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COVID-19

Changed by Mostafa Elfeky, 15 Apr 2020
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Updates to Article Attributes

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For a quick reference guide, please see our COVID-19 summary article.

COVID-19 (coronavirus disease 2019) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), previously known as 2019 novel coronavirus (2019-nCoV), a strain of coronavirus. The first cases were seen in Wuhan, China, in December 2019 before spreading globally 1,2,10. The current outbreak was officially recognized as a pandemic on 11 March 2020 44.

The non-specific imaging findings are most commonly of atypical or organising pneumonia, often with a bilateral, peripheral, and basal predominant distribution 32. No effective treatment or vaccine exists currently (April 2020) 20.

Terminology

The World Health Organisation (WHO) originally called this illness "novel coronavirus-infected pneumonia (NCIP)", and the virus itself had been provisionally named "2019 novel coronavirus (2019-nCoV)" 1.

On 11 February 2020, the WHO officially renamed the clinical condition COVID-19 (a shortening of COronaVIrus Disease-19) 15. Coincidentally, on the same day, the Coronavirus Study Group of the International Committee on Taxonomy of Viruses renamed the virus "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2) 16,22,46. The names of both the disease and the virus should be fully capitalised, except for the 'o' in the viral name, which is in lowercase 16,22,41. 

The official virus name is similar to SARS-CoV, the virus strain that caused epidemic severe acute respiratory syndrome (SARS) in 2002-2004, potentially causing confusion 38. The WHO has stated it will use "COVID-19 virus" or the "virus that causes COVID-19" instead of its official name, SARS-CoV-2, when communicating with the public 45.

Epidemiology

On 15 April 2020, the number of cases of confirmed COVID-19 globally surpassed two million 5. COVID-19 has now been diagnosed in 185 territories, in six continents according to an online virus tracker created by the medical journal, The Lancet, and hosted by Johns Hopkins University 5,13. As of 15 April 2020, there are 5 countries with >100,000 cases, 19 countries with 1,000 to 10,000 confirmed cases and 50 countries with between 1000 and 10,000 confirmed cases 5. 

NB: Surveillance methods and capacity vary dramatically between countries. Presymptomatic carriers may be present in many communities and presymptomatic transmission has been documented; asymptomatic carriers have been uncommonly reported and no asymptomatic transmission has been documented (2 Apr 2020) 113.

The R0 (basic reproduction number) of SARS-CoV-2 has been estimated between2.2 and 3.28 12,33, that is each infected individual, on average, causes between 2-3 new infections. 

The incubation period for COVID-19 was initially calculated to be ~5 days, which was based on 10 patients only 12. An American group performed an epidemiological analysis of 181 cases, for which days of exposure and symptom onset could be estimated accurately. They calculated a median incubation period of 5.1 days, that 97.5% became symptomatic within 11.5 days (CI, 8.2 to 15.6 days) of being infected, and that extending the cohort to the 99th percentile results in almost all cases developing symptoms in 14 days after exposure to SARS-CoV-2 92.

The number of deaths from COVID-19 exceeded 128,000 globally on 15 April 2020 5. The case fatality rate is ~2-3% 5,93. It is speculated that the true case fatality rate is lower than this because many mild cases are not being tested, which thus skews the apparent death rate upwards 93.

A paper published by the Chinese Center for Disease Control and Prevention (CCDC) analysed all 44,672 cases diagnosed up to 11 February 2020. Of these, ~1% were asymptomatic, and ~80% were classed as "mild" 25. 

Another study looked at clinical characteristics in COVID-19 positively tested close contacts of COVID-19 patients 81. Approximately 30% of those COVID-19 positive close contacts never developed any symptoms or changes on chest CT scans. The remainder showed changes on CT, but ~20% reportedly developed symptoms during their hospital course, none of them developed severe disease 81. This suggests that a high percentage of COVID-19 carriers are asymptomatic.

In the Chinese population, 55-60%% of COVID-19 patients were male; the median age has been reported between 47 and 59 years 12,93.

Paediatric

Children seem to be relatively unaffected by this virus, or indeed other closely-related coronaviruses 31,47,90 with large cohort studies reporting that 1-2% of COVID-19 patients are children 59,90,91. However, there have been cases of critically-ill children with infants under 12 months likely to be more seriously affected 59. A very low number of pediatric deaths has been reported 90,91. In children, male gender does not seem to be a risk factor 59. The incubation period has been reported to be shorter than in adults, at about two days 90.

NB: it is important to appreciate that the known epidemiological parameters of any new disease are likely to change as larger cohorts of infected people are studied, although this will only to some extent reflect a true change in the underlying reality of disease activity (as a disease is studied and understood humans will be simultaneously changing their behaviours to alter transmission or prevalence patterns).

Clinical presentation

COVID-19 typically presents with systemic and/or respiratory manifestations 93. Some individuals infected with SARS-CoV-2 are asymptomatic and can act as carriers 70. Some also experience mild gastrointestinal or cardiovascular symptoms, although these are much less common 18,50. 

The full spectrum of clinical manifestation of COVID-19 remains to be determined 1,13. Symptoms and signs are non-specific 68:

Common:

  • fever (85-90%)
  • cough (65-70%)
  • fatigue (35-40%)
  • sputum production (30-35%)
  • shortness of breath (15-20%)

Less common:

Rare:

  • nausea, vomiting, nasal congestion (<10%), diarrhoea (<5%) 93
  • palpitations, chest tightness 50

COVID-19 sufferers have reported high rates of disturbances of smell and taste, including anosmia, hyposmia, ageusia and dysgeusia. Numbers of patients affected vary and current evidence points more towards a neurological than a conductive cause of the olfactory dysfunction 79,98,105-107. 

Various reports suggest patients with the disease may have symptoms of conjunctivitis, and those affected, may have positive viral PCR in their conjunctival fluid 103,104. 

A recent report suggests that cutaneous lesions may also be seen, similar to many other viral infections. In a cohort of 88 patients, 20% developed skin disease, most commonly an erythematous rash. Most of the skin abnormalities were self-limited, resolving in a few days 100.

Paediatric

In the main, the clinical presentation in children with COVID-19 is milder than in adults 59,90. Symptoms are similar to any acute chest infection, encompassing most commonly pyrexia, dry cough, sore throat, sneezing, myalgia and lethargy. Wheezing has also been noted 59,90. Other less common (<10%) symptoms in children included diarrhoea, lethargy, rhinorrhea and vomiting 91.

Diagnosis

The definitive test for SARS-CoV-2 is the real-time reverse transcriptase-polymerase chain reaction (RT-PCR) test. It is believed to be highly specific, but with sensitivity reported as low as 60-70% 32 and as high as 95-97% 56. Thus, false negatives are a real clinical problem, and several negative tests might be required in a single case to be confident about excluding the disease.

Multiple radiological organisations and learned societies have stated that CT should not be relied upon as a diagnostic/screening tool for COVID-19 52,57,87,88. On 16 March 2020, an American-Singaporean panel published that CT findings were not part of the diagnostic criteria for COVID-19 56. However, CT findings have been used as a surrogate diagnostic test by some 2,32,89. 

Markers

The most common ancillary laboratory findings in a study of 138 hospitalised patients were the following 13,89:

Mild elevations of inflammatory markers (CRP 89 and ESR) and D-dimer are also seen.

Complications

In one of the largest studies of hospitalised patients, reviewing 1,099 individuals across China, the admission rate to the intensive care unit (ICU) was 5% 93. In this same study, 6% of all patients required ventilation, whether invasive or non-invasive. 

ICU patients tend to be older with more comorbidities 13,93. Commonly reported sequelae are:

In a small subgroup of severe ICU cases:

Pathology

Aetiology

On 9 January 2020, the World Health Organisation (WHO) confirmed that SARS-CoV-2 was the cause of COVID-19 (2019-nCoV was the name of the virus at that time) 14,37. It is a member of the Betacoronavirus genus, one of the genera of the Coronaviridae family of viruses. Coronaviruses are enveloped single-stranded RNA viruses that are found in humans, mammals and birds. These viruses are responsible for pulmonary, hepatic, CNS, and intestinal disease. 

As with many human infections, SARS-CoV-2 is zoonotic. The closest animal coronavirus by genetic sequence is a bat coronavirus, and this is the likely ultimate origin of the virus 11,19,26. The disease can also be transmitted by snakes 24.

Six coronaviruses are known to cause human disease. Two are zoonoses: the severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), both of which may sometimes be fatal. The remaining four viruses cause the common cold. 

Pathophysiology

The SARS-CoV-2 virus, like the closely-related MERS and SARS coronaviruses, affects its cellular entry via attachment of its virion spike protein (a.k.a. S protein) to the angiotensin-converting enzyme 2 (ACE 2) receptor. This receptor is commonly found on alveolar cells of the lung epithelium, underlying the development of respiratory symptoms as the commonest presentation of COVID-19 50. It is thought that the mediation of the less common cardiovascular effects is also via the same ACE-2 receptor, which is also commonly expressed on the cells of the cardiovascular system 50.

Transmission

Although originating from animals, COVID-19 is not considered a direct zoonosis as its transmission is now primarily human-to-human. It is primarily transmitted in a similar way to the common cold, via contact with droplets of infected individuals' upper respiratory tract secretions, e.g. from sneezing or coughing 19.

A recent Bayesian regression model has found that aerosol and fomite transmission are plausible 58.

Orofaecal spread was seen with the SARS epidemic, and although it remains unclear if SARS-CoV-2 can be transmitted in this way, there is some evidence for it 19,43.

A recently published cohort study (26 March 2020) could not rule out the possibility of vertical transmission with 9% of neonates (n=3/33) developing an early onset SARS-CoV-2 infection despite strict infection control measures during delivery 94. However, a retrospective study of nine pregnant patients infected by SARS-CoV-2 did not show any evidence of vertical/intrauterine infection 21. More recent published (20 March 2020) guidance from a joint American-Chinese consensus panel stated that it remains unclear if vertical transmission can occur 82.

Considerations for medical imaging departments

Imaging indications

The threshold for the imaging of patients with potential/confirmed COVID-19 demonstrates a degree of variation globally due to local resources, the published guidelines of individual learned bodies and sociocultural approaches to imaging. 

According to a Fleischner Society consensus statement published on 7 April 2020 101:

  • imaging is not indicated in patients with suspected COVID-19 and mild clinical features unless they are at risk for disease progression
  • imaging is indicated in a patient with COVID-19 and worsening respiratory status
  • in a resource-constrained environment, imaging is indicated for medical triage of patients with suspected COVID-19 who present with moderate-severe clinical features and a high pretest probability of disease
Infection precautions

Given that the staff in a medical imaging department are often in the frontline when dealing with COVID-19 patients, clear infection control guidelines are imperative. At the time of writing (8 March 2020) droplet-type precautions are in place for COVID-19 patients, that is, medical mask, gown, gloves, and eye protection (aerosol-generating procedures require N95 masks and aprons) 39.

Patients requiring general radiography should receive it portably (to limit transporting patients) or in dedicated auxiliary units. Patients that require transport to departments must wear a mask to and from the unit. Machines, including any ancillary equipment used during examinations, should be cleaned after examinations 40. It is recommended that any imaging examinations have two radiographers in attendance using the 'one clean, one in contact with the patient' system to minimize cross-contamination 89. The causative organism, SARS-CoV-2, can survive on surfaces for up to 72 hours, reinforcing the need for protection of equipment with barriers such as covers and thorough cleaning of equipment between patients 58.

There are case studies of portable chest x-rays performed through the glass window of the patient's room to decrease both staff exposure and amount of personal protective equipment 102, although departmental protocols will vary significantly.

Please follow your departmental policies on personal protective equipment (PPE).

Non-urgent care

Both the American College of Radiology (ACR) and the Centers for Disease Control and Prevention (CDC) in the United States advise that non-urgent outpatient appointments should be rescheduled 83,84. The British Society of Skeletal Radiologists has advised that intra-articular, soft tissue and perineural steroid injections may reduce viral immunity and therefore should not be performed unless they are unavoidable 85.

CT protocol

Patients requiring CT should receive a non-contrast chest CT (unless iodinated contrast medium is indicated), with reconstructions of the volume at 0.625-mm to 1.5-mm slice thickness (gapless) 57. If iodinated contrast medium is indicated, for example a CT pulmonary angiogram (CTPA), a non-contrast scan should be considered prior to contrast administration, as contrast may impact the interpretation of ground-glass opacification (GGO) patterns 89.

Radiographic features

The primary findings of COVID-19 on chest radiograph and CT are those of atypical pneumonia 40 or organising pneumonia 32,34.

Imaging has limited sensitivity for COVID-19, as up to 18% demonstrate normal chest radiographs or CT when mild or early in the disease course, but this decreases to 3% in severe disease 89,93. Bilateral and/or multilobar involvement is common 6,78.

Plain radiograph

Although less sensitive than chest CT, chest radiography is typically the first-line imaging modality used for patients with suspected COVID-19 97. For ease of decontamination, use of portable radiography units is preferred 52.

Chest radiographs may be normal in early or mild disease. Of patients with COVID-19 requiring hospitalization, 69% had an abnormal chest radiograph at the initial time of admission, and 80% had radiographic abnormalities sometime during hospitalization 97. Findings are most extensive about 10-12 days after symptom onset 97.

The most frequent findings are airspace opacities, whether described as consolidation or, less commonly, GGO 89,97. The distribution is most often bilateral, peripheral, and lower zone predominant 89.97. In contrast to parenchymal abnormalities, pleural effusion is rare (3%) 97.

CT

The primary findings on CT in adults have been reported 13,17,27,28,36:

The ground-glass and/or consolidative opacities are usually bilateral, peripheral, and basal in distribution 2,32.

A retrospective study of 112 patients found 54% of asymptomatic patients had pneumonic changes on CT 67.

Some papers suggest that CT has a sensitivity that could justify its use in the early imaging in the acute setting in select cases. Yet its use as a primary screening tool is currently discouraged, not least because these studies tended to suffer from selection bias 52,57,87,88. In a recent investigation, these chest CT findings had the highest discriminatory value (p<0.001) 51:

  • peripheral distribution
  • ground-glass opacity
  • bronchovascular thickening (in lesions)
Atypical CT findings

These findings only seen in a small minority of patients should raise concern for superadded bacterial pneumonia or other diagnoses 2,32,89:

Temporal CT changes

Four stages on CT have been described 17,24,32,86:

  • early/initial stage (0-4 days): normal CT or GGO only
    • up to half of patients have normal CT scans within two days of symptom onset
  • progressive stage (5-8 days): increased GGO and crazy paving appearance
  • peak stage (9-13 days): consolidation
  • absorption stage (>14 days): with an improvement in the disease course, "fibrous stripes" appear and the abnormalities resolve at one month and beyond
Paediatric CT

In a small study of five children that had been admitted to hospital with positive COVID-19 RT-PCR tests and who had CT chest performed, only three children had abnormalities. The main abnormality was bilateral patchy ground-glass opacities, similar to the appearances in adults, but less florid, and in all three cases the opacities resolved as they clinically recovered 48.

On 18 March 2020, the details of a much larger cohort of 171 children with confirmed COVID-19, and evaluated in a hospital setting was published as a letter in the New England Journal of Medicine. Ground-glass opacities were seen in one-third of the total, whereas almost 16% of children had no imaging features of pneumonia 91.

Ultrasound

Initial work on patients in China suggests that lung ultrasound may be useful in the evaluation of critically ill COVID-19 patients 55. The following patterns have been observed, tending to have a bilateral and posterobasal predominance:

  • multiple B-lines
    • ranging from focal to diffuse with spared areas 64
    • representing thickened subpleural interlobular septa
  • irregular, thickened pleural line with scattered discontinuities 63
  • subpleural consolidations
    • can be associated with a discrete, localized pleural effusion
    • relatively avascular with colour flow Doppler interrogation
    • pneumonic consolidation typically associated with preservation of flow or hyperemia 65
  • alveolar consolidation
    • tissue-like appearance with dynamic and static air bronchograms
    • associated with severe, progressive disease 
  • restitution of aeration during recovery
Nuclear medicine
PET-CT

An initial small case series published on 22 February 2020 demonstrated that FDG uptake is increased in ground-glass opacities in those with presumed COVID-19 42. A commentary in the same issue of the journal as this paper suggested that those with higher SUVs in lung lesions take longer to heal 77. A further single case detailed in a letter to Radiology corroborated the FDG avidity of COVID lung lesions 75.

Radiology report

The Radiological Society of North America (RSNA) has released a consensus statement endorsed by the Society of Thoracic Radiology and the American College of Radiology (ACR) that classifies the CT appearance of COVID-19 into four categories for standardised reporting language 99:

  • typical appearance
    • peripheral, bilateral, GGO +/- consolidation or visible intralobular lines (“crazy“crazy paving” pattern)
    • multifocal GGO of rounded morphology +/- consolidation or visible intralobular lines (“crazy paving” pattern)
    • reverse halo sign or other findings of organizing pneumonia
  • indeterminate appearance
    • absence of typical CT findings and the presence of
      • multifocal, diffuse, perihilar, or unilateral GGO +/- consolidation lacking a specific distribution and are non-rounded or non-peripheral
      • few very small GGO with a non-rounded and non-peripheral distribution
  • atypical appearance
    • absence of typical or indeterminate features and the presence of
      • isolated lobar or segmental consolidation without GGO
      • discrete small nodules (e.g. centrilobular, tree-in-bud) 
      • lung cavitation
      • smoother interlobular septal thickening with pleural effusion
  • negative for pneumonia:no CT features to suggest pneumonia, in particular, absent GGO and consolidation
CO-RADS

The COVID working group of the Dutch Radiological Society has proposed a CT scoring system for COVID-19, called CO-RADS (COVID-19 Reporting and Data System). This assigns a score of CO-RADS 0 to 6, dependent on the CT findings. Currently the new system is neither validated nor in widespread use 109.

Treatment and prognosis

Treatment

No specific treatment or vaccine exists for COVID-19 (April 2020). Therefore resources have been concentrated on public health measures to prevent further interhuman transmission of the virus. This has required a multipronged approach and for individuals includes meticulous personal hygiene, the avoidance of large crowds/crowded environments and where necessary, self-isolation 11.

In healthcare facilities, concerted efforts are required to effect rapid diagnosis, quarantine infected cases and provide effective supportive therapies. This will encompass empirical treatments with antibiotics, antivirals, and supportive measures. Mechanical ventilation and extracorporeal membrane oxygenation (ECMO) have also been used where clinically necessary. 

Antiviral therapy

Whilst specific antiviral therapies for SARS-2-CoV do not currently exist, the combination of the protease inhibitors, ritonavir, and lopinavir, or a triple combination of these antiviral agents with the addition of ribavirin, showed some success in the treatment of SARS 20, and early reports suggested similar efficacy in the treatment of COVID-19 23. However, a more recent randomized, controlled open-label trial failed to demonstrate any added benefit of lopinavir-ritonavir combination therapy 66.

Remdesivir, a drug originally developed to treat Ebola virus and shown to be effective against MERS-CoV and SARS-CoV, showed promising in vitro results against SARS-CoV-2 29 and is undergoing phase III trials 30. Other antivirals in phase III trials include oseltamivir, ASC09F (HIV protease inhibitor), lopinavir, ritonavir, darunavir, and cobicistat 80.

Early reports demonstrated that treatment with two antimalarial drugs, chloroquine, and its close chemical derivative, hydroxychloroquine, have a beneficial effect on the clinical outcome, and it was also shown that they demonstrate anti-SARS-2-CoV activity in vitro. This was further corroborated by a recent open-label, randomized clinical trial, which demonstrated a significant reduction of viral carriage, and a lower average carrying duration in patients treated with hydroxychloroquine. Furthermore, a combination with the antibiotic azithromycin resulted in a synergistic effect 69. 

Treatment with convalescent plasma has shown some success in some critically ill patients. Reports are still preliminary and about a small number of patients 110-112.

Vaccines

The primary target in developing coronavirus vaccines has been the spike protein (S protein) which is on the surface of the virion particle, and in vivo is the most important antigen for triggering an immune response 75. 

Vaccines for the coronaviruses have been under development since the SARS outbreak, but none are yet available for humans 11,26. A phase I trial in humans of a potential vaccine against MERS-CoV has already been performed in the UK 26.

NSAIDs

Emerging expert opinion is that non-steroidal anti-inflammatory drugs (NSAIDs) are relatively contraindicated in those with COVID-19. This is based upon several strands of "evidence" 61:

  • since 2019 the French government National Agency for the Safety of Medicines and Health Products has advised against the routine use of NSAIDs as antipyretic
  • previous research has shown that NSAIDs may suppress the immune system 
  • anecdotal reports from France suggest that young patients on NSAIDs, otherwise previously fit and well, developed more severe COVID-19 symptoms

However, it is important to note that there is currently (March 2020) no published scientific evidence showing that NSAIDs increase the risk of developing COVID-19 or worsen established disease. Also, at least one report shows antiviral activity by indomethacin (an NSAID) against SARS-CoV (cause of SARS) 60.

Prognosis

Progressive deterioration of imaging changes despite medical treatment is thought to be associated with poor prognosis 27. There is an increased risk of death in men over the age of 60 years old 62. The mortality rate is estimated to be 3.6% 89.

Early reports show that in some well patients, the RT-PCR test remains falsely positive despite an apparent clinical recovery. This raises the concern that asymptomatic carriage may occur 35.

Risk factors for severe illness or poor outcome

History and etymology

The first mention in the medical press about the emerging infection was in the British Medical Journal (BMJ) on 8 January 2020 in a news article, which reported "outbreak of pneumonia of unknown cause in Wuhan, China, has prompted authorities in neighbouring Hong Kong, Macau, and Taiwan to step up border surveillance, amid fears that it could signal the emergence of a new and serious threat to public health" 54. On 9 January 2020, the World Health Organisation confirmed that SARS-CoV-2 was the cause of the new disease 14,37.

The first scientific article about the new disease, initially termed 2019‐new coronavirus (2019‐nCoV) by the World Health Organisation (WHO), was published in the Journal of Medical Virology on 16 January 2020 53.

On 13 January 2020, the first confirmed case outside China was diagnosed, a Chinese tourist in Thailand 10. On 20 January, the first infected person in the United States was confirmed to be a man who had recently returned from Wuhan 9. The infection was declared a Public Health Emergency of International Concern (PHEIC) on 30 January 2020 by the WHO 7. On 28 February 2020, the WHO increased the global risk assessment of COVID-19 to “very high” which is the highest level. On 11 March 2020, COVID-19 was declared a pandemic by the WHO 44.

On 27 March 2020, the USA surpassed China as the country with the most confirmed cases 5. The number of confirmed cases globally exceeded one million for the first time on 3 April 2020, and two million on 15 April 5. The number of global deaths surpassed 100,000 on 10 April 2020 5.

The WHO originally called this illness "novel coronavirus-infected pneumonia (NCIP)" and the virus itself had been named "2019 novel coronavirus (2019-nCoV)" 1. On 11 February 2020, the WHO officially renamed the clinical condition COVID-19 (a shortening of COronaVIrus Disease-19) 15. On the same day, the Coronavirus Study Group of the International Committee on Taxonomy of Viruses renamed the virus "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2) 16,22,46. 

Differential diagnoses

Resources

These lists are in alphabetical order:

See also

  • -<li>peripheral, bilateral, GGO +/- consolidation or visible intralobular lines (“crazy paving” pattern)</li>
  • +<li>peripheral, bilateral, <a title="GGOs" href="/articles/ground-glass-opacification-3">GGO</a> +/- consolidation or visible intralobular lines (“<a title="Crazy paving" href="/articles/crazy-paving">crazy paving</a>” pattern)</li>
  • -<li>for a "crazy paving" predominant manifestation also consider conditions such as <ul><li><a href="/articles/pulmonary-alveolar-proteinosis">pulmonary alveolar proteinosis</a></li></ul>
  • +<li>for a "<a title="Crazy paving" href="/articles/crazy-paving">crazy paving</a>" predominant manifestation also consider conditions such as <ul><li><a href="/articles/pulmonary-alveolar-proteinosis">pulmonary alveolar proteinosis</a></li></ul>
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Case 46: early stage mild

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Case 50: early stage mild

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Case 57: early stagemild

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