 treatment for patients with confirmed COVID-19. There are many ongoing clinical trials testing various potential medical counter measures. Until specific therapies become available, any medication should be given as part of a randomized controlled trial.

Collect standardized clinical data on all hospitalized patients to improve our understanding of the natural history of disease.

Use of investigational anti-COVID-19 therapeutics should be done under ethically approved, randomized, controlled trials.

Do not routinely give systemic corticosteroids for treatment of viral pneumonia outside of clinical trials.

10.0 Acknowledgments

This guidance document was prepared by: Dr. R. Fowler, Dr. T. Hatchette, Dr. M. Salvadori, Dr. M. Ofner, Dr. G Poliquin, Dr. T. Yeung & Dr. J Brooks on behalf of the COVID-19 Clinical Care Guidance Working Group.

Scientific Writer: Dr. S. Tamblyn.

The guidance document has been endorsed by: Canadian Critical Care Society and Association of Medical Microbiology and Infectious Disease (AMMI) Canada.

COVID-19 Clinical Care Guidance Working Group members: Dr. R. Fowler (Co-chair), Dr. T. Hatchette (Co-chair), M-E Delvin, Dr. D. Kitty, Dr. J. Leis, Dr. D. Money, Dr. S. Murthy, Dr. M. Ofner, Dr. G. Poliquin, Dr. S. Tamblyn, Dr. M. Salvadori, P. St-Louis & Dr. T. Yeung.

Canadian Critical Care Society reviewers: Dr. K. Burns, Dr. F. D’Aragon, Dr. J. Downar, Dr. C. Farrell, Dr. B. Haroon & Dr. A. Fox-Robichaud.

Association of Medical Microbiology and Infectious Disease (AMMI) Canada reviewers: Dr. G. Evans, Dr. S. Forgie, Dr. S. Hota, Dr. S. Mubareka, Dr. J. Papenburg.

Additional reviewers: Dr. G. Emeriaud, Dr. N. Adhikari, Dr. S. Funnel, Dr. T. Haffner, Dr. A Kara, Dr. A. Kestler & Dr. T. Wong.

PHAC support: Y-E Chung, M. Kamkar, M. Kamanga & T. Wang.

Footnotes

Footnote 1

Team NCPERE. Vital surveillances: the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) – China. China CDC Weekly. 2020;2(8):113-22.

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Footnote 2

Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020. Epub 2020/02/28. doi: 10.1016/S2213-2600(20)30079-5. PubMed PMID: 32105632.

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Footnote 3

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. Epub 2020/01/28. doi: 10.1016/S0140-6736(20)30183-5. PubMed PMID: 31986264.

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Footnote 4

Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective study. Lancet, 2020. doi: 1016/S0140-6736(20)30566-3.

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Footnote 5

Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304-77. Epub 2017/01/20. doi: 10.1007/s00134-017-4683-6. PubMed PMID: 28101605.

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Footnote 6

Weiss SL, Peters MJ, Alhazzani W, Agus MSD, Flori HR, Inwald DP et al. Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children. Pediatr Crit Care Med. 2020;21(2):e52-e106. Epub 2020/02/08. doi: 10.1097/PCC.0000000000002198. PubMed PMID: 32032273.

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Footnote 7

Cai J, Xu J, Lin D, Yang Z, Xu L, Qu Z et al. A case series of children with 2019 novel coronavirus infection: clinical and epidemiological features. Clin Infect Dis. 2020. Epub 2020/03/01. doi: 10.1093/cid/ciaa198. PubMed PMID: 32112072.

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Footnote 8

Xia W, Shao J, Guo Y, Peng X, Li Z, Hu D. Clinical and CT features in pediatric patients with COVID-19 infection: different points from adults. Pediatr Pulmonol. 2020. Epub 2020/03/07. doi: 10.1002/ppul.24718. PubMed PMID: 32134205.

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Footnote 9

Wei M, Yuan J, Liu Y, Fu T, Yu X, Zhang ZJ. Novel coronavirus infection in hospitalized infants under 1 year of age in China. JAMA. 2020. Epub 2020/02/15. doi: 10.1001/jama.2020.2131. PubMed PMID: 32058570.

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Footnote 10

Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020. Epub 2020/02/25. doi: 10.1001/jama.2020.2648. PubMed PMID: 32091533.

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Footnote 11

Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507-13. Epub 2020/02/03. doi: 10.1016/S0140-6736(20)30211-7. PubMed PMID: 32007143.

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Footnote 12

Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020. Epub 2020/02/29. doi: 10.1056/NEJMoa2002032. PubMed PMID: 32109013.

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Footnote 13

Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020. Epub 2020/02/08. doi: 10.1001/jama.2020.1585. PubMed PMID: 32031570.

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Footnote 14

WHO. Volume 2 IMAI District Clinician Manual. Hospital care for adolescents and adults. Geneva: World Health Organization; 2011 (https://apps.who.int/iris/bitstream/handle/10665/77751/9789241548290_Vol2_eng.pdf?sequence=3, accessed 4 March 2020).

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Footnote 15

Russell FM, Reyburn R, Chan J, Tuivaga E, Lim R, Lai J et al. Impact of the change in WHO's severe pneumonia case definition on hospitalized pneumonia epidemiology: case studies from six countries. Bull World Health Organ. 2019;97(6):386-93. Epub 2019/06/19. doi: 10.2471/BLT.18.223271. PubMed PMID: 31210676; PMCID: PMC6560369.

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Footnote 16

WHO. Pocket book of hospital care for children: guidelines for the management of common childhood illnesses. Geneva: World Health Organization; 2013 (http://www.who.int/maternal_child_adolescent/documents/child_hospital_care/en/, accessed 4 March 2020).

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Footnote 17

Force ADT, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307(23):2526-33. Epub 2012/07/17. doi: 10.1001/jama.2012.5669. PubMed PMID: 22797452.

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Footnote 18

Khemani RG, Smith LS, Zimmerman JJ, Erickson S, Pediatric Acute Lung Injury Consensus Conference G. Pediatric acute respiratory distress syndrome: definition, incidence, and epidemiology: proceedings from the Pediatric Acute Lung Injury Consensus Conference. Pediatr Crit Care Med. 2015;16(5 Suppl 1):S23-40. Epub 2015/06/04. doi: 10.1097/PCC.0000000000000432. PubMed PMID: 26035358.

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Footnote 19

Riviello ED, Kiviri W, Twagirumugabe T, Mueller A, Banner-Goodspeed VM, Officer L et al. Hospital incidence and outcomes of the acute respiratory distress syndrome using the Kigali modification of the Berlin Definition. Am J Respir Crit Care Med. 2016;193(1):52-9. Epub 2015/09/10. doi: 10.1164/rccm.201503-0584OC. PubMed PMID: 26352116.

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Footnote 20

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