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

Transmission

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

Incubation period

Median incubation period is 4-5 days

symptoms develop: between 2 and 7 days in 75% of cases (Guan W. et al. 2020) after 14 days in less than 1% of cases (Lauer S. et al. 2020)



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)



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 Illness Person not presenting any clinical features suggesting a complicated course of illness.

Characteristics:

– no symptoms or mild upper respiratory tract symptoms

– stable clinical picture Moderate Illness Stable 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 Illness Patients 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 Illness Patient 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

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 May benefit from protective lung ventilation and usual ARDS therapies (potentially including an “open lung approach”)

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) Sensitivities range from 60-85% in respiratory specimens (Chan, JFW et al 2020) Highly specific, some approaching 100% (Chan, JFW et al 2020)



Sensitivity varies with specimen origin (Wang et al. 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

Point of care testing under development with viral PCR remaining the current test of choice (see above).

These may allow a result within 15 minutes and in the field.

May be antigen or serology based Serological (Li, Z et al 2020, Dohla, M et al 2020) – multiple tests under development.



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

Viral PCR (see “diagnosis” section above)

Full Blood Count Lymphocytopenia is characteristic in most studies (43%) (Rodriguez-Morales AJ et al 2020) In critically ill may be as high as 85% (Huang, C et al 2020)



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



CT imaging of the lungs

Changes seen in 86% of cases (Guan, WJ et. al. 2020)

Common features Include (Ye, Z et al 2020):

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



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

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

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

Other

Empiric Anticoagulation and Thrombolysis

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

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:

Special populations

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:

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).

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