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Coronavirus disease 2019 (COVID-19)

Authors: Dr Greg Brogan, Dr Neil Campbell, Dr Matthew Durie, and Dr Chris Nickson from the Alfred ICU (@INTENSIVEblog)

First published 6 April 2020; reviewed and revised 19 June 2020; updates since 30 May 2020 include:

  • Clear reference to National COVID-19 Clinical Evidence Taskforce guidelines
  • Updated evidence on remdesivir, hydroxychloroquine and convalescent plasma
  • Stratified novel/experimental treatments by probability of benefit
  • Moved remdesivir to ‘specific treatments’ given ACTT-1 but also kept in experimental section given uncertainty for critically ill patients
  • Cut down experimental anticoagulation section
  • Included recommendation for increased dose VTE prophylaxis
  • Changed NIV section to be in line with current Australian guidelines

Editor’s note: This document continues to be reviewed monthly given our rapidly evolving understanding of the assessment and management of COVID-19 from a critical care perspective.

OVERVIEW

The unfolding COVID-19 pandemic has led to a global crisis which threatens to become a health, economic and humanitarian disaster

  • SARS-CoV-2 is a betacoronavirus first described following a case cluster of patients with pneumonia of unknown cause in the Wuhan province in China (Zhu N. et al. 2020).
  • “COVID-19” or COronaVIrus Disease 2019 is the term used by the WHO to refer to disease caused by this virus. The virus was also called 2019-nCoV (or 2019 novel CoronaVirus) prior to being official named by the WHO. [Coronaviridae Study Group. 2020]
  • COVID-19 is predominantly a respiratory disease, with severity ranging from mild to fatal, and transmission mostly from the spread of respiratory droplets.

Pandemic timeline:

  • Disease first identified in Wuhan City, Hubei Province, China in November 2019
  • WHO declared a global emergency on 30 January 2020
  • WHO declared a global pandemic on 11 March 2020

CAUSE AND RISK FACTORS

Virology

  • SARS-CoV-2 is the seventh strain of coronavirus known to infect humans (Coronaviridae Study Group. 2020; Chen Y. et al. 2020). Coronaviruses are named for their characteristic halo when visualised by electron microscopy. Four strains circulate freely among humans (HCoV-229E, HCoV-OC43, HCoV-NL63 and HKU1), while many others infect animal hosts (Chen Y. et al. 2020).
  • In addition to the four endemic strains, two others have demonstrated animal-to-human transmission and resulted in documented outbreaks (Chen Y. et al. 2020): 
    • Severe Acute Respiratory Syndrome (SARS-CoV) in 2002 
    • Middle East Respiratory Syndrome (MERS-CoV) in 2012 
  • SARS-CoV-2 probably has a zoonotic origin. 
    • SARS-CoV-2 shares 96% genetic similarity to a bat coronavirus (Zhou P. et al. 2020), although the source species is not known with certainty.
    • Some household animals, including dogs, can be infected with SARS-CoV-2, but they are not known to have a role in transmission to humans (Sit et al, 2020).

Transmission

  • SARS-CoV-2 is transmitted person-to-person, predominantly by respiratory droplet spread and contact, similar to the MERS and SARS coronaviruses (Otter J. et al. 2015, Lai C. et al. 2020)
    • Larger respiratory droplets (>5 μm) remain in the air for only a short time (<17 minutes) and travel only short distances, generally <1 m (Kutter et al, 2018).
    • Respiratory droplets can probably transmit > 1 m in certain circumstances, such as being driven by airflow from air conditioned ventilation (Lu et al, 2020) or by sneezing (Bourouiba, 2016).
    • The dichotomy between “airborne” and “droplet” precautions is based on arbitrary droplet size cutoffs may not accurately reflect what actually occurs with respiratory emission (Bourouiba, 2020). 
    • SARS-CoV-2 has a higher level of shedding from the upper respiratory tract than SARS-CoV-1, even in asymptomatic/ presymptomatic cases, which may have contributed to its wider spread (Gandhi, M. et al 2020)
  • Contact transmission
    • The SARS-CoV-2 virus may survive for up to 4 days when respiratory droplets settle on surfaces, based on in vitro experiments (van Doremalen N. et al. 2020).
    • Transmission occurs when contact with virus-laden objects (fomites) is followed by contact with mucous membranes (e.g. eye, nose, mouth) from face touching.
  • Aerosol transmission
    • Aerosol transmission of SARS-CoV-2 virus has not been demonstrated, but remains a possibility (Morawska, 2020).
    • Aerosolised coronavirus (non-SARS-CoV-2) particles ≤ 5µm have been demonstrated from infected subjects (Leung N. et al. 2020) and some studies found transmission that could be explained by “opportunistic” airborne spread (Roy et al, 2004)
    • The SARS-CoV-2 virus may be viable for at least 3 hours in aerosolised environments, based on in vitro experiments (van Doremalen N. et al. 2020).
    • The effectiveness of airborne precautions for respiratory viruses, compared with droplet precautions, is controversial (Shiu et al, 2019), 
    • SARS-CoV-2 RNA has been detected from ambient air samples in patient isolation rooms (Zhen-Dong G. et al. 2020).

Other routes

  • The SARS-CoV-2 virus may be shed in stool, raising the unconfirmed possibility of fecal-oral transfer (Yeo C. et al. 2020). In some cases this may persist beyond the duration of respiratory viral shedding (Tang A. et al. 2020). 
  • Vertical transmission (mother to child) rates appear low (as with SARS-CoV) (Zhu H. et al. 2020)

Figure 1. Summary of viral structure, life cycle, clinical course, and immune response for COVID-19. Image shared by Abby Schiff, PhD (@liraphila). Image source: https://twitter.com/liraphila/status/1250871681591267328. Source of original work: https://www.cell.com/pb-assets/products/coronavirus/CELL_11362_S5.pdf

PATHOGENESIS AND DISEASE PROGRESSION

Pathogenesis

  • Coronaviruses express trans-membrane glycoproteins (“spike” proteins) which allow the virus to attach to and gain entry to the target cell.
  • Spike proteins on SARS-CoV-2 share many similarities with those of SARS-CoV and bind to surface Angiotensin Converting Enzyme 2 (ACE2) receptors (Walls A. et al. 2020; Zhang C. et al. 2020). 
    • ACE2 is expressed predominantly on type II pneumocytes but also on upper respiratory tract epithelial cells and small intestine enterocytes (Hamming I. et al. 2004).
    • The SARS-CoV-2 spike protein appears to bind ACE2 with higher affinity than SARS-CoV, which may account for its greater transmissibility (Wrapp D.et al. 2020)
    • Other cofactors are likely required, including TMPRSS2 (Hoffman M. et al. 2020)
  • Viral RNA replication occurs within the target cell, utilising RNA-dependent RNA polymerase (rdRp) (Lung J. et al. 2020).

Incubation period

Disease progression

  • Asymptomatic viral shedding may occur at some stage in up to 50% of patients, although this remains contentious (see below)
  • Most (80%) COVID-19 cases experience mild-to-moderate URTI symptoms for the first 7 days followed by recovery (Bouadama L. et al. 2020).
  • Approximately 20% of patients develop dyspnoea requiring hospital admission, typically at day 6-8.
  • A small proportion of patients with SARS-CoV-2 infection develop life threatening lung disease characterised by severe pneumonitis that may progress to acute respiratory distress syndrome (ARDS)
  • Involves diffuse, direct and indirect damage to alveoli
  • profound hypoxaemia with relatively preserved lung compliance appears common early
  • Some severely affected patients also develop:
    • “Cytokine storm” – a severe reaction akin to hemophagocytic lymphohistiocytosis (HLH) (Ruan Q. et al. 2020)
  • Myocarditis/ cardiomyopathy (rare) (Arentz M. et al. 2020)
  • Disseminated intravascular coagulation, which portends a poor prognosis (Tang et al. 2020), and thrombotic complications
  • Post-mortem findings include: (Menter T. et al. 2020, Wichmann D. et al. 2020)
    • Diffuse alveolar damage typical for ARDS
    • Lymphocytic infiltration
    • Microvascular and large vessel thrombosis
    • In some cases, a secondary bacterial pneumonia with or without underlying diffuse alveolar damage
    • Extrapulmonary features including lymphocytic myocarditis
    • Presence of SARS-CoV-2 RNA in lung and other tissues

Spectrum of severity 

SARS-CoV-2 infection may result in illness ranging in severity from no symptoms, to mild, moderate or severe COVID-19.

  • Asymptomatic
    • a small proportion may remain asymptomatic though the exact proportion unknown (see below)
  • The proportion of severity experienced in one large cohort of patients was (Wu Z. & McGoogan J. 2020):
    • Mild or moderate – 81% 
    • Severe – 14 % (dyspnoea, RR ≥30, oxygen saturation ≤93%,  PF ratio <300, and/or lung infiltrates)
    • Critical – 5% (respiratory failure, septic shock and/or multi organ dysfunction)

Severity classification according to Australian guidelines for the clinical care of people with COVID-19 (v2):

Mild IllnessPerson not presenting any clinical features suggesting a complicated course of illness.
Characteristics:
– no symptoms or mild upper respiratory tract symptoms
– stable clinical picture
Moderate IllnessStable patient presenting with respiratory and/or systemic symptoms or signs. Able to maintain oxygen saturation above 92% (or above 90% for patients with chronic lung disease) with up to 4L/min oxygen via nasal prongs.
Characteristics:
– prostration, severe asthenia, fever > 38 ̊C or persistent cough
– clinical or radiological signs of lung involvement
– no clinical or laboratory indicators of clinical severity or respiratory impairment
Severe IllnessPatients meeting any of the following criteria:
– respiratory rate ≥ 30 breaths/min
– oxygen saturation ≤ 92% at a rest state
– arterial partial pressure of oxygen (PaO2)/ inspired oxygen fraction (FiO2) ≤ 300
Critical IllnessPatient meeting any of the following criteria:
– Respiratory Failure
– Occurrence of severe respiratory failure (PaO2/FiO2 ratio < 200), respiratory distress or acute respiratory distress syndrome (ARDS).
This includes:
– patients deteriorating despite advanced forms of respiratory support (NIV, HFNO) OR
– patients requiring mechanical ventilation OR
– other signs of significant deterioration, hypotension or shock, impairment of consciousness, or other organ failure
Propose staging of COVID19. Siddiqi et al, 2020png
Figure 2. Proposed staging of COVID19 (note that potential therapies are indicated, which should only be used in the setting of clinical trials) (Siddiqi et al, 2020). Image source: https://els-jbs-prod-cdn.literatumonline.com/pb/assets/raw/Health%20Advance/journals/healun/Article_2-1584647583070.pdf

CLINICAL PRESENTATION

Common symptoms

Common presenting features include (Bouadama L. et al. 2020, Young B. et al. 2020): 

  • Fever
    • Incidence varies depending on study (~40-90%)
    • Tends to be high and persistent
  • Cough
  • Breathlessness
    • Dyspnoea onset tends to be around Day 6
    • Multiple reports, especially in elderly, of ‘silent hypoxia’ – severe hypoxaemia without breathlessness
  • Anosmia
    • Olfactory and/or taste disturbance in approximately one third of patients (Giacomelli A. et al. 2020)
    • In South Korea, 30% of those testing positive had anosmia as their major presenting symptom in otherwise mild cases (Iacobucci G. 2020)
  • Less commonly or rarely
    • Rhinorrhoea
    • Sore throat
    • Myalgia
    • Gastrointestinal symptoms (e.g. diarrhoea)
    • Other neurological features
      • Meningitis/ encephalitis and hemorrhagic necrotizing encephalopathy (including altered mental state and coma) (Moriguchi, 2020; Poyiadji, 2020)
      • Guillain-Barre Syndrome (Toscana, 2020)
      • encephalopathy, agitation, confusion, and corticospinal tract signs in COVID-19 ICU patients with ARDS (Helms, 2020)

Asymptomatic infection

COVID-19 pneumonia “phenotypes”

  • A controversial report suggested that COVID-19 patients appear to have at least two phenotypes, from the perspective of ICU management (Gattinoni et al, 2020). However, this classification is largely based on anecdote, remains preliminary and management should be optimised for each individual patient as clinically indicated.
    • L-phenotype
      • Typical of early presentation viral pneumonitis
      • Hypoxaemia with preserved CO2 clearance (Type 1 respiratory failure)
      • Low
        • Elastance (i.e. high compliance)
        • V/Q matching (possibly due to abnormal hypoxic vasoconstriction)
        • Recruitability (poor response to PEEP and proning)
      • Implications
        • May be able to avoid mechanical ventilation with appropriate oxygen therapy
        • May be responsive to pulmonary vasodilators (e.g. inhaled nitric oxide)
    • H phenotype
      • Typical of later illness and classic ARDS, including patients who have had prolonged non-invasive ventilation (potential for patient-induced lung injury from volutrauma and barotrauma) and co-existing lung disease or complications
      • Hypoxaemia +/- impaired CO2 clearance (Type 1 and/or 2 respiratory failure)
      • High
        • Elastance (i.e. low compliance)
        • V/Q matching 
        • Recruitability ( response to PEEP and proning)
      • Implications
  • The existence and utility of these phenotypes is being increasingly called into question  as observed cohorts suggest that COVID-19 presentations are consistent with prior descriptions of ARDS (Ziehr D. et al. 2020).

DIAGNOSIS

The case definition for suspected COVID-19 has changed over time. A set of definitions is available from Communicable Disease Network Australia (CDNA v2.7, 2020), but clinicians should note that this may differ from the criteria for testing within their state or region. Testing is suggested by CDNA in suspect and enhanced testing categories.

Diagnosis is confirmed by testing via one of the methods below. 

  • Confirmed Case
    • Positive on nucleic acid test
    • Virus identified by electron microscopy
    • Viral culture 
  • Probable Case
    • A person who has not been tested
    • WITH a fever of >/38 degrees OR acute respiratory infection (cough, shortness of breath, sore throat)
    • AND is a household contact with a confirmed or probable case
  • Suspect Case 
    • Meets the following Clinical AND Epidemiological criteria
    • Clinical
      • Fever >/38 degrees OR history of feer
      • OR acute respiratory infection (as above)
    • Epidemiological 
      • In the last 14 days prior to illness onset:
        • Close contact with confirmed or probable case
        • International or interstate travel
        • Passengers or crew from a cruise ship
        • Healthcare, aged or residential care workers and staff with direct patient contact
        • People who have lived in or travelled through specifically designated areas with elevated community transmission (defined on this website)
      • OR Hospitalised patients where no other focus or alternate explanation for illness is evident
  • Enhanced testing 
    • It is important to check relevant state and territory case definitions as they vary of location and time, however, the Australian national recommendations as of 24/4/2020 include:
      • Testing beyond the suspect case definition in patients with: 
        • Fever >/38 or history of same
        • OR acute respiratory infection where no other clinical focus or alternate explanation is evident.

INVESTIGATIONS

Diagnostic tests

Viral PCR 

  • Real time Reverse Transcriptase Polymerase Chain Reaction (RT PCR) test of respiratory samples is the test of choice 
    • Nasopharyngeal or oropharyngeal samples recommended by CDC and CDNA (CDC, 2020)(CDNA, 2020) 
    • Samples taken from both oropharynx and nasopharynx to optimise virus detection
    • Multiple PCR targets are available and improved tests are under development: (Corman, VM 2020)
  • Bronchoalveolar lavage shows highest positive rates (93%), but diagnostic bronchoscopy should be avoided where possible due to risk of aerosolization.
  • Positive rates of other specimens includesputum (72%), nasal swabs (63%), fiberscopic brush biopsy (46%), pharyngeal swabs (32%), faecal (29%) and urine (0%). 
  • Viral shedding/positive rate may vary between both cases and throughout the course of disease (Farkas J et al 2020) – hence a single negative test does not exclude infection

Serological tests

  • Acute and convalescent testing of sera to identify presence of IgM or IgG antibodies specific to SARS-CoV-2.
  • Does not detect virus per se, just evidence of recent infection.
  • Test will be negative until development of humoural immunity (up to two weeks, Zhao J. et al. 2020). See Immunity below.
  • Limited by potential cross reactivity with other viruses.

Bedside Tests

  • Antigen based – potentially allows detection of active or new infection, compared with serological tests.
    • Though the sensitivity is not known, similar tests for other viruses range in sensitivity from 34-80% (WHO 8/4/2020)
  • Until properly validated, the WHO recommends the use of point of care testing in a research setting only (WHO 8/4/2020)

Other

  • Other methods of detection include (CDNA, 2020):
    • Imaging – see Investigations below
    • Viral culture – not widely recommended due to safety concerns
    • Electron microscopy – may allow visualisation of virions when the viral aetiology of a disease is uncertain or when no other known tests are available. Although included by the CDNA as a method of confirming a positive case, in practice it is rarely used except in the early phases of an outbreak or for research purposes.

Screening tests

  • Utility of screening asymptomatic (and pre-symptomatic) patients remains unclear (Yuen KS et al 2020).
  • Antibody based screening may allow estimation of true disease prevalence and guide public health policy, however in low prevalence areas (<5%), screening tests with poor specificity may have a false positive rate higher than the true positive rate.

Diagnostic pitfalls

  • False negative tests (see above)
  • Co-infection with other viruses has been observed (Wu et al. 2020)  
  • Secondary/ co-existent bacterial infection can occur
  • There is potential for hospital acquired COVID-19 to become an issue as COVID-19 becomes more prevalent among hospital inpatients.
  • Unrelated co-existent conditions may be falsely attributed to COVID-19 infection if prevalence is high.

Laboratory Tests

Though many laboratory abnormalities are being described in the literature in association with COVID-19, clinicians should only order investigations that will guide ongoing management

  • 40-76% of all cases  (Rodriguez-Morales AJ et al 2020)
  • 92% of ICU cases (Huang, C et al 2020)
  • Possible marker of severity
  • Acute Phase Reactants (Rodriguez-Morales AJ et al 2020)
    • ESR increased (85%)
    • CRP increased (86%; may be marker of severity)
    • Albumin decreased (75%)
    • Ferritin increased (63%; may be marker of severity)
  • High ferritin (>700ng/ml) suggests risk of “cytokine storm syndrome” / HLH (Cron, R, Chatham, W 2020)
  • Other laboratory tests
    • Elevation of these parameters is more common in ICU COVID-19 patients:
      • D-dimer
      • Troponin
      • Procalcitonin (not well defined, may lag behind CRP (though neither test has a clear role in management
    • Lumbar puncture and CSF analysis should be considered if suspected meningitis or Guillain-Barre Syndrome
    • Antiphospholipid antibodies (case reports in hypercoagulable COVID-19 patients)
Imaging
  • In general:
    • COVID-19 findings are consistent with a viral pneumonia – i.e. there are no findings specific to CIVD-19
    • COVID-19 pneumonia commonly manifests as ground glass opacities distributed bilaterally in bases and peripheries 
    • Findings evolve rapidly (eg. from unilateral to bilateral) and lung involvement is associated with severity; Findings progress over 1-3 weeks, hitting maximum at 10-12 days 
    • Findings may be present in asymptomatic individuals or pre-symptomatic individuals 
  • Ground Glass opacities (GGOs) (98%)
  • Reticular Pattern 
  • Consolidation 
  • Crazy Paving Pattern 
  • Uncommon manifestations seen in COVID patients (Salehi S et al. 2020, Rodriguez JCL. et al 2020)
    • Pleural effusion
    • Pericardial effusion 
    • Lymphadenopathy
    • Cavitation
    • CT Halo sin
    • Pneumothorax
  • Involved lung is proportional to severity of disease  (Zhao, W et al. 2020)
    • When followed over time, a pattern to stages of disease emerges (Li, M et al 2020)
      • Early Phase – Moderate clinical manifestations with lesions limited to single or multiple areas
      • Progressive phase – Lesions progress in extent and density with the accumulation of cellular exudate in alveoli 
      • Severe Phase – Pulmonary lesions reach a peak at around 14 days with dense bilateral infiltration and a large amount of cellular exudate
      • Dissipative Phase – after 14 days, gradual absorption of lesions occurs (may occur earlier if disease course shorter) 
  • Role in Diagnosis: 
    • High sensitivity (97%), but low specificity (25%) to detect disease in a Wuhan epidemic context (Ai, T et al. 2020)
      • A small study of CT-radiologists were able differentiate COVID from non-COVID viral pneumonias (Bai, HX et al. 2020), however they had a wide range of sensitivity (67-93%) and specificity (7-100%)
    • Changes can be seen in asymptomatic patients (Shi, H et al. 2020) and be absent early in disease (Rodriguez JCL. et al 2020)
  • Ultrasonography
    • Clinicians must consider infection control and prevention of transmission via contact with ultrasound machine when assessing COVID-19 patients
    • Lung ultrasound
      • Role is still being defined but no specific COVID-19 findings are yet noted from case reports  (Soldati G et al. 2020)
      • Cases exhibit presence of viral pneumonia with features including (Buonsenso, D et al. 2020):
        • Irregular pleural line
        • B-lines (may be irregular and even confluent)
        • Patchy pattern with bilateral sparing
        • Areas of white lung
        • Subpleural consolidations
    • Echocardiography, consider if:
      • Hemodynamically unstable (e.g. cardiac causes, pericardial effusion, pulmonary embolism)
      • Refractory hypoxaemia (e.g. diagnose patent foramen ovale using bubble study)
      • Suspected right ventricular dysfunction (e.g. prolonged hypoxaemia/ pulmonary hypertension)
      • Failed extubation (exclude cardiac cause)
  • Neuroimaging
    • Rare cases of COVID-19 encephalitis/ encephalopathy have been reported  (Moriguchi, 2020; Poyiadji, 2020)
    • CT brain
      • symmetric hypoattenuation of medial thalami
      • normal CT angiogram and CT venogram
    • MRI brain
      • May affect bilateral thalami, medial temporal lobes, hippocampi, and subinsular regions
      • hyperintensity of affected regions on DWI and FLAIR
      • hemorrhagic rim enhancing lesions
      • Frontal hypoperfusion on perfusion imaging and strokes in patients with ARDS in ICU (Helms, 2020)
Other investigations
  • Diagnostic bronchoscopy is not recommended due to risk of viral transmission from an AGP
  • Nerve conduction studies if suspected Guillain-Barre Syndrome

MANAGEMENT – GENERAL

A set of ‘living guidelines’ for the management of patients with COVID-19 in Australia is published by the National COVID-19 Clinical Evidence Taskforce, and available from covid19evidence.net.au.

  • Readers are encouraged to refer to the above resource for the latest treatment recommendations.

Resuscitation

  • Ensure safety of the healthcare team in accordance with local hospital protocols
    • All team members MUST don appropriate PPE equipment prior to attending to a patient, regardless of the urgency of the situation
    • Droplet contact precautions are required for most patient care episodes, however, airborne/contact precautions are required for aerosol generating procedures (AGPs)
  • Rapid, coordinated assessment and management with attention to immediate life threats, including: 
    • Severe hypoxaemia
      • Treat with high flow oxygen to target SpO2 92-96%
      • Avoid aerosol generating devices if possible, and ensure airborne/contact precautions if they are required
      • Hypoxaemia an occur without significant respiratory distress
      • Intubation is high risk if pre-oxygenation is inadequate
    • Other life threats are uncommon (Yang et al, 2020), especially in the early stages of the disease, but may include:
  • Post-intubation hypotension (e.g. patient may be dehydrated due to poor fluid intake and PEEP may markedly reduce venous return in combination with compliant lungs and sedative agents)
  • Viral cardiomyopathy/ myocarditis (dysrhythmias, heart failure)
  • Cytokine Storm Syndrome
  • Pulmonary hypertension and right heart failure secondary to hypoxic pulmonary disease
  • Multi-organ dysfunction (including acute kidney injury)
  • Secondary bacterial infection
  • Potential neurological involvement (e.g. affecting cardio-respiratory centers) (Li Y-C, 2020; Baig, 2020)

Specific therapies

  • With the exception of remdesivir, for which there is some preliminary evidence of potential benefit (see novel & investigational therapies below),  are no specific therapies with proven effectiveness currently available for the management of COVID-19
  • Antimicrobial Therapy
    • Empiric treatment of severe community acquired pneumonia and influenza according to local guidelines is usually appropriate as COVID-19 cannot be reliably distinguished from other viral and bacterial pneumonias on presentation
    • Antimicrobial therapy should be assessed for de-escalation daily in light of clinical progress and microbiology results
  • Oxygenation and ventilation strategies specific to COVID-19  are discussed below

Supportive care

  • A comprehensive approach to supportive care is appropriate for all intensive care patients (e.g. FAST HUGS IN BED Please approach) and should be guided by local protocols.
  • Fluid management
    • Use a conservative fluid management strategy
    • Avoid positive fluid balance/ hypervolaemia
    • Excessive negative fluid balance (e.g. diuretics) could contribute to AKI and the need for CRRT (anecdotal experience from UK centers)
    • Fluid resuscitation may be required in the early phase, especially prior to intubation and initiation of positive pressure ventilation (to avoid hypotension from impaired venous return)
  • Analgesia/ sedation
    • RASS 0 to -2 is ideal as over-sedation is harmful for intubated ICU patients
    • Deeper sedation may be required to ensure safety, due to the risk of unplanned extubation and virus transmission
  • Thromboprophylaxis
    • Chemical prophylaxis (e.g. enoxaparin) according to ICU protocols
    • COVID-19 patients may be at greater risk of venous-thromboembolism (VTE), DIC, and clotting of extracorporeal circuits (e.g. CRRT). 
    • A 20-50% rate of VTE in critically unwell patients has been observed in some ICU cohorts (see Complications, below)
    • National COVID-19 clinical evidence taskforce guidelines (11 June 2020) recommend considering  higher than usual doses of chemoprophylaxis  in critically unwell patients (e.g. enoxaparin 40mg twice daily in patients with normal renal function or 40mg once daily in those with impaired renal function). 
  • Head up positioning (30-45°) to improve oxygenation and reduce risk of ventilator associated pneumonia
  • Ulcer prophylaxis (follow local protocols for gastric acid suppression)
  • Glucose control 
  • Skin and eye care (including pressure injury and review of line sites, especially if prone positioning used)
  • Indwelling urinary catheters, nasogastric tubes
  • Bowel care (e.g. laxatives)
  • Environment (e.g. negative pressure room, optimise for delirium management)
  • De-escalation (discuss goals of care early, de-escalate all of the above interventions (including removal of central lines) promptly once no-longer required) 
  • Psychosocial support to patient, staff, and family
    • Vitally important to COVID-19 patients, as staff are potentially at risk of transmission, patient visitation is restricted and family may need to self-isolate or may also be ill.
    • Provide families with frequent updates over phone/ video calls
    • Enable communication between patient can family using diaries, communication boards, and technologies (e.g. telephone, video calls)
    • Staff well being checks, use of PPE buddies, 

Seek and treat complications

Disposition and referrals

  • Alfred Hospital Guidelines: Mandatory ICU review for all patients with:
    • Oxygen >8L/min via face mask
    • FiO2 >0.5 on HFNC
    • All patients commenced on NIV
  • All patients need early consideration of Goals of Care 
  • Specialist teams which may need to be involved:
    • Infectious Diseases
    • Respiratory
    • Cardiology (if cardiac complications of COVID present)
    • Other teams as required for patient comorbidities and complications

MANAGEMENT – OXYGENATION AND VENTILATION

Oxygenation strategies

  • Usual oxygen therapy targets apply, e.g.
    • SpO2 92-96% for most patients
    • SpO2 88-92% for patients with COPD and CO2 retention
    • Expert clinicians may choose other targets tailored to the individual patient (e.g. in some patients with refractory hypoxaemia, a lower target may be chosen to avoid the requirement for more invasive therapies and their associated risks)
  • Oxygen devices that can be used with droplet/contact precautions in most settings (local protocols may differ):
    • Nasal prongs (Standard)
    • Face mask (e.g. Hudson)
    • Non-rebreather mask (with reservoir bag)
    • Venturi mask
  • High-flow nasal cannula (HFNC) oxygen and Non-invasive ventilation (NIV)
    • Current guideline recommendations
      • Current Australian guidelines (v8.1) support the use of HFNC in acutely hypoxic patients, as does WHO guidance (WHO 2020/3/12)
      • Current Australian guidelines  (v8.1) recommend use of NIV with  appropriate precautions against aerosol transmission. Note that earlier versions of the guideline recommended against the use of NIV. 
    • Risks of viral transmission
      • Both HFNC and NIV have the potential to generate dispersal jets containing droplet or aerosolized viral particles (Hui DS. et al. 2019; Hui DS. et al 2009; ; Hui DS. et al. 2006)) 
      • The use of NIV was associated with an increased risk of healthcare worker infection during the SARS epidemic (Raboud J. et al. 2010)
      • HFNC may increase the distance travelled by droplet particles during coughing (Loh et al. 2020) however there is insufficient clinical evidence that HFNC increases the risk of viral transmission.
      • Current Australian guidelines (v8.1) recommend that HFNC and NIV can be used in negative pressure rooms, single rooms or cohorted COVID areas and to avoid its use in shared wards, interhospital transport or Emergency Department cubicles.
    • Potential benefit
      • In patients with ARDS, the FLORALI trial found HFNC to be associated with a lower mortality than NIV (Frat et al. 2015), particularly in those with an FiO2:PaO2 ratio ≤ 200mmHg. NIV was also associated with increased mortality in the observational LUNG-SAFE trial (Bellani G. et al. 2020). In MERS cases there was a high failure rate from the use of BiPAP (Alraddadi BM. et al. 2019)
      • It is uncertain what role NIV has in patients with SARS-CoV-2 infection presenting with other conditions in which NIV is typically indicated, such as exacerbation of chronic obstructive pulmonary disease (COPD) (Osadnik CR. et al. 2017)  or cardiogenic pulmonary oedema (Berbenetz N. et al. 2019)
    • A suggested approach
      • Only use HFNP and NIV with appropriate airborne/contact precautions
      • Patients who are COVID-19 positive but their comorbid conditions (e.g. OSA/COPD) are a major contributor to their respiratory illness may receive these therapies if they usually benefit from HFNP/NIV.
      • NIV use in patients with COVID-19 should be used cautiously. CPAP may be the modality of choice for treatment of hypoxaemia and avoidance of excessive tidal volumes. Failure to improve (e.g. improved oxygenation, respiratory rate (e.g. <30/min), or work of breathing) over 1-2 hours suggests that ongoing NIV is unlikely to be beneficial.
      • CPAP may be useful for optimisation of oxygenation prior to planned intubation in hypoxic CVOID19 patients
      • HFNP and NIV use should not delayed intubation and initiation of mechanical ventilation if indicated
      • HFNP and NIV patients require close monitoring as removal of the device or oxygen disconnection may result in life-threatening hypoxaemia

Intubation

  • Refer to the Safe Airway Society Consensus Guideline (Brewster et al, 2020) for principles and the Alfred ICU intubation guideline for an example of a context-specific local protocol.
  • Indications
    • Early intubation has been recommended based on early COVID-19 experience in China, that some patients progress to refractory hypoxaemia rapidly, and an awareness that preparation for intubation (an AGP) takes longer given the need for airborne/contact precautions
    • However, reports from the UK/Europe/USA experience of the COVID-19 pandemic suggest that some patients who have severe hypoxaemia can avoid intubation if they are undistressed and otherwise stable (awake proning is being used in some centers)
  • Pre-oxygenation
    • Should involve a tight-fitting mask, e.g. BVM apparatus, CPAP mask attached closed circuit, Mapelson/ Waters apparatus.
    • Patients refractory to pre-oxygenation (e.g. unable to achieve SpO2 >90-95%) likely have “shunt” physiology and may require CPAP/PPV for preoxygenation
  • The intubation procedure itself is of high risk to clinical staff. Risk of viral transmission can be reduced by:
    • Airborne/contact PPE precautions
    • Avoid HFNC and nasal cannula under a mask due to risk of leak/ aerosolization
    • Use of viral filter on BVM/ ventilators
    • Rapid sequence induction with avoidance of BVM ventilation (unless required for re-oxygenation)
    • Avoid cricoid pressure (may stimulate cough/ vomiting and worsen view)
    • Routine use of videolaryngoscopy
    • Avoiding auscultating the chest post-intubation
  • There are wide-spread reports of post-intubation instability and deterioration in critically ill COVID-19 patients, possibly related to:
    • Refractory hypoxaemia with in-effective pre-oxygenation
    • Effect of PPV/ PEEP on venous return and/or right heart function
  • Reduce risk of aerosol generation post-intubation:
    • ETT cuff pressure checks to prevent cuff leak
    • Use in-line suctioning
    • Tight circuit connections (some centers tape connections)

Mechanical Ventilation

  • Most guidance is based on extrapolation from ARDS management and previous experience with severe coronavirus disease (e.g. SARS, MERS, and COVID-19)
  • A protective lung ventilation strategy is recommended
    • Tidal volumes (VT) of 4-6 mL/kg PBW
    • Aim for plateau pressures (Pplat) < 30 cmH20
    • Allow permissive hypercapnia unless significant acidemia (e.g. pH <7.15) or otherwise contra-indicated
  • The role of positive-end expiratory pressure (PEEP) is controversial
    • The original ANZICS guidelines (version 1) recommended higher PEEP levels (e.g. >15 cmH20) for ongoing hypoxia. However, much lower PEEP settings may be appropriate for the subset of COVID19 patients (e.g. “L phenotype”) with highly compliant lungs as little evidence of “recruitability”.
    • Australian guidelines (v2) now make no PEEP recommendations.
    • In general, PEEP should be incrementally adjusted using the minimum PEEP required for optimisation. How to best optimise PEEP is controversial, though the simplest approach is to adjust to target SpO2. The ARDSNet ventilation strategy provides a step-wise approach to adjusting PEEP settings based on the FiO2 required. An example of a guide to titrated FiO2/PEEP settings is available here.

Other strategies for refractory hypoxaemia

  • Ensure simple measures considered:
    • Patent well positioned ETT of an appropriate size with appropriate ventilator settings and oxygen flow
    • Chest physiotherapy and patient positioning
    • Optimise fluid balance (e.g. diuretics, renal replacement therapy)
  • Prone positioning
    • Widely used globally with reported benefits in oxygenation
    • For mechanically ventilated adults with COVID-19 and hypoxaemia despite optimising ventilation, consider prone positioning  (Australian guidelines (v2.1)).
  • Neuromuscular blockade
    • May be required to optimise mechanical ventilation and decrease oxygen consumption
    • Intermittent dosing should be used as first line in preference to continuous infusions
  • Inhaled Nitric Oxide (iNO) and pulmonary vasodilators (e.g. prostacyclin)
    • Not recommended for routine use
    • A trial of iNO is reasonable for refractory hypoxaemia, as abnormal hypoxic vasoconstriction play place a role
    • Need to consider risk of aerosol generation and circuit disconnections and their implications for viral transmission if used
  • Recruitment manoeuvres
    • May be beneficial for patients with evidence of “recruitable lung”
    • For mechanically ventilated adults with COVID-19 and hypoxaemia despite optimising ventilation, consider using recruitment manoeuvres (Australian guidelines (v2.1))
    • If recruitment manoeuvres are used, do not use staircase or stepwise (incremental PEEP) recruitment manoeuvres  (Australian guidelines (v2.1)).
  • Bronchoscopy
    • Therapeutic bronchoscopy may relieve sputum plugging
    • Bronchoscopy is considered an AGP, patients should have adequate neuromuscular blockade and airborne/contact precautions are required
  • Extracorporeal membrane oxygenation (ECMO)
    • The utility of ECMO for COVID19 is uncertain and there are concerns about the resource implications of ECMO in the context of a global pandemic
    • Currently, WHO recommends its use be “considered” in centres with appropriate expertise (WHO, 13/3/2020). 
    • Australian guidelines (v2.1) recommend that mechanically ventilated adults with COVID-19 and refractory hypoxaemia (despite optimising ventilation, use of rescue therapies and proning), should be considered for venovenous extracorporeal membrane oxygenation (VV ECMO) (e.g. referral to an ECMO center).

Tracheostomy

  • Tracheostomy is an AGP and it’s role in the context of a COVID19 pandemic is uncertain.

Extubation

  • Extubation is an AGP, primarily due to the risk of patient coughing
  • Timing
    • Optimize timing to decrease the likelihood of needing High Flow Nasal Prongs (HFNP), Non Invasive Ventilation (NIV) or re-intubation following extubation
    • Timing is further complicated by:
      • Anecdotal reports of increased rates of extubation from airway oedema and even cardiovascular collapse (possible cardiomyopathy)
      • Potential for late deterioration in COVID19 lung disease (e.g. transition from high compliance to low compliance lungs)
    • Cuff leak tests have been recommended by some centers to guide decision making, however practitioners need to be aware that the cuff leak test is a potential AGPs.
  • Procedure
    • All team members should have PPE appropriate for airborne/ contact precautions

Refer to the Alfred ICU extubation guideline for an example of a local protocol for extubation

NOVEL AND INVESTIGATIONAL THERAPIES

The following therapies are under investigation for use in patients with SARS-CoV-2 infection. They lack the robust clinical evidence required to recommend for routine practice. They should only be used as part of a clinical trial with appropriate ethical approval until such time that further evidence of their safety and efficacy becomes available. 

Clinicians should also refer to the National COVID-19 Clinical Evidence Taskforce ‘living guidelines’ for up to date recommendations. 

Many large trials including are ongoing, including:

  • World Health Organisation SOLIDARITY trial: multi-arm remdesivir, lopinavir/ritonavir, hydroxychloroquine, Interferon Beta-1A.
  • REMAP-CAP: a multifactorial adaptive platform trial of community acquired pneumonia, which includes a pandemic response arm. Investigations include lopinavir/ritonavir, hydroxychloroquine, corticosteroids and immune therapies (Angus D. et al. 2020).
  • RECOVERY: UK-based multifactorial adaptive platform trial, similar to REMAP-CAP (NCT04381936).

Antiviral Therapy

Possible benefit:

  • Remdesivir
    • Adenosine analogue and RNA-dependent RNA-polymerase inhibitor, required for viral replication (Lung J. et al. 2020). Not licensed by TGA and limited availability in Australia.
    • Some evidence of effective use in MERS (de Wit E. et al. 2020).
    • Not associated with reduced time to clinical improvement, mortality or viral clearance in a double blind, multicentre RCT (China, n=237) of hospitalised patients (Wang Y. et al. 2020). This trial was terminated early due to a lack of recruitment and may have been underpowered (further analysis on INTENSIVE).
    • ACTT-1 trial (Beigel J et al. 2020): In preliminary results from this US-led RCT (n=1063), remdesivir for up to 10 days was associated with a shorter time to ‘clinical recovery’ of 11 (95% CI 9 to 12) vs.15 (95% CI 13-19) days. In patients requiring oxygen therapy (but not high-flow oxygen or mechanical respiratory support) 15-day mortality was reduced from 10.9 to 2.4% (HR 0.22, 95% CI 0.08 to 0.58). Final results including 28 day outcomes are awaited (further analysis on INTENSIVE).
    • Further large RCTs are awaited as above.

Uncertain effect:

  • The following  currently have no no role in the clinical management of COVID-19 except in the context of well-designed clinical trials.
  • Agents currently under investigation include:
    • Lopinavir/Ritonavir (Kaletra)
      • Antiretroviral agent developed for use in HIV infection. 
      • In an open label study of 199 patients in China, lopinavir/ritonavir was not associated with a reduction in mortality or time to clinical resolution of symptoms (Cao et al. 2020). 
    • Ribavirin
      • Guanosine and adenosine analogue, used in other RNA viruses including hepatitis C virus.
      • In a small, open label multicentre RCT (Hong Kong) use in combination with interferon beta-1b and lopinavir/ritonavir was associated with a shorter time to a SARS-CoV-2 PCR negative result. Due to the complex treatment regime the relative contribution of ribavirin is uncertain (Hung IF et al. 2020).

Low likelihood of benefit or potential for harm

  • Chloroquine – In vitro data suggests that chloroquine can inhibit COVID-19 (Wang M. et al. 2020) however clinical trials have been associated with potential harm:
    • ChloroCovid-19: RCT (Brazil; n=81) low vs. high dose chloroquine in hospitalised patients with suspected COVID-19, terminated early due to increased 14 day mortality with high dose chloroquine (39 vs. 15% OR 3.6; 95% CI 1.2-10.6; Borba et al. 2020)
  • Hydroxychloroquine 
    • In a widely publicised, non-randomised, open label trial in combination with azithromycin, hydroxychloroquine was associated with reduced viral load (Gautret P. et al. 2020). Significant methodological concerns have been raised with this trial (Intson K. et al. 2020) and others have not been able to replicate this result (Molina et al. 2020). Further analysis of this trial on INTENSIVE.
    • No benefit in mild to moderate disease based on an open label MRCT (China, n=150; Tang W. et al. 2020).
    • Not associated with benefit two large US observational studies (Geleris J. et al. 2020; Rosenberg E. et al. 2020)
    • May increase QTc especially in combination with azithromycin (Mercuro N et al. 2020).
    • On June 5 the RECOVERY trial investigators announced a finding of no benefit although full results are awaited.
    • Ongoing investigation in multiple trials including REMAP-CAP, SOLIDARITY (WHO) & RECOVERY (UK).
      • SOLIDARITY continues to recruit
      • REMAP-CAP has ceased recruitment in the UK.
  • On June 15, the FDA (US) revoked emergency use authorization for hydroxychloroquine and chloroquine in COVID-19 and use in the US is no longer permitted outside of a clinical trial.

Corticosteroids

  • Not recommended for routine use by national Guidelines
  • Evidence lacking in SARS-CoV-2 infection
  • Systematic review and meta-analysis of SARS & MERS coronavirus suggests increased mortality (RR 2.1, 95% CI 1.1-3.9; Yang Z. et al. 2020)
  • Previous studies using steroids in SARS found that they may increase viral shedding (Nelson L. et al 2004)
  • Proponents argue that there is a role for corticosteroids (Villar et al, 2020) in:
    • COVID-19 ARDS to prevent pulmonary fibrosis
    • COVID-19 cytokine storm
  • Corticosteroids is one of the therapeutic arms of the REMAP-CAP, RECOVERY and SOLIDARITY trials and may be used in the treatment of septic shock as a vasopressor- sparing agent.
    • On 16 June RECOVERY announced preliminary results suggesting mortality benefit, but full results including peer review are awaited.

Immunotherapy

  • Severe COVID19 disease may have features of cytokine storm syndrome/ hemophagocytic lymphohistiocytosis (HLH). Immune modulator therapy has been used in HLH and has been hypothesised to modulate severe COVID-19 (Mehta et al. 2020)
  • Examples include:
    • Interferon-beta (see trial of combination with ribavirin above, Hung IF et al. 2020)
    • Anti-interferon-gamma (emapalumab) – trials ongoing (NCT04324021)
    • Anakinra (IL-1) – trials ongoing (NCT04324021)
    • Anti-IL6 Agents (Toscilizumab, Siltuximab)
    • Convalescent plasma:
      • Removal of  plasma of patients recently recovered from COVID-19 and transfusing it into current patients to elicit immune response. Also hyperimmune fractionated immunoglobulin.
      • In a small RCT (n=103) use was associated with clinical improvement in patients who were not invasively ventilated, as well as a shorter time to viral clearance (Li L. et al. 2020).  
      • “Living” Cochrane review (Valk S. et al. 2020).
      • Further trials ongoing.

Other

Empiric Anticoagulation and Thrombolysis

  • COVID-19 may be complicated by a pro-thrombotic coagulopathy and its presence is associated with a high mortality (Tang, N et al 2020, Yin, S. et al 2020)
  • Use of prophylactic heparin/low molecular weight heparin is considered in the regular care of Intensive Care patients (see ‘Supportive Care’ above) and is considered standard of care for critically unwell patients in the absence of contraindications.
  • Therapeutic anticoagulation
    • Due to the high incidence of thromboembolic events, some groups suggest the use of therapeutic doses of heparin/low molecular weight heparin (Lin, L et al. 2020, Tang, N et al 2020), however prospective evidence is lacking and caution is essential given the risk of bleeding complications.
  • Heparin may have many putative effects in COVID-19 (Thachil, J. 2020, Tang, N et al 2020) including reduced microvascular and large vessel thrombosis, anti-inflammatory effects and endothelial protection. 
  • Other experimental therapies (use should be limited to clinical trials):

Renin-Angiotensin-Aldosterone System (RAAS) Inhibitors and Modulators (Vaduganathan et al, 2020)

  • ACE2 physiologically counters RAAS activation and functions as a receptor for SARS-CoV-1 and SARS-CoV-2 viruses.
  • Preclinical studies have suggested that RAAS inhibitors may increase ACE2 expression, but it is unknown if this occurs in humans or is clinically relevant.
  • Clinical trials are under way to test the safety and efficacy of RAAS modulators, including recombinant human ACE2 and the ARB losartan in Covid-19
  • Discontinuation of RAAS Inhibitors (e.g. AT2 antagonists, ACE inhibitors) in patients with a pre-existing indication is not recommended in patients with suspected or confirmed COVID-19 (see also Prognosis below)

High Altitude Pulmonary Edema (HAPE) therapies

  • A role for HAPE therapies in treatment of COVID-19 has been proposed, based on parallels between the two diseases, including: Nifedipine, Acetazolamide, and Sildenafil (Solaimanzadeh, 2020)
  • However, the pathophysiology of the two conditions is very different (hypoxic pulmonary vasoconstriction vs. viral induced parenchymal injury)

The risk/benefit of these agents for the treatment of COVID-19 is unknown and there is the potential that treatments used for HAPE could be harmful in COVID-19, despite clinical and radiological similarities (Luks A. et al. 2020).

PROGNOSIS

Length of Stay

  • Median hospital length of stay in China:
    • 12 days (IQR 10-14) when applied across all severity groups
    • 14.5 days (IQR 11-19) in those admitted to ICU, requiring mechanical ventilation or who died (Guan W. et al. 2020) 

Mortality 

  • Chinese CDC data suggests a case-fatality rate of of 0.25-3% (Wilson N. et al. 2020) 
  • Estimates vary by location of disease – range from ~1.5% in South Korea (KCDC 2020), 2.3% in China (Wu Z. & McGoogan J. 2020, to 7.2% in Italy (Onder G. et al. 2020). 
  • Case-fatality rates may be higher in disease epicentres due to system breakdown leading to a higher mortality and/or reduced resources to undertake screening programs of ambulatory patients (Mizumoto K. & Chowell G. 2020)
  • Fatality estimates may also be influenced by:
    • Population demographics (Italy has an older age distribution to China), 
    • Differences in screening programs, as above, may underestimate the denominator and overestimate fatality rates if mild cases are not tested
    • Different definitions of COVID-19 related deaths (eg. Italy defined COVID-19 deaths as all deaths occurring in SARS-CoV-2 positive patients independent of other pre-existing diseases which may have contributed to death; Onder G. et al. 2020)). 
  • COVID-19 appears to have a lower fatality rate than SARS (9.6%) and MERS (34.4%) however it has led to numerically more deaths due to its greater spread. (Wu Z. & McGoogan J. 2020) 
  • In-hospital cardiac arrest outcomes are very poor in COVID-19 patients with a respiratory cause (Shao et al, 2020)
    • Of 136 COVID-19 patients in Wuhan, China, only one had favourable neurological recovery at 30 days after IHCA, despite 89% of patients receiving CPR <1min. Most had asystole as an initial rhythm (90%) and a respiratory cause (87.5%).

Disease Severity

Risk factors for severity of disease and fatality:

  • Age (Wu Z. & McGoogan J. 2020) 
    • Any age can develop a severe respiratory failure
    • Fatality is correlated to age with highest mortality 14-20% in ≥80 years
      • Fewer children tend to suffer severe disease (5.2%) or critical disease (0.2%) (Ludvigsson, J. 2020)
      • Until March 2020 there were no reported deaths directly from COVID in children <9 years old, however there are now emerging reports of infant deaths in news media (Sibthorpe, C. 2020)
      • Odds of 1.10 increase in death per year in hospitalised patients (Zhou F et al. 2020)
  • Gender
  • Disease severity
  • Comorbidity
    • Presence of co-existing disease is more common in patients with severe disease (Guan W. et al. 2020), including:
      • Cardiovascular disease 
      • Diabetes 
      • Chronic Respiratory disease
      • Hypertension
      • Cancer
    • In Italy, of those who died (Onder G. et al. 2020):
      • 0.8% had no disease
      • 25.1% had a single disease
      • 25.6% had two diseases
      • 48.5% had 3 or more diseases
    • Hypertension and cardiovascular disease are associated with severe disease and mortality, however use of ACEI/ARB does not appear to independently increase risk (Jarcho J. et al. 2020)
  • Laboratory features associated with severity/mortality (Zhou F. et al. 2020):
    • D-Dimer > 1ug/mL on admission (OR 18)
    • Others include: 
      • Leukocytosis with lymphopenia
      • Anaemia
      • Thrombocytopenia
      • Elevated ALT, LDH
      • Ferritin and IL-6
      • hs-Troponin or CK-MB (Shi S. et al. 2020)
      • Elevated CRP or procalcitonin

Special populations

  • Children (Ludvigsson J. 2020)
    • Appear to develop milder disease with a very low risk of mortality from COVID-19 
    • As of April, 2020 there have only been reported a handful of paediatric deaths worldwide in association with SARS-CoV-2 infection
  • Pregnancy and neonates
    • Vertical transmission rates appear low (as with SARS-CoV) (Zhu H. et al. 2020; Chen H. et al. 2020)
    • SARS (SARS-CoV) was associated with high incidence of neonatal adverse events, however limited case series (so far) suggests the rate of adverse events may be low in SARS-CoV-2 (Qiao J. 2020; Rasmussen S. et al. 2020)
    • SARS-CoV-2 infection does not appear to be associated with an increased rate of maternal adverse outcome, unlike the H1N1 influenza pandemic in which pregnant patients were over-represented in mortality (Rasmussen S. et al. 2020)
  • Immunocompromised (Weinkove R. et. al. 2020)
    • Little direct evidence on the impact of COVID-19 infection in immunocompromised patients.
    • May be at increased risk of severe COVID-19 based on experience with other respiratory viruses.
    • Differential diagnosis may be difficult given frequency of pulmonary infiltrates and potential for co-infection.
    • Impact of treatment interruption from population transmission control also uncertain. 

Immunity

  • Humoural immunity occurs with presence of IgM and IgG antibodies in plasma following exposure.
  • In one study of 173 patients, median time to seroconversion was 11-12 days.
    • 94% of patients were IgM positive and 80% of patients were IgG positive two weeks after illness onset. (Zhao J. et al. 2020).
  • Duration of humoural response unknown, however post SARS-CoV infection 100% of patients had positive IgG titres up to 16 months, with approximately 90% still IgG positive at two years, declining to 50% at four years. (Lin Q. et al. 2020)

PREVENTION

Measures used to prevent SARS-CoV-2 transmission in healthcare settings include:

  • Individual level approaches (Ferioli et al, 2020)
    • droplet/ contact precautions for all staff involved in COVID19 patient interactions
    • airborne/ contact precautions for all staff involved in AGPs, which should be performed in a closed room (ideally with negative pressure)
    • Hand hygiene
    • Avoid touching one’s face
    • minimise equipment use (e.g. avoid stethoscope use)
  • System level approaches
    • Clear, consistent communication and education of staff and patients
    • Regular cleaning of environmental surfaces
    • Equipment cleaning
    • appropriate room ventilation (e.g. increased ventilation rate, using natural ventilation, avoiding air recirculation, and negative pressure rooms for AGPs)
    • Social distancing of staff (e.g. at lunch breaks)
    • Cohorting of patients and patient care areas (including separate locations for triage and care)
    • High risk staff members (e.g. age >65 years, pregnant, immunocompromised) not assigned to care of COVID-19 patients
    • Appropriate rostering and shift breaks
    • limiting the number of healthcare workers involved in care
    • Telemedicine and use of remote technologies
    • Prioritise PPE availability and SARS-CoV-2 testing for healthcare, transportation, safety, security, and infrastructure workers
    • Vaccine development (Lurie, 2020)

CONTROVERSIES

There are many controversies concerning our understanding of COVID-19, including issues relevant to assessment and management:

  • Potential for airborne transmission
  • The existence of L and H phenotypes and their implications for ICU management (see Is COVID-19 ARDS? What about lung compliance?)
  • Potential for neurotropic effects of the virus (e.g. effects on cardio-respiratory centers and role in cardiac arrest and response to hypoxaemia)
  • Role of HFNC and NIV
  • Thresholds and timing of interventions, including different oxygenation strategies and intubation (see “Silent hypoxaemia” and COVID-19 intubation)
  • How to maintain oxygenation during intubation
  • Appropriate PEEP settings in mechanical ventilation (see COVID-19: “To PEEP, or not to PEEP”?)
  • Utility of specific therapies (e.g. antivirals, steroids, immunotherapy) (see Novel drug therapies and COVID-19 clinical trials)
  • Extubation and tracheostomy timing and procedures
  • Therapies for refractory hypoxaemia, including vasodilators (iNO), recruitment manoeuvres, and ECMO
  • Care of isolated patients and families, including including compassionate care at the end-of-life (Wakam, 2020)
  • Long term outcomes and recovery of COVID-19 survivors
  • Pandemic resourcing and ethics
  • Staff wellbeing and moral distress, and the mental health burden of the COVID-19 pandemic
  • Rapid implementation of device and process innovations (see MacGyverism and “hacking COVID-19”)

Harms caused by the socioeconomic effects and disruption of usual services from pandemic precautions (e.g. disruption of elective health services, lack of employment, impacts on education, domestic violence) (Rosenbaum, 2020).

REFERENCES

LITFL

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FOAM and web resources

SARS-CoV-2

novel coronavirus of COVID-19

Updates

8 Comments

  2. Hi thanks for all the excellent info.

    I’m a rural emerg doc 40 mins away from the closest ICU.

    There seems to be a lot in the FOAMed world this week about not necessarily jumping to intubate our COVID patients (perhaps trying HFNC>NIPPV +/- proning).
    Any recommendations for transporting these patients safely (for both the patient and the ems crew). Any thoughts on how to transport this subset of patients with high oxygen requirements safely and stave off intubation? Is it even an option to transport on CPAP?

    Stay well!

    • Hi Bradley
      Transport of COVID-19 patients, even within hospital, can be challenging as it involves balancing the risks of deterioration with the risks of virus transmission, and trying to keep things simple.
      Early intubation may still be required for safe transfer.
      Adequate oxygen supply can be a major issue for HFNC.
      CPAP on a transport ventilator is feasible but should be part of a standard operating procedure.
      Increasingly, awake proning and proning during transport is being performed around the world – though I have no personal experience of this. Similarly, I am aware of inhaled NO having been used for transports by experts.
      Any retrieval medicine experts, wish to comment on this?
      Cheers
      Chris

  3. In the “prognosis” subsection, under the bullet point that reads “fatality estimates may also be influenced by”, please add a bullet point that says something to the effect of “lack of widespread antibody testing.” Because we don’t know how many people have already been infected and recovered and we don’t know how long the virus has been circulating, the denominator when estimating the fatality rates is most likely much larger, and therefore, the fatality rates that are being reported based on number of cases from positive tests or assumed positive are inflated.

  5. CoViD impairs hypoxic pulmonary vasoconstriction hypothesis:

    Consider these interventions to reduce intra-pulmonary shunting:
    (60 years of physiology research)

    Mild hyperthermia
    L-lactic acid infusion, buffered.
    TASK-1 channel blocker infusion eg doxapram, almitrine.
    Desferrioxamine infusion, Mn.
    Anandamide infusion
    Asymmetric dimethylarginine (AMDA) infusion
    Arginase inhibitor (nor-NOHA) infusion
    Angiotensin II infusion
    Beta-2 agonist infusion
    Avoid vasodilators (CCB)
    Position CoViD lobules upper.

    Also note that hypoxia and acute phase reactants increase thromboxane production. Thromboxane maybe responsible for some of the pathophysiology of COVID-19.

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