Coronavirus disease 2019 is a respiratory disease caused by the virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Coronavirus disease 2019 (COVID-19) emerged in 2019 in Wuhan, the capital of Hubei Province in China. On 8th December 2019, there were initial reports of an unusual pneumonia which following investigation were reported to the World Health Organisation (WHO) by the Chinese authorities on 31st December 2019.
By January 2020, the causative organism of COVID-19 was identified as a novel coronavirus and termed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Unfortunately, the virus spread significantly throughout the world and was declared a pandemic on 11th March 2020. A year later in March 2021 there had been > 120 million cases and > 2.7 million deaths globally.
The assessment and management of COVID-19 is an area of great ongoing change and development. These notes aim to give a general overview of the disease and current treatments as of March 2021.
The epidemiology of COVID-19 is changing rapidly with significant geographical differences.
There is a wealth of up to date information available that is tracking the rapidly changing epidemiology of the COVID-19 pandemic. Three excellent resources are the WHO, Johns Hopkins University and the UK government.
Coronaviruses are a family of positive strand RNA viruses.
Coronaviruses are common pathogens that can infect a range of mammals (including humans) and birds.
SARS-CoV-2 is part of a wider family of coronaviruses, a group of related RNA viruses. This family of cororonaviruses are further divided into the subfamily Orthocoronavirinae, which is again divided into four genera known as alpha, beta, gamma, and delta.
In humans, coronaviruses commonly cause respiratory tract infections that range in severity from mild to lethal. These human coronaviruses (HCoV) belong to either the alpha or beta genera.
Coronaviruses are enveloped, positive-stranded RNA viruses. The terminology ‘positive’ or ‘negative' strand essentially refers to the similarity to mRNA:
Coronaviruses have a very large viral genome (27-32 kb), which encodes four or five structural proteins known as S, M, N, E and HE. They form roughly spherical particles 50-200 nm in diameter
SARS-CoV-2 is the cause of the global contagious respiratory disease COVID-19.
The term ‘SARS’ known as severe acute respiratory syndrome was initially coined in 2003 by WHO following an outbreak of a rapidly progressive respiratory illness that was identified to be caused by a novel coronavirus.
Following identification of another novel coronavirus as the cause of COVID-19, genetic analysis showed it was a beta coronavirus in the same subgenus as SARS, now known as SARS-CoV-1. This led to it being termed SARS-CoV-2, which showed RNA sequence similarity to two coronaviruses that infect bats. These animals are postulated as the origin of the virus, although whether an intermediate host was involved in transmission to humans is unclear.
SARS-CoV-2 is structurally similar to other coronaviruses with an RNA genome that encodes four structural proteins known as S, M, N and E. The virus is able to gain entry into the host by binding to angiotensin converting enzyme 2 receptors on human cells via its Spike protein (S).
Thousands of variants of SARS-CoV-2 have emerged due to viral mutations. Most of these mutations have no effect on viral function. However, several variants have enabled greater transmission and lethality. One such variant is B.1.1.7, more colloquially known as the ‘UK variant’. This contains numerous mutations, particularly to the region encoding the spike protein that enables greater transmission (up to 40%). There is also a small, but significant, increase in mortality.
Other significant variants have been identified across the globe.
The primary means of transmission is direct person-to-person respiratory transmission.
COVID-19 is primarily a respiratory disease that is transmitted from direct person-to-person transmission. This occurs due to close contact (i.e. within two metres or six feet) via respiratory particles.
Respiratory particles may be transmitted via respiratory secretions or saliva that are inhaled or make contact with mucous membranes (e.g. eyes, nose, mouth). Respiratory secretions and saliva may be spread by:
Several other methods of transmission have been recognised but these are less well established. These methods include:
The incubation period of COVID-19 is generally 4-6 days (median 5), but can be as long as 14 days. The incubation period describes the time from exposure to onset of symptoms. During this ‘pre-symptomatic’ period, patients can be contagious and transmit the virus to other individuals.
Infectivity generally begins 2-3 days before symptom onset and patients are more likely to be contagious during the early stages of illness when viral RNA levels are highest.
The risk of transmission depends on the closeness between the infected person and other individuals as well as the duration of contact. The risk is highest during prolonged indoor contact. Furthermore, risk of transmission appears to be less if the infected person is asymptomatic compared to one who is symptomatic.
There are well recognised risk factors that increase the risk of severe illness and death.
The predominant risk factors that increase a patients risk of having a severe illness include age and co-morbidities. A list of risk factors are discussed below:
The angiotensin converting enzyme 2 receptor has been identified as the binding site for SAR-CoV-2.
Following transmission, coronavirus particles target the angiotensin converting enzyme 2 receptor (ACE-2r) on cells of the upper and lower airways, namely nasal and bronchial epithelial cells and pneumocytes. Binding between ACE-2r and coronavirus particles is mediated by the spike protein.
Following binding, a host protein known as type 2 transmembrane serine protease (TMPRSS2) promotes viral uptake through activation of the spike protein. One inside the host cell, the particle releases viral RNA and undergoes replication using RNA polymerase. Viral proteins are translated from RNA and they are integrated into the host endoplasmic reticulum, which is facilitated by the M protein. From here, the nucleocapsid is formed and they are transmitted to the plasma membrane via golgi vesicles. They then undergo exocytosis taking some of the host cell membrane to form the viral envelope of the new coronavirus particle, which can then infect adjacent cells.
The initial binding and replication within the airways continues for a couple of days before an immune response is generated. The patient may still be asymptomatic during this early stage. The virus then propagates further down the respiratory tract to involve the upper airways, which prompts development of typical symptoms of cough, fever and malaise.
This leads to a more pronounced immune response with release of inflammatory cytokines (e.g. CXCL-10, IFN-beta, IFN-gamma) and migration of immune cells (e.g. lymphocytes). The coronavirus particles are able to infect and kill T lymphocytes leading to the classic lymphopaenia seen in laboratory testing as well as disrupt the normal immune response. However, the majority of patients are enable to mount a sufficient response to clear the virus at this stage.
In approximately 1/5th of patients, there is progressive disease with coronavirus particles infecting type II pneumocytes in the lower airways. This promotes a much stronger immune response with release of many pro inflammatory cytokines (e.g. IL-1, IL-6, TNF-alpha). This causes chemoattraction of white blood cells to the lungs where they initiate a profound immune response. In an attempt to clear the virus there is significant lung injury. With the increasing destruction of pneumocytes there is diffuse alveolar damage that can lead to adult respiratory distress syndrome. This can be life-threatening leading to severe respiratory failure and multi-organ failure. On imaging, this inflammation can be seen as widespread white infiltrates on chest x-ray and ground-glass opacities on CT.
The exaggerated immune response developing in severe COVID can promote widespread activation of the coagulation system leading to development of microthrombi and a high incidence of venous thromboembolisms including pulmonary embolism, deep vein thrombosis, and arterial thrombosis (e.g. stroke, ischaemia limb).
A significant proportion of patients with COVID-10 remain asymptomatic.
There are a wide range of clinical features in COVID-19. The incubation period is estimated to occur within 14 days (median 5), but the vast majority will show symptoms within 10 days. As high as 40% of patients may be asymptomatic.
The majority of symptomatic patients experience fever, cough, fatigue and shortness of breath.
NOTE: gastrointestinal symptoms may be the presenting complaint in some patients (e.g. abdominal pain, diarrhoea).
Over the course of 7-10 days, patients may develop worsening symptoms with progressive shortness of breath and hypoxia on testing. Development of dyspnoea occurs over a median of 5 days with hospital admission occuring at day 7 (on average) from symptom onset.
Numerous organ-specific complications may occur in COVID-19 due to the profound inflammatory response to the virus.
A proportion of patients may take significant time to recover from COVID-19, which can last several months and even longer. Symptoms such as fatigue, dyspnea and cough may persist. This clinical picture is often referred to as ‘long COVID’.
The severity of illness from COVID-19 is very broad and divided into mild, moderate, severe and critical.
The severity of COVID-19 can be based on a classification in NICE 191: Managing COVID-19.
Refers to evidence of COVID-19 without evidence of viral pneumonia or hypoxia. Clinical features consistent with early infection. Older people or those who are immunosuppressed may have atypical presentations.
Consistent with viral pneumonia. Typical features of pneumonia including fever, cough and tachypnoea. May see typical changes of COVID-19 on imaging. No signs of severe pneumonia (sats ≥90% on room air).
Consistent with severe pneumonia. Characterised by typical clinical features with severe tachypnoea (>30 breaths per minute), hypoxia (<90% on room air) or severe respiratory distress.
Patients with critical disease may fall into one of several different types:
Diagnosis of COVID-19 is based on nucleic acid amplification testing to detect SARS-CoV-2 RNA.
COVID-19 is usually diagnosed based on identification of the SARS-CoV-2 RNA from a respiratory sample. This is typically obtained from a nasopharyngeal or oropharyngeal swab.
Nucleic acid amplification testing (NAAT) is a way of amplifying genetic material to detect levels of the viral RNA. It is used for may different pathogens. The most common method is by reverse-transcription polymerase chain reaction (rt-PCR).
A patient who has a positive swab for SARS-CoV-2 RNA is diagnosed with COVID-19. There are some issues with false negative results (i.e. a patient who has COVID-19 based on clinical symptoms or imaging but is swab negative). Hospitals have local guidelines for these situations.
These are easy to use tests that can deliver a result within 30 minutes. A sample (e.g. nasopharyngeal swab) is mixed with solution and applied to the testing area. SARS-CoV-2 antigens are detected by specific antibodies bound to the test line that results in a colour change.
Lateral flow devices are less sensitive than the standard PCR tests.
The detection of antibodies to SARS-CoV-2 in the serum of patients is known as serological testing. These types of tests are unlikely to be positive in early infection until an immune response has been generated. This means they are not useful in the acute setting.
Antibody testing can be used to determine previous exposure to SARS-CoV-2 and formation of an immune response. However, it is unclear whether this confers long-term immunity. The duration of detectable antibodies also varies depending on the initial antibody response and severity of illness.
Investigations are crucial to determine the severity of illness in patients presenting to hospital.
Further investigations depend on the clinical context and suspected complications. These may include:
Treatment of COVID-19 is mainly conservative unless patients have severe disease requiring hospital admission.
NICE have recently published an excellent ‘rapid guideline’ (NG191) on the management of patients with COVID-19. This is an excellent summary of the current management strategies for patients with COVID-19.
The UK government has also published numerous articles on the prevention of spread and management of COVID-19 in a non-clinical setting. This includes how to prevent spread of COVID-19, current government guidelines on social mixing and social distancing rules.
The basic principles of management include:
Current NHS advice is to self-isolate for a full 10 days from the day of symptom onset (or the day you had the test, if you do not have symptoms) if you test positive for coronavirus. This is longer if symptoms continue. There is further advice on what to do if symptoms are persistent on the NHS website.
The majority of patients with COVID-19 will not require hospital admission.
Approximately 80% of patients with COVID-19 will have a mild illness that does not require medical intervention or admission to hospital. The following basic measures can be given to most patients:
Numerous pharmacological agents are now used in the management of COVID-19 among patients admitted to hospital.
Since the outbreak of the pandemic in March 2020, numerous medications have been trialed for the treatment of COVID-19. Randomised controlled trials are still ongoing to determine the most effective treatments and this will be a changing landscape.
Antibiotics are not used in the treatment of COVID-19. They may be used if there is a strong clinical suspicion of a secondary bacterial infection.
Currently dexamethasone or hydrocortisone are recommended for the treatment of severe or critical COVID-19.
Dexamethasone is recommend at 6 mg (PO/IV) daily for 7-10 days. Treatment should be stopped if discharged from hospital. Co-prescription with a PPI should be considered and close monitoring of blood glucose is required. This is because of the risk of gastric ulceration and steroid-induced hyperglycaemia, respectively.
These recommendations are based on evidence from a meta-analysis of seven randomised controlled trials. The largest contribution of these trials was the UK-based RECOVERY trial. Within the trial, dexamethasone reduced the all-cause mortality at 28 days compared to standard care in ventilated patients at study entry (29.3% vs 41.4%). There was no statistically significant benefit among patients not requiring ventilation at study entry.
Remdesivir is an anti-viral agent that works through inhibition of RNA-dependent RNA polymerase. It may be used for treatment of severe COVID-19. However, in the UK, it is currently only used in the setting of a clinical trial.
Tocilizumab is a monoclonal antibody directed against the IL-6 receptor blocking the binding of IL-6. The use of tocilizumab has shown to improve survival among patients admitted to hospital with COVID-19. There are certain criteria for its administration and it is currently being investigated in clinical trials.
Sarilumab is another monoclonal antibody directed against the IL-6 receptor that is being explored as a treatment for COVID-19.
The procoagulant effects of COVID-19 is well recognised. Consequently, several trials have looked at the benefit of administrating treatment dose anticoagulation.
In the absence of contraindications, treatment dose low molecular weight heparin (LMWH) for 14 days (minimum) or until discharge may be considered for young people and adults who meet the following conditions:
The dose of LMWH may be altered depending on need for high-flow or ventilation (non-invasive and invasive). Most hospitals have local guidelines on the use of anticoagulation and should be followed, which may include post-discharge use.
Vitamin D should not be offered to solely treat or prevent COVID-19 unless part of a clinical trial.
Patients with COVID-19 can develop progressive respiratory failure requiring increasing levels of respiratory support.
Patients with severe COVID-19 are hypoxic and oxygen is the principle treatment. The amount of oxygen that can be delivered depends on the device. As the disease progresses patient may require positive pressure ventilation (non-invasive or invasive) to help maintain airway opening and adequate ventilation.
Oxygen should be used to maintain a patients saturations in the target range. This should be 94-98% or 88-92% in patients at risk of type 2 respiratory failure. Over the course of the pandemic alteration to global saturation targets have been made at local and regional levels based on evidence, resources and guidelines. Always follow local hospital guidelines.
Different devices can be used to maintain oxygen saturations.
Non-invasive ventilation (NIV) is a way of supporting ventilation without having to undergo invasive tracheal intubation. NIV is indicated if high inspired oxygen concentrations (>60%) are not sufficient to maintain adequate oxygenation in patients with respiratory failure (e.g. COVID-19 pneumonia).
There are several methods of delivering NIV:
Invasive ventilation is also known as mechanical ventilation. It involves general anaesthesia, invasive tracheal intubation with placement of a tracheal breathing tube, and connection to a mechanical ventilator that does the breathing for the patient. Patients with COVID-19 who worsen despite NIV, or have so severe symptoms they would not tolerate NIV, require invasive ventilation.
In very severe cases, patients may require Extracorporeal membrane oxygenation (ECMO), which is essentially an artificial lung. This is a very specialised treatment that involves diverting a patients blood to an artificial oxygenator before being pumped back to the patients body. It is used when mechanical ventilation is not sufficient to maintain adequate oxygenation and there is deemed a reasonable chance of recovery.
Vaccination against SARS-CoV-2 is a crucial tool in the prevention of spread of COVID-19.
In March 2020, the first human clinical trials were underway for the prevention of COVID-19. Since then, numerous vaccines have been in development at various stages within clinical trials. A select number of these vaccines have already been licensed for use.
Current licensed vaccines in the UK:
Recently, there are have been reports of cerebral venous sinus thrombosis (CSVT) and disseminated intravascular coagulation (DIC) following administration of the Oxford/AztraZeneca vaccine. At the time of writing (April 2021) there is mounting evidence and suspicion that there is indeed a causal link. In the UK, as of March 31st 2021, there were 79 potential cases, 19 of whom died, with an age range of 18-79. Women were affected more frequently than men (51 of the 79 cases). From a risk vs benefit viewpoint the balance changes depending on age and other risk factors for severe COVID disease. Countries have adopted different approaches with some limiting use of the Oxford/AztraZeneca vaccine to older patient groups whilst others have discontinued it entirely.
COVID-19 can be a life-threatening illness associated with significant complications.
Primarily, COVID-19 is a respiratory illness that can lead to progressive respiratory failure and death. It can cause widespread organ dysfunction and abnormal neurological sequelae.
This is not an exhaustive list of the complications associated with COVID.
It is estimated that up to 10% of patient will develop persistent symptoms lasting >4 weeks. This is often collectively termed ‘long COVID’. There are a variety of symptoms that may form part of ‘long COVID’, which include chronic respiratory symptoms (e.g. cough, shortness of breath), cardiovascular symptoms (e.g. chest tightness), protracted loss of smell and taste, severe fatigue and many others.
The mortality associated with COVID-19 is changing as we understand more about the condition and treatments evolve.
Mortality from COVID-19 varies greatly depending on geographical location. Overall, mortality in patients under 65 years old without co-morbidity is rare. There are various ways to determine mortality:
The Centers for Disease Control and Prevention in the United States gives as estimate for the current IFR based on age (as of 21st March 2021):
In the UK, the intensive Care National Audit and Research Centre has excellent data on the mortality among patients critically ill from COVID-19 requiring intensive care admission. Among patients admitted to ITU between 1st September 2020 to 25th March 2021, the overall 28-day survival was 63% (95% CI: 62.4-63.6). The mortality was much higher among older patients (> 60% for patients aged 80+, compared to < 25% for those aged < 50 years).
Public Health England (PHE) have reported on the disparity between survival among different ethnic groups. The data varies between studies but overall appears to show those of Black ethnicity are at greater risk of severe disease than those of Asian ethnicity, who themselves are at greater risk of severe disease than those of White ethnicity. A biobank study quoted by PHE found Black ethnic groups had a 3 times and Asian ethnic groups 2 times higher risk of severe COVID-19 compared to White ethnic groups.
There are a number of significant confounders, some of which are unmeasured or difficult to accurately measure in these studies. Further high-quality research is required to both confirm and explain such observed differences.
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