Note: This remains a novel disease with new information becoming available daily. The information here will aim to be kept as up-to-date as possible but may change.
COVID-19 is coronavirus originating in Wuhan of Hubei province, China. It is now identified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It causes the disease termed COVID-19. Responsible for the 2020 pandemic (although first detected in Dec 2019, hence the name). As a novel virus, immunity to the virus with a population is very low, allowing a much greater impact that ‘common’ corona viruses. It probably originated in bats, with an intermediary pangolin host.
The betacoronavirus SARS-CoV-2 is a member of the coronavirus family. It is a positive, single stranded RNA virus. It is enveloped, with the proteins in the envelope creating a crown-like appearance that gives the virus group its name. This family includes many pathogens that contribute to the ‘common cold’ (about 25% of colds are caused by them), but also the more severe respiratory tract infectious outbreaks of SARS and MERS. It seems particularly closely related to the SARS virus, hence the viral name. There are 2 described strains: L-type and S-type. The significance of this is under investigation.
The virus affects primarily the respiratory system. It appears to use the angiotensin converting enzyme 2 (ACE2) receptor for entry into the cell, with this receptor found on type 2 alveolar cells. As with other viruses, the virus hijacks the cellular machinery to create new copies. Cellular damage from this, or from the subsequent immune response causes the disease. There can be progression to pneumonia in severe cases. The consequences of this appear to be primarily hypoxia, with less of an impact on CO2 exchange or respiratory mechanics.
It is seeming that there are 2 main phases of the disease, with different prodiminating pathophysiology. There appears to be an initial, primary vascular phase. There appears to be some preponderance of microvascular thrombi, impairing oxygenation whilst lung compliance being largely unaffected.. There may then be a transition to a picture that is more of a traditional ARDS pattern. There can also be secondary bacterial pneumonia complicating this second phase.
There is some description of significant CVS effects, which follows from the relationship with the ACE2 receptor mechanism of action. In cases where these receptors are upregulated, e.g. ACE inhibitor or ARB use, there is a concern that the symptoms may be worse. Myocardial injury, with acute myocarditis and heart failure, was recognised as a complication of MERS infection, and appears to complicate some COVID-19 cases too. The mechanism of injury here is not clear. It may be that there is similar injury effect as seen in the lungs, as ACE2 receptors are also expressed throughout the CVS. An alternative is that the injury is secondary in nature, either in relation to a cytokine storm, or from the respiratory impact of the virus e.g. hypoxia.
Transmission is primarily through droplet spread. When an infected patient coughs or sneezes, droplets containing the virus are expelled. These can directly land on other people, including entering the respiratory tract, or on surfaces (termed fomites).. The distance that droplets spread may include is somewhere in the range of 1-2m. Viruses on surfaces may subsequently be transmitted to the hands of other people, and then to target sites when people touch their face. The viability of the virus in the environment is not fully established. It appears to be dependent on the surface, with plastic and stainless steel potentially retaining viable viruses for up to 72. The decline in numbers appears to follow an exponential decay (with half life values of several hours), with the threshold for infectivity being unclear. General household cleaners are generally thought to be effective at decontamination. It is not thought that the virus transmission is airborne, but certain procedures can potentially increase this risk.
There has been evidence of viral RNA in blood and stool samples. However, these are not thought to represent a route of transmission in any significant way.
The incubation period (time from infection until symptoms) is on average 4-5 days, with a range of 2-14 days. Asymptomatic transmission may be possible, but is thought to be less significant due to the likely low viral levels in such patients.
The R0 is a term used to describe the infectivity of a virus. This refers to the number of other people that an infected person will pass the virus onto (as an average). A value of below 1 represents exponential decline, 1 represents steady state, and above 1 exponential growth. This concept has some notable limitations because of the myriad of factors that impact upon it, but it can be useful to compare how easily transmitted the virus is. The R0 of SARS-CoV-2 is probably around 2-2.5. This is similar to other respiratory viruses e.g. influenza (although worse than ‘normal’ flu in this regard), although notably less than some of the highly transmittable conditions e.g. measles, R0 around 15.
It presents similarly to other lower respiratory tract viral infections, including some similarities with seasonal influenza. Importantly, travel history is no longer particularly relevant in the history, as the disease is now pandemic, being considered widespread in the community. History of contact with a patient with known COVID-19 is clearly useful.
Common initial symptoms include:
Fever (about 90%)
Cough (dry- about 60%))
It can remain mild like this in about 80% of cases. Loss of the sense of smell (and relatedly an impact on taste) is increasingly being identified as common symptoms in the disease, and their rareness in other conditions should prompt a high level of suspicion. Some of the symptoms of more common viral illnesses are notably rare in covid: nasal congestion, tonsillar/lymph enlargement, rash.
More severe cases can result in significant respiratory complications (about 15%).
In about 5% of cases it may manifest as critical disease:
Asymptomatic infection has been described, but the incidence is not known at this time. Some studies (such as looking at those on the Diamond Princess cruise ship) have suggested asymptomatic rates of between 20-40%. GI upset (nausea, diarrhoea) has been a feature of some presentations. The recovery time appears to be about 2 weeks in mild disease, and 3 to 6 weeks in more severe disease.
There has been some description of an association between COVID-19 and secondary hemophagocytic lymphohistiocytosis. This is something that should be considered in some of these patients, such as those with persisting pyrexia and cytopenias.
A systematic assessment approach is important, but will be affected by infection control measures. Key examination features include:
Increased work of breathing
Appears very common - 99%
May be mild in some cases (<38 degrees)
Cardiovascular failure and shock has been described
Lymphopenia (80%), leucopenia, leucocytosis
Normal procalcitonin - >0.5 in only 5%
CRP usually moderately elevated
Baseline assessment in view of potential myocardial involvement
Ground glass opacification
Ground glass opacification
Addition respiratory virus testing e.g. influenza
The severity of the disease, and by extension to outcome, may have some relationship to some biomarkers. This remains based on largely observational study, but may be useful. Some features that have been described as associated with a worse clinical course include:
Raised D-Dimer - >1microgram/ml
Microbiology Reverse transcriptase polymerase chain reaction (RT-PCR) is the identification technique. Amplification of the viral RNA is used on samples to enable detection. Samples are taken from the upper (nasopharyngeal, oropharyngeal) or lower (sputum, BAL) airways. Test sensitivity is currently described as 60-70%. BAL and sputum samples appear to have the highest sensitivity (93 and 72%), but there would appear to be a higher risk of aerosol generation when collecting these. Combined nasal and oral swabs are currently employed for most testing. The risk of false negatives leading to relaxing of isolation precautions has led to advice for test repetition in cases with high clinical suspicion.
There appears to be replication of the virus in the GI tract, with positive samples being obtained from stools. The faecal-oral route does not appear to be a method of transmission however (no reported cases so far). Similarly, blood levels of the virus appear low and appear to not represent a significant transmission mode (if at all).
These can occur together, with ground glass opacification being the first feature seen. Changes are most commonly:
The extent of changes is reported to be associated with the severity and progression of the disease, being more prevalent in severe cases, and improving as the disease resolves. Radiographic features may appear before symptoms and before positive test results. Findings that are not typically associated with the disease include:
Lymph node enlargement
Ultrasound Lung ultrasound may provide useful diagnostic information in the disease. The advantages of portability may be particularly desirable when it comes to the challenges of transporting infectious patients to CT scan. Potential findings on imaging include:
B lines - multifocal, confluent
Management is separated in:
The novelty of the illness means that clear guidance on the best management approach has been an ongoing process. Some useful sources of guidance include:
Surviving Sepsis Campaign
Rapid dissemination summary (ICS, UCL)
This currently forms the mainstay of management. Many patients with mild disease will need only very simple over the counter medications (e.g. paracetamol) for their minor symptoms, and rest and self care. In these patients, the priority of management advice will be of a public health nature, including self-isolation.
More severe disease may require hospital care for additional supportive measures:
Antibiotics for bacterial complication
In these sicker patients, the adherence to evidence based best practice is important to minimise the risk of complications e.g. lung protective ventilation. The general principles of good critical care practice are all very relevant.
Respiratory Support Provision of standard flow oxygen supplementation is a key part of initial supportive management of patients with COVID-19. Anecdotally, there seems to be some variation in the presentation of hypoxia, with some patients tolerating surprisingly low SpO2 values with minimal distress. Oxygen targets of 92-96% are recommended as the target for oxygenation.
Non-invasive ventilation (NIV), including CPAP, and high flow oxygen (HFO) therapy is contentious. Its use may promote the spread of the virus (consider it an aerosol generating procedure), whilst not necessarily providing significant benefit beyond optimal standard flow oxygen. The use of earlier invasive mechanical ventilation (IMV) has been proposed in these patients. Some of the cases may benefit from NIV though, and it has been employed to some effect in Italy, under close observation. High flow oxygen has been similarly contentious because of:
Potential to delay IMV when it is needed
High drain of oxygen supplies when it will be in high demand (risk of depleting supplies)
Increasing dispersal of virus
Again, it has got proposed benefits in these patients and its use has been described. Some have described the additional use of surgical masks in these patients to try and assist in droplet capture.
Of note, CPAP has been supported by key UK groups: https://www.ficm.ac.uk/news-events-education/news/letter-regarding-use-continuous-positive-airway-pressure-cpap-covid-19 The Surviving Sepsis Campaign (SSC) COVID-19 guidance suggests the use of high flow oxygen over NIV, although recognising that much of this is based on ARDS and other hypoxic respiratory failure pathology rather than COVID-19 specific. They are unconvinced about there being an increased transmission risk from HFNC above standard oxygen therapy. They do feel that this is more of a risk with NIV, and recognise that there is less general evidence for its benefit outside of specific indications e.g. pulmonary oedema. Key features of use seem to be:
Consider aerosol generating procedures
Cohorting/isolation of patients
Meticulous PPE for medical staff
Close monitoring for treatment failure
Continue to monitor international guidance/evidence
Intubation and IMV Ongoing respiratory failure in COVID-19 patients is an indication for initiation of invasive mechanical ventilation (IMV). The threshold for this is likely to lie with the treating clinician, with some variation in practice internationally as to trialling alternative strategies first (NIV, HFNC).
Progression to providing IMV for these patients may be challenging. Part of this will be the clinical status of the patient, whilst another major factor will be the infectious risk associated with it. There is some excellent guidance from the FICM, ICS, AoA and RCOA available here: https://icmanaesthesiacovid-19.org/airway-management The key principles they highlight include:
Recognise it is an aerosol generating procedure -high risk for staff
Limit number of people in room
Meticulous use of PPE
Prepare everything beforehand outside room
Can be high risk for patient if severe COVID-19
Most experienced/skilled intubator to perform
Familiar technique to achieve rapid intubation - VL is being proposed by some
Aim to minimise aerosol generation
Avoid high flow
Minimise hand ventilation where possible - gentle 2 person technique if needed
Minimise any breaks in circuit - tube should be clamped and ventilator on standby before this happens.
Use checklists where possible to guide
Clear communication throughout is essential
Use simulation training beforehand where able
Hypoxia is described as being the primary initial problem of these patients, and can be severe. CO2 clearance and lung compliance appear to be less affected (at least initially in the disease process). As such, ventilatory strategy should follow standard current principles of ventilating patients from an ARDS perspective. Lung protective ventilation should be employed, as with ARDS.
Key features include:
Low tidal volumes - 6ml/kg predicted body weight
Target plateau pressures <30cmH20
High PEEP strategy - titration to FiO2
Whilst being important to deliver a lung protective strategy to reduce the risk to ARDS, there is recognition of an initial phase of the disease seen in patients that is not ARDS. This initial phase therefore also warrants different considerations, being described as of a primarily vascular nature. This may include:
Less aggressive use of PEEP initially - 10cmH2O being described (and perhaps even lower)
Early use of proning
Use of pulmonary vasodilation therapy - inhaled nitric oxide or prostacyclin
Implementation of muscle relaxants is recommended as an aid to achieving effective ventilation. The SSC guidance recommends initially trying a bolus approach, with an infusion of up to 48 being appropriate in cases of ongoing ventilator dyssynchrony. Sedation should clearly be optimised in these circumstances.
The use of re-recruitment maneuvers is also described by the SSC as an option for improving oxygenation. They promote the use of a single (traditional) rather than staged technique.
Proning is also described as being effective. There is some evidence of changes from an initial diffuse viral pneumonitis picture to bibasal consolidation, in keeping with disease that may benefit from the prone position. However, there is also a description of early proning to aid oxygenation, even before the development of ARDS. This should probably be for 12-16 hours at a time. Care needs to be taken to minimise the adverse effects. The Italian experience describes considering up to 7 cycles of prone position. Interestingly, there has been much description of prone positioning prior to IMV, including with standard oxygen therapy and NIV.
ECMO may be beneficial in some patients with COVID-19. The remains an area of ongoing study, given the significant risks and costs of ECMO. This is likely to only be a fairly select cohort of patients.
Extubation The progress of patients with COVID-19 is repeatedly reported as being slower than expected. Weaning is challenging, and there has been a higher than expected reintubation rate, suggesting that readiness for extubation may be deceptive. There is also a higher than usual rate of airway compromise following extubation, being attributed to airway oedema. The ICS summary describes the prophylactic use of dexamethasone, and having adrenaline nebulisers available.
Cardiovascular Consideration of fluid therapy appears to be an important consideration in these patients. This is specifically related to the negative impact of increased lung water on oxygenation. As such, a conservative fluid strategy is recommended. This is based on the apparent benefits of this approach in ARDS, and the association of COVID-19 with cardiac dysfunction, which may potentially further impair the physiological handling of fluids. The SSC recommends using dynamic markers of fluid status to guide management:
Passive leg raise
As is generally the guidance now, the use of a balanced crystalloid is the recommended fluid if needed for resuscitation (guided by above). Outside of this indication, it is recommended that maintenance fluids are unlikely to be required in addition to feeding. This must be balanced against the harms of an excessively restrictive approach. There appears to be a higher level of AKI arising in this group of patients (20-35%), potentially from overzealous dehydration, especially when coupled with high PEEP levels.
The SSC guidance on CVS support is not notably different. The target MAP (a balance of risks vs benefits is 60-65mmHg) They described a staged approach of:
Dobutamine may be considered in patients with ongoing shock and evidence of cardiac dysfunction. Low dose corticosteroids (hydrocortisone 200mg/day) are also suggested in refractory shock states, based on previous evidence of effects on improving CVS parameters, if not mortality.
Some myocardial injury and cardiac dysfunction appears to be a potential feature of the disease. Myocardial injury was reported in between 7-23% of the patients in Wuhan.
There is limited knowledge about the best treatment strategy for this specific virus, in part due to its novelty. There is no specific treatment that is identified as effective. Medications currently showing promise include:
Remdesivir This is a novel nucleotide analogue. It has shown evidence of efficacy against SARS-CoV-2 in vitro, and against the related MERS virus in vitro and in animal studies.
Steroids Steroids are not currently recommended (unless otherwise indicated). There is no evidence of benefit and there has been evidence of harm in some of the related viral pneumonias. They may also prolong the period of viral shedding, increasing transmission risk.
Nitric Oxide There is no current strong support for inhaled nitric oxide in this pathology. The SSC note it as a potentially rescue therapy for patients with severe refractory hypoxia, based on some evidence of improving oxygenation in ARDS. The lack of mortality benefit and renal injury suggests against use outside of these severe situations. However, the ICS statement suggests a potential role for pulmonary vasodilator therapy in the initial phase, although with recognition of the short-lived effects of iNO.
Antibiotics Routine antibiotic use is not recommended. However, there should remain the appropriate level of awareness of a bacterial cause for any deterioration, especially later in the disease process. Use of procalcitonin levels where available may be useful here.
Current mortality rates are not fully clear. A major issue has been the lack of a clear case denominator because of the limited testing in many of the clinical environments. Also, many mild cases may not have presented to healthcare providers. From a positive perspective, this probably means that the mortality rate associated with the disease is probably lower than initial estimates.
Some initial descriptions have included mortality rates between 2-4%. However, a case morality of 0.6% has been described as being a reasonable average (see podcast with Harris and Adalja). This may turn out to be lower as the extent of mild disease is better appreciated. This compares with 0.1% for influenza. However, there is an impact from the event of a pandemic on healthcare resources. A healthcare system that is overwhelmed by a surge of the disease is likely to result in a higher mortality because of being unable to provide optimal supportive care, as has occured in North Italy.
There is an impression of this being variable across different age groups. Children appear to have a notably milder disease course. The reason for this is not yet understood, in line with the ongoing research of the pathophysiology, but may be explained by their relatively immature (and dampened) immune response, in a similar manner to why chickenpox is actually more benign in children.
Similarly, the increasing risk with age has not got a specific mechanism. The relationship with ACE2 receptor upregulation has been described, but remains theoretical.
Risk factors for mortality include:
>80 years most notably
Chronic renal disease
Much of the effective management of this pandemic will be dependent on public health measures. Initial containment measures for the virus failed. The public health approach therefore moved to one of delay. The goal of this is to minimise the peak of disease numbers, instead spreading the cases out over time. The principle is that this reduced the risk of healthcare services (such as ICUs) being overwhelmed by severely ill patients, which would subsequently increase the risk of mortality from the disease (and of other conditions needing critical care, or healthcare more generally).
Prevention measures Key parts of individual practice include:
Avoid face touching
Isolation of illness
Basic hygiene measures
Social distancing describes the changes in social activity that can help reduce transmission. This essentially involves minimising close contact with other people, especially in environments that could be high risk for droplet transmission. There has been a variation in advice provided by different governments on such activities e.g. school opening, and this will no doubt change over time.
For clinicians caring for infected (or potentially infected) patients, key precautions are advised to protect them and others. There is also a need to be able to run hospitals effectively to cope with the surge in demand that severe cases of COVID-19 may result in. The key parts can be broken down into:
Personal protective equipment (PPE)
Each organisation will provide their own guidance on this, which should be used. This information acts as a representation and guide to other useful resources. PPE involves droplet and contact precautions includes:
There will be significant demands placed on healthcare organisations by this pandemic. There are ongoing strategies being designed and implemented to cope. These will vary between institutions. These descriptions of how the Italian systems have approached the pandemic are useful:
There have been concerns about a potential shortage of key critical care equipment, most notably ventilators. Whilst the possibility of ventilating more than one patient per ventilator has been described, there are some well established concerns with this: Anaesthesia Patient Safety Foundation, et al. Joint statement on multiple patients per ventilator. 26th March 2020. https://www.apsf.org/news-updates/joint-statement-on-multiple-patients-per-ventilator