Citation, DOI & article data
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), a strain of coronavirus. The first cases were seen in Wuhan, China, in December 2019 before spreading globally. The current outbreak was officially recognized as a pandemic by the World Health Organization (WHO) on 11 March 2020.
A definitive diagnosis of COVID-19 requires a positive RT-PCR test. The current best practice advises that CT chest is not used to diagnose COVID-19, but may be helpful in assessing for complications. The non-specific imaging findings are most commonly of atypical or organizing pneumonia, typically with a bilateral, peripheral, and basal predominant distribution.
For most sick patients, respiratory support is the cornerstone of successful treatment. Dexamethasone and monoclonal antibody based agents have been shown to be effective in reducing severity of illness. Multiple vaccines are available.
The official name of the illness is COVID-19 (a shortening of COronaVIrus Disease-2019) 15 and it is caused by the "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2) 16,22,46. The names of both the disease and the virus should be fully capitalized, except for the letter 'o' in the viral name, which is in lowercase 16,22,41.
The official virus name is similar to SARS-CoV-1, the virus strain that caused epidemic severe acute respiratory syndrome (SARS) in 2002-2004, potentially causing confusion 38. The World Health Organization (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.
As of May 2022, the number of cases of confirmed COVID-19 globally is over 515 million, having affected virtually every territory 5,156.
The R0 (basic reproduction number) of the original wild type SARS-CoV-2 has been estimated between 2.2 and 3.3 in a non-lockdown population, that is each infected individual, on average, causes between 2-3 new infections 12,33. Multiple variants have emerged, and some variants are more transmissible (see "Variants" in Pathology below) 211, 212.
The incubation period for COVID-19 was initially calculated to be about 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. A large meta-analysis of 53 studies worldwide showed a mean incubation period of 6.0 days 234.
As of May 2022, the official number of deaths from COVID-19 exceeds six million globally 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/asymptomatic 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) analyzed 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 in 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.
As of May 2022, more than 11 billion vaccine doses had been administered globally 5.
Children seem to be less seriously affected by this virus than adults, or indeed other closely-related coronaviruses 31,47,90 with large cohort studies reporting that 1-2% of symptomatic 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. In a small proportion of the patients however a severe, delayed complication termed multisystem inflammatory syndrome in children (MIS-C) can develop, which is characterized by systemic shock with multiorgan involvement.
NB: Surveillance methods and capacity vary dramatically between countries.
COVID-19 typically presents with systemic (multiple organ dysfunction, MODS-SARS-CoV-2) 227 and/or respiratory manifestations 93,170. Some also experience mild gastrointestinal or cardiovascular symptoms, although these are less common 18,50. Others may rarely present solely with a gastroenteritis-like illness, which may not initially be recognized to be COVID-19 171.
Individuals infected with SARS-CoV-2 can remain asymptomatic throughout the course of their illness acting as potential carriers 70,113,164.
The full spectrum of clinical manifestations of COVID-19 is broad 1,13. Symptoms and signs are non-specific 68:
- fever (85-90%)
- cough (65-70%)
- anosmia and other taste and/or smell disturbances (40-50%) 79,98,105-107,139
- fatigue (35-40%)
- sputum production (30-35%)
- shortness of breath (15-20%)
- myalgia/arthralgia (10-15%)
- headaches (10-36%) 121
- cutaneous lesions (~20%), most commonly erythematous rash 100,210
- sore throat (10-15%)
- chills (10-12%)
- pleuritic pain
- diarrhea (3-34%) 171
- splenomegaly 210
- nausea, vomiting, abdominal pain, GI bleeding 93,171
- nasal congestion (<10%) 93
- stroke (6%) 149-151,210 (most commonly cryptogenic 150,151)
- palpitations, chest tightness 50
- hemoptysis (<5%) 134
- confusion 137, seizures, paresthesia, altered consciousness 121,210
- ocular symptoms, e.g. conjunctivitis (1%) 103,104,140,141, epiphora 210
- hiccups 232
In the main, the clinical presentation in children with COVID-19 is milder than in adults 59,90,210. Symptoms are similar to any acute chest infection, encompassing most commonly pyrexia, dry cough, wheezing, sore throat, sneezing, myalgia, and/or lethargy 59,90. Less common (<10%) symptoms in children include diarrhea, lethargy, rhinorrhea and/or vomiting 91.
The gold standard diagnostic test for SARS-CoV-2 is the real-time reverse transcriptase-polymerase chain reaction (RT-PCR) test. This also allows searching for specific sequences from the viral genome: E (envelope protein gene), N (nucleocapsid protein gene) and RdRP (RNA-dependent RNA polymerase gene) 207. It is believed to be highly specific, but with sensitivity reported as low as 60-70% 32 and as high as 95-97% 56. Meta-analysis has reported the pooled sensitivity of RT-PCR to be 89% 116. 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.
Its sensitivity is predicated on time since exposure to SARS-CoV-2, with a false-negative rate of 100% on the first day after exposure, dropping to 67% on the fourth day. On the day of symptom onset (~4 days after exposure) the false-negative rate remains at 38%, and it reaches its nadir of 20% three days after symptoms begin (8 days post-exposure). From this point on, the false-negative rate starts to climb again reaching 66% on day 21 after exposure 138.
Serological and immunological tests
Lateral flow assay
Lateral flow immunochromatographic assays, a.k.a. lateral flow assays, are immunoassay-based techniques, in which an analyte, such as antigens or antibodies, may be detected in a test sample from a human subject. These are often binary (i.e. a 'yes' or 'no' result) tests. The urine pregnancy test is probably the most commonly used of this type of assay.
A body fluid sample is applied to the end of a rectangular test strip and via capillary action flows along the absorbent substrate. Towards the other end of the strip are antibodies attached to the substrate which will react with any active viral proteins in the body fluid as it moves along. When this fluid (containing viral antigens) reaches the test strip it will induce a chemical reaction producing a visible colored line 235. Further along the strip, the fluid will then encounter the control line inducing a second reaction to show a second line.
During the COVID-19 pandemic, lateral flow tests of small samples from the upper respiratory tract have become widely used for detecting whether SARS-CoV-2 antigens are present or absent 235.
CT as a diagnostic test
Multiple radiological organizations and learned societies stated early in the pandemic that CT should not be relied upon as a diagnostic/screening tool for COVID-19 52,57,87,88,116. 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 controversially as a surrogate diagnostic test by some 2,32,89.
The most common ancillary laboratory findings in patients, including a study of 61,742, were the following 13,89:
Other commonly identified abnormalities include:
- mild elevated inflammatory markers (CRP 89 and ESR)
- elevated D-dimer
- mildly elevated serum amylase: 17% patients (study of 52 cases) 145
- mildly deranged liver function tests are common, primarily elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 145,146,210
In one study of hospitalized 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:
- acute respiratory distress syndrome (ARDS): ~22.5% (range 17-29%) 89
- acute thromboembolic disease 130
- acute cardiac injury: elevated troponin levels 210
- delirium (15%) 137,210
- viral encephalitis 121
- diffuse leukoencephalopathy 157
- juxtacortical white matter and corpus callosum (particularly of the splenium)
stroke (6%): cryptogenic/ischemic 150,151,210
- higher mortality and greater severity of stroke in the context of COVID-19 150
- Guillain-Barré syndrome (GBS): rare 182
- secondary infections, e.g. bacterial pneumonia, mucormycosis 215
- renal 210
- hepatobiliary: liver is the most frequently affected organ after the lungs, although serious sequelae are rare 210
- acute pancreatitis 210
- gastrointestinal 210
- infarctions of solid abdominal viscera (18%) 210
- gonads 210
- rhabdomyolysis (late sequela, case reports only) 210
- multiorgan failure (MOF) 66
In a small subgroup of severe ICU cases:
Risk factors for pulmonary thromboembolism
In a multivariate analysis, an elevated risk of developing PE was associated with 133:
- elevated D-dimer
- elevated CRP
- rising D-dimer over time
In April 2020, reports started to appear of critically-ill children presenting with a severe inflammatory state like atypical Kawasaki disease and toxic shock syndrome 126,127. This is now called pediatric multisystem inflammatory state (PMIS).
Other sequelae have also been reported in children, including 210:
On 9 January 2020, the World Health Organization (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 one of the two strains of the SARS-CoV species known to cause human disease, the other being the original severe acute respiratory syndrome coronavirus (SARS-CoV-1), the cause of SARS. 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 diseases.
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 other coronaviruses are known to cause human disease. Two are zoonoses: the severe acute respiratory syndrome coronavirus (SARS-CoV-1) and Middle East respiratory syndrome coronavirus (MERS-CoV), both of which may sometimes be fatal. The remaining four viruses all cause the common cold.
The SARS-CoV-2 virus, like the closely-related MERS and SARS coronaviruses, effects its cellular entry via attachment of its virion spike protein (a.k.a. S protein) to the angiotensin-converting enzyme 2 (ACE2) 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 ACE2 receptor, which is also commonly expressed on the cells of the cardiovascular system 50.
The SARS-CoV-2 virus, like all viruses, continually mutates, thereby creating new variants perpetually, certain variants, are particularly worrisome to scientists. These might be particularly transmissible or pathogenic. These have been termed "variants of concern" (VOC) by the World Health Organization 220. The "original" virus, i.e. as it was before the alpha variant arose, is now known as "wild type" virus.
Other "variants of interest" (VOI), have genetic sequences that may affect important viral characteristics, e.g. transmissibility, pathogenicity, ability to circumvent vaccines, etc., and also have been found to form multiple disease clusters or substantial transmission in the community but are not currently designated variants of concern 220.
Some previous variants of interest are no longer thought of as such and have been downgraded (e.g. epsilon variant) to the lowest named tier, "variants under monitoring" (VUM) or not designated at all (e.g. theta variant) 220. This could also potentially happen to variants of concern, although this has not as yet happened 220.
Originally all variants were officially given formal scientific designations, however, the media and general public assigned them easy to remember names based on their site of first identification. This led to geographic-related stigmatisation, and thus the variants were renamed by the WHO on 31 May 2021, using sequential letters from the Greek alphabet (i.e. α (alpha), β (beta), γ (gamma) etc.).
The formal scientific designations remain in use for virologists and epidemiologists; one of these is the Pango lineage, which ascribes a letter and numbers to SARS-CoV-2 strains which share similar genomes and hence phylogenetic relationships (e.g. B.1.1.7) 217,220,221.
Variants of concern (VOC)
- delta (B.1.617.2 - India, Oct 2020)
- omicron (B.1.1.529 - multiple countries Nov 2021). It appears to circumvent some of the current vaccines; this is most likely due to mutations in the spike protein (S371L, N440K, G446S and Q493R) 237.
- alpha (B.1.1.7 - Kent, UK, discovered Sep 2020)
- beta (B.1.351 - South Africa, May 2020)
- gamma (P.1 - Brazil, Nov 2020)
Variants of interest (VOI)
The epsilon (B.1.427/B.1.429), eta (B.1.525), iota (B.1.526), kappa (B.1.617.1), lambda (C.37) and mu (B.1.621) variants are no longer considered to be VOIs (on 20 September 2021) 220.
Variants under monitoring (VUM)
- B.1.640 (Sep 2021)
- XD (France, Jan 2022)
Theta (P.3) and zeta (P.2) variants were formerly VUMs, but now are not formally labeled 220.
Although originating from animals, COVID-19 is now considered to be an indirect zoonosis, as its transmission is now primarily human-to-human. It was initially thought to be predominantly 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.
It is now thought that aerosol transmission of SARS-CoV-2, i.e. airborne transmission, also occurs 58,161,162,172. In the early stages of the pandemic aerosol risk was thought to be limited to so-called aerosol-generating procedures (AGPs) in healthcare facilities. However, there is an increasing evidence base to show that aerosols are also produced by talking, singing, coughing and expiration 162.
Fomites transmission is also seen, explaining the emphasis on regular handwashing and regular cleaning of surfaces that might have been exposed to droplets/aerosols containing virion particles 58,162,172-174. The SARS-CoV-2 has a short half-life on some non-porous surfaces, including copper and latex, but is more persistent on other materials such as glass, plastics, stainless steel and porous fabrics 174.
Sexual transmission has not been seen in the field but remains possible, not least because the SARS-CoV-2 virus has been found in all bodily secretions including seminal and vaginal fluids 143.
It remains unclear if COVID-19 could be transmitted through a blood transfusion although no cases have yet been seen. Nevertheless, many national bodies have instituted controls to reduce the chance of this happening including advising that potential donors do not give blood until 28 days after recovering from COVID-19 142.
Cohort studies have been unable to rule out the possibility of vertical transmission (mother-to-fetus transfer of COVID-19), but it seems to be a rare event if it does occur 21,82,94,152,210. A large prospective cohort study of 427 pregnant women from all 194 birth units across the UK found that 5% of 265 live births were confirmed as COVID-19 on RT-PCR 152.
Presymptomatic carriers are likely to present in many communities and presymptomatic transmission has been documented 163.
Asymptomatic carriage and transmission are also thought to occur 163,164.
Considerations for medical imaging departments
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.
The use of CT as a primary screening tool is discouraged, not least because these studies tended to suffer from selection bias 52,57,87,88,115, with a meta-analysis, in April 2020, reporting a pooled sensitivity of 94% and specificity 37% 116. In low prevalence (<10%) countries, the positive predictive value of RT-PCR was ten-fold that of CT chest 116.
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
Moreover performing CT routinely for large cohorts of patients carries additional risks 115:
- depletion of finite resources, especially PPE due to excessive usage
- increased risk of viral transmission (to staff, patients and carers) as COVID-19 positive and negative patients come into close proximity in the radiology department
- additional ionizing radiation exposures
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 (September 2021) droplet-type precautions are in place for COVID-19 patients, that is, medical masks, gowns, gloves, and eye protection (aerosol-generating procedures require N95 masks and aprons). A study of 420 clinical staff found that personal protective equipment (PPE) protected the development of SARS-CoV-2 infection 39,155.
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 102,165, although departmental protocols will vary significantly.
Please follow your departmental policies on personal protective equipment (PPE).
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. This decision has been criticized for its uncompromising approach, especially when the underlying evidence is far from being clear-cut, with a suggestion that for many the risk-benefit calculation is in favor of performing the joint injection 181.
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.
Currently, there is no diagnostic benefit to performing a CTPA examination on initial presentation 203. Although the risk of pulmonary thrombosis is higher in severe cases of COVID-19, it is recommended that D-dimer values are used to guide clinical pathways to justify a CTPA 203-205.
However 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.
The current recommendation of the vast majority of learned societies and professional radiological associations is that imaging should not be employed as a screening/diagnostic tool for COVID-19, but reserved for the evaluation of complications 115.
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, the use of portable radiography units is preferred 52.
Chest radiographs may be normal in early/mild disease. In those COVID-19 cases 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.
Although cardiac manifestations of COVID-19 are well-recognized, there is no published evidence of cardiac disease on chest radiographs 175.
The primary findings on CT in adults have been reported as 13,17,27,28,36:
- ground-glass opacities (GGO): bilateral, subpleural, peripheral
- crazy paving appearance (GGOs and inter-/intra-lobular septal thickening)
- air space consolidation
- bronchovascular thickening in the lesion
- traction bronchiectasis
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.
The following chest CT findings have been reported to have the highest discriminatory value (p<0.001) 51:
- peripheral distribution
- ground-glass opacity
- bronchovascular thickening (in lesions)
A small number of patients have shown a pulmonary target sign 196, which has only been reported in COVID-19 patients so far. At present, it is unclear if this new sign is pathognomonic or simply newly recognized.
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:
- mediastinal lymphadenopathy 17
- pleural effusions: may occur as a complication of COVID-19
- multiple tiny pulmonary nodules (unlike many other types of viral pneumonia)
- atoll sign
- pneumomediastinum 206
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
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.
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
- irregular, thickened pleural line with scattered discontinuities 63
- subpleural consolidations
- can be associated with a discrete, localized pleural effusion
- relatively avascular with color flow Doppler interrogation
- pneumonic consolidation is 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
- reappearance of bilateral A-lines
The British Society of Thoracic Imaging (BSTI) has published a reporting proforma for the plain chest radiographic appearances of potential COVID-19 cases 168.
- lower lobe and peripheral predominant multiple opacities that are bilateral (>> unilateral)
indeterminate for COVID-19
- does not fit classic or non-COVID-19 descriptors
- pneumothorax / lobar pneumonia / pleural effusion(s) / pulmonary edema / other
- COVID-19 not excluded
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 standardized reporting language 99:
- typical 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
- absence of typical CT findings and the presence of
- 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
- absence of typical or indeterminate features and the presence of
- negative for pneumonia: no CT features to suggest pneumonia, in particular, absent GGO and consolidation
A study evaluating the RSNA chest CT classification system for COVID-19 against RT-PCR results found moderate interobserver agreement. Using a cohort of 96 patients, it reported that 76.9-96.6% of "typical" scans, 51.2-64.1% of "indeterminate" scans, 2.8-5.3% "atypical" scans and 20-25% of "negative" scans returned a RT-PCR confirming COVID-19 99,147.
In March 2020, the "COVID-19 standardized reporting working group" of the Dutch Association for Radiology (NVvR) proposed a CT scoring system for COVID-19. They called it CO-RADS (COVID-19 Reporting and Data System) to ensure CT reporting is uniform and replicable. This assigns a score of CO-RADS 1 to 5, dependent on the CT findings. In some cases, a score of 0 or 6 may need to be assigned as an alternative. If the CT is uninterpretable then it is CO-RADS 0, and if there is a confirmed positive RT-PCR test then it is CO-RADS 6 109,124.
The first study investigating the use of CO-RADS found a reasonable level of interobserver variation, with a Fleiss' kappa score of 0.47 (cf. 0.24 for PI-RADS and 0.67 for Lung-RADS) 124. Another study found that CO-RADS is sensitive and specific for diagnosing COVID-19, using RT-PCR as the gold standard 184. CO-RADS-AI, a system using deep machine learning has been validated for diagnosing COVID-19 on CT chest 183.
In April 2020, American radiologists based at the University of Southern California proposed the COVID-19 imaging reporting and data system (COVID-RADS), which has a confusingly similar name to CO-RADS (see above) 125.
CO-RADS vs COVID-RADS
A 2020 study comparing the head to head performance of the CO-RADS and COVID-RADS reporting systems for 200 cases of COVID-19, found that interobserver consensus was similarly moderate to good, however, CO-RADS demonstrated a higher median intraobserver consensus 216.
Treatment and prognosis
Most 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 11:
- meticulous hand-washing
- wearing of face masks
- social distancing
- avoidance of large crowds/crowded environments
There is now increasing concern that aerosol transmission has a more significant role in viral spread than initially thought and this means that additional public health measures will need to be introduced, these will include 161,162:
- better ventilation, especially in indoor public spaces, workplaces, educational establishments, healthcare facilities, and community residential centers for the elderly, in many cases this will be as simple as opening windows
- specific aerosol infection control systems, such as:
- high throughput and effective air filtration
- virucidal UV (ultraviolet) lighting
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.
Historical studies have demonstrated a net benefit for patients with moderate to severe ARDS being turned prone 118. Many health care facilities have adopted the practice of turning the sicker COVID-19 patients into a prone position, so-called "proning" to improve their lung oxygenation 119.
Ronapreve, a branded formulation of potent two monoclonal antibodies, casirivimab and imdevimab, was the first licensed specific antiviral treatment for COVID-19 in adult patients 231.
Molnupiravir, is a chemical analog of cytodine, a ribosomal nucleoside, which was originally developed for treating the influenza virus. It is now in phase 3 trials, and showing promise, as the first specific antiviral for COVID-19. However, whilst initial trial data looks promising, conclusive peer-reviewed data remains to be published 229,230.
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.
A combination of remdesivir and baricitinib showed to be effective against MERS-CoV and SARS-CoV, showed promising in vitro results against SARS-CoV-2 29,197. A preliminary trial in May 2020 showed a small decrease in time to recovery, from 15 to 11 days, in those treated with remdesivir 153. However there are concerns about this evidence, and remdesivir has not been shown to decrease mortality nor reduce the length of hospital stay 169. Other antivirals in phase III trials include oseltamivir, ASC09F (HIV protease inhibitor), lopinavir, ritonavir, darunavir, and cobicistat 80.
Dexamethasone, a synthetic steroid, was demonstrated in the large RECOVERY (Randomized Evaluation of COVid-19 thERapY) randomized controlled trial, in June 2020 to decrease deaths by a third in those on mechanical ventilation (p=0.0003), and by a fifth of those non-ventilated patients requiring oxygen (p=0.0021). No benefit was seen in those not needing respiratory support 148,198.
In early 2020, published reports showed that two antimalarial drugs, chloroquine, and its close chemical derivative, hydroxychloroquine, had strong anti-SARS-2-CoV activity in vitro. An initial open-label, randomized clinical trial, 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 69,228. However, this trial was later strongly criticized for methodological flaws and questionable conclusions. Later studies have failed to replicate the beneficial effects of these agents and also highlight potential side-effects 135.
There are a number of studies exploring the use of ivermectin, the literature is quite heterogeneous. The World Health Organization recommends, that for patients with COVID-19, regardless of disease severity, "not to use ivermectin, except in the context of a clinical trial" 240.
From a very recent retrospective cohort study, it emerged that the early treatment (<72 hours) of Covid-19, with drugs such as indomethacin, aspirin (low dose), omeprazole, bioflavonoids plus azithromycin, heparin and - if necessary - betamethasone, reduces the severity of the disease and the rate of hospitalizations 238.
Treatment with convalescent plasma (plasma from patients who have recovered from COVID-19 which therefore contains anti-SARS-CoV-2 antibodies) or hyperimmune immunoglobulin (purified antibodies prepared from convalescent plasma) has shown some success in some critically ill patients. Reports are still preliminary and about a small number of patients 110-112,136. A Cochrane review in May 2020 failed to find convincing evidence that convalescent plasma was an effective treatment, but this will be kept under active review 136.
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 75,222,223. Human vaccines for coronaviruses have been under development since the SARS outbreak 2002-2004, none have been approved for immunisation against SARS or MERS 11,26. Over 125 SARS-CoV-2 vaccine candidates were originally in development 154. Ten (or so) of these are now in use globally, whilst others remain in development or have been abandoned due to lack of efficacy 222,223.
Vaccines for SARS-CoV-2 may be classified by their different mechanisms of action 222,223:
- genetic vaccines
- mRNA-based e.g. Pfizer
- adenoviral vector e.g. AstraZeneca
- protein vaccines
- inactivated virion e.g. Sinopharm
- subunit e.g. Novavax
In December 2020, a novel mRNA vaccine originally designated BNT162b2, now called tozinameran 202,233, and co-developed by BioNTech and Pfizer, demonstrated 95% efficacy in protecting adult (>16 years old) subjects, inoculated with two 3-week apart doses, from COVID-19 infection 200. The vaccine - made up of molecules of messenger ribonucleic acid (mRNA) and inserted into lipid nanoparticles (LNPs: ALC-0315 and ALC-0159) to facilitate their entry into human cells - contains the instructions for human cells to synthesize spike protein. The proteins thus produced will stimulate the immune system to produce specific antibodies 200. This messenger RNA, compared to that of viral origin, presents changes to consider, the most important of which is the replacement of uracil with the 1-methylpseudouridine base (U vs Ψ) 236; modifications that allow it to evade the immune system to be used correctly by ribosomes 208,209. This vaccine's side-effects were mild including pain at the injection site, headaches and fatigue. Anaphylaxis has been reported in two vaccinated people in the UK 201. This vaccine has received regulatory approval in multiple territories 201.
The Moderna vaccine is very similar to the Pfizer vaccine, the main differences being in the quantity of RNA (Moderna has more) and the lipids used for formulating the nanoparticles 223.
Adenoviral vector vaccines
The adenovirus vector type of vaccine is typified by the annual influenza vaccine. Several SARS-CoV-2 vaccines are based on a viral vector platform, such as the Oxford-AstraZeneca vaccine which was developed in the UK at the University of Oxford 222-224. It relies on a modified adenovirus to deliver the genetic material to the target cell.
Other vaccines using adenovirus vector technology are the Sputnik V vaccine (developed by the Gamaleya Research Institute, Russia) and the Janssen-Johnson & Johnson vaccines (jointly developed in the Netherlands and USA).
High efficacy has been demonstrated for the AstraZeneca vaccine in symptomatic patients with COVID-19 in randomized controlled trials 224,225.
Inactivated vaccines historically were the most common form of the vaccine (e.g. rabies vaccine). They rely on creating an inert form of the virus that primes the immune system without leading to the disease. The Sinopharm vaccine (developed by the Beijing Institute of Biological Products Company in China) is one such agent employing an inactivated form of the SARS-CoV-2 virus particle 223.
In early 2020 there were concerns raised about the safety of non-steroidal anti-inflammatory drugs (NSAIDs) in those with COVID-19. This was based upon anecdotal reports and expert opinion rather than published scientific evidence 61,166. There remains no evidence that the use of NSAIDs increases the risk of developing COVID-19 or worsens established disease 166.
Since the SARS-CoV-2 virus acts via the angiotensin-converting enzyme 2 (ACE2) receptor, there have been questions raised about the effect that being on ACE inhibitors or angiotensin receptor blockers might have on COVID-19. A randomized controlled trial in Brazil could find no difference in survival between those stopping or continuing taking the agents 214.
In Italy, a document detailing 6801 patients who died from COVID-19 discovered that the median time from the first symptoms to hospital admission was five days, and nine days from symptom onset to death 178.
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.
In a study of 101 patients with COVID-19 who were referred for palliative care, breathlessness, delirium, drowsiness and agitation were the most frequently found symptoms 180.
Risk factors for severe illness or poor outcome
Studies have shown that the most important risk factors for poor outcomes are increasing age, male sex and obesity 68,95,188. Indeed obesity seems to trump all other comorbidities as a risk factor and its risk is not limited to inpatient populations 188.
- vitamin D deficiency 190-195
- old age
- male gender
- people in a long-term care facility or nursing home
- comorbidities 68,95,188
- patient condition and laboratory values at hospital admission 96
There is no evidence that pregnant women are more likely to contract COVID-19 or more likely to experience complications from it 152,210. In a cohort of 427 women in the UK, 10% required admission to critical care for respiratory support and 1% succumbed to the disease 152.
The imaging of pregnant COVID-19 patients has found the same typical CT findings as other infected adults 210.
"Long covid" has been used to refer to the condition whereby those who have recovered from COVID-19 still experience persistent manifestations or those with COVID-19 suffer symptoms for a longer time than normal 177.
As of September 2021, there is growing published evidence of the long term effects following COVID-19 infection. An Italian study of 143 patients who had been discharged from hospital following a recovery from COVID-19 reveals that almost 90% of people were still complaining of at least one symptom 60 days after the illness had begun 176. Common symptoms included lethargy, breathlessness, arthralgia and chest discomfort 176.
History and etymology
The first cases were seen in Wuhan, China, in early December 2019 before spreading globally 1,2,10.
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 neighboring 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 Organization 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 Organization (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 on 3 April 2020, two million on 15 April, five million on 21 May, 10 million on 28 June, 15 million on 23 July, 20 million on 11 August, 25 million on 30 August, 50 million on 7 November 2020, 100 million on 26 January 2021 and 250 million on 8 November 2021 5. The number of global deaths surpassed 100,000 on 10 April, 200,000 on 26 April, 500,000 on 28 June, 750,000 on 13 August, one million on 29 September 2020, two million on 15 January 2021, three million on 17 April 2021, four million on 9 July 2021, and five million on 1 November 2021 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.
viral pneumonia including 71,72:
influenza pneumonia A and B
- distribution more along the bronchovascular bundles
- bronchial wall thickening
- paramyxovirus pneumonia
- cytomegalovirus (CMV) pneumonia
- adenovirus pneumonia 71,72
- SARS-CoV pneumonia
- MERS coronavirus
- in immunocompromised patients
- often shows pleural effusions
- respiratory syncytial virus (RSV) pneumonia
- influenza pneumonia A and B
- atypical bacterial pneumonia
- community-acquired pneumonias 175
- pulmonary edema 71
- interstitial lung disease 73
- certain drug-induced pneumonitides
- neutropenic sepsis
- aspiration pneumonitis
- for a "crazy paving" predominant manifestation also consider conditions such as
Clinical differential diagnoses
The clinical differential diagnosis is very similar to the imaging differential when patients present with typical symptoms, e.g. cough and fever. However, some divergence might be seen if there are less typical presentations, e.g. acute breathlessness, which might raise suspicion for acute pulmonary embolism which is not an imaging differential in many cases 134.
These lists are in alphabetical order:
- general information
- research publications and datasets
- ARRS - AJR Open Access COVID-19 Collection
- British Medical Journal COVID-19 collection
- COVID-19 Open Research Dataset (CORD-19)
- European Radiology COVID-19 - latest articles
- New England Journal of Medicine COVID-19 resources
- RSNA COVID-19 research
- The Lancet COVID-19 resource center
- World Health Organization Database of publications on COVID-19
- government information
- Australia (Department of Health)
- Australia (Smartraveller)
- Canada (Government of Canada)
- Canada (Infection Prevention and Control Canada)
- Europe (European Center for Disease Prevention and Control)
- Israel (Ministry of Health)
- Italy (Dipartimento della Protezione Civile)
- Mexico (Secretaría de Salud)
- New Zealand (Ministry of Health)
- Singapore (Ministry of Health)
- United Kingdom (National Health Service UK)
- United States of America (Centers for Disease Control and Prevention)
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