History
Coronavirus disease was first described in 1931, with the first coronavirus (HCoV-229E) isolated from humans in 1965. Until the outbreak of severe acute respiratory syndrome in late 2002, only two human coronaviruses (HCoV) were known – HCoV-229E and HCoV-OC43. Once the SARS coronavirus (SARS-CoV) had been identified, two further human coronaviruses were identified. Three groups of coronaviruses exist: group 1 (HCoV-229E and HCoV-NL63), group 2 (HCoVOC43 and HCoV-HKU1), group 3 (no human CoVs as yet). SARS-CoV is an outlier to all three groups, although some place it in group 2.
Fig. 1.
Coronavirus.
Fig. 2.
Replication cycle of coronaviruses.
Table 1.
Classification
| Order: Nidovirales | |
|---|---|
| Family: Coronaviridae | |
| Genus | Species |
| Coronavirus | Human coronavirus 229E |
| Human coronavirus OC43 | |
| Human coronavirus NL63 | |
| Human coronavirus HKU1 | |
| Severe acute respiratory syndrome coronavirus | |
| Human enteric coronavirus | |
| Torovirus | Human torovirus |
Table 2.
Structure and replication
| Structure | |
|---|---|
|
|
Table 3.
Structure and replication
| Replication |
|---|
Group 1 and 2 coronaviruses
Epidemiology
All four of these human coronaviruses have been reported from around the world. Most studies have focused on children, where disease is more significant, although they infect adults as well. Infections are seen throughout the year, although more often in winter and spring, with larger outbreaks every 2–4 years.
Pathogenesis
Viruses enter the respiratory tract, where they replicate in the epithelial cells of the upper respiratory tract. Spread to the lower respiratory tract occurs.
Shedding of virus is from the respiratory tract during acute infection, and virus may continue to be shed for some time from the gastrointestinal tract after recovery.
Clinical picture
Coronaviruses are an important cause of the common cold – 2–10%, second after rhinoviruses. In adults, the illness is usually limited to common cold symptoms of rhinitis, sore throat and sometimes coughing. In asthmatic patients, and patients with chronic bronchitis and other chronic lung diseases, the underlying illness may be worsened.
In infants, the infection can be more severe, causing tracheolaryngobronchitis (croup), bronchitis and pneumonia.
Diagnosis
Due to the mild and passing nature of the illness, diagnosis is seldom required and is usually limited to diagnosis in the recovery period or of past infections in epidemiological studies. Few laboratories test for coronaviruses, and fewer offer such testing as a diagnostic service. In more severe cases of infection in infants, many other more treatable causes are usually excluded first. The future may hold easier access to rarer diagnostic tests such as these:
Serology: this is of little clinical use; it is used for epidemiological purposes.
Isolation: cell culture, e.g. vero cells.
Molecular: polymerase chain reaction (PCR) – usually used in specialised centres.
Specific treatment
There is no specific treatment for coronaviruses. Treatment is symptomatic and supportive.
Prevention
General hygiene and disinfection can prevent person-to-person spread. No vaccine is available.
Severe acute respiratory CoV
Epidemiology
Between November 2002 and July 2003, 8096 probable SARS cases were reported to the World Health Organization. The total number of deaths rose to 774, with a case mortality rate of 9.6%. Since then, three laboratory-associated outbreaks occurred, with a total of 11 cases. Since then SARS has not been circulating.
SARS-CoV entered the human population from an animal source – several animals have been found to have very closely related viruses. The epidemic began in Guangdong province, China, from where it spread to Vietnam and Hong Kong, and then to other countries. Spread of the virus was via respiratory droplets and, therefore, contact with surfaces was important. Since it was excreted via the gastrointestinal tract, faecal–oral transfer was a possibility. Certain individuals, called super-spreaders, were more infectious than others, and are thought to have been responsible for most cases of transmission. The incubation period was 4–6 (range 1–14) days and patients were only infectious during the symptomatic period and most infectious during the second week of illness.
Pathogenesis
Determining the pathogenesis of SARS was difficult, based on autopsy findings confused by the effects of treatment, e.g. ventilation and medication. The virus replicates in the lower respiratory tract, followed by an innate and a specific immune response, and both viral factors and immune response (e.g. cytokine dysregulation) play a role in the pathogenesis. The first stage of the disease is associated with diffuse alveolar damage, macrophage and T-cell infiltration, and type 2 pneumocyte proliferation. The pulmonary infiltrate appears patchy on the chest X-ray. In the second stage, organisation occurs. The infection is not limited to the pulmonary system. The virus replicates in enterocytes, resulting in diarrhoea, and is shed in the stool, as well as urine, and possibly other body fluids.
Clinical picture
The first phase of the disease consists of fever > 38°C with rigors, myalgia, sore throat and gastrointestinal symptoms, with cough and often shortness of breath beginning after about 3–7 days of symptoms. Hypoxia may develop and 10–20% require ventilation. A relative lymphopenia and neutropenia may occur. Some patients showed a biphasic course, with apparent recovery followed by worsening of the clinical condition. Mortality was highest in the elderly and lowest in the younger population, and co-existing illness worsened morbidity and mortality.
Diagnosis
Initially, the aetiological agent had to be identified, and this was done rapidly, through a concerted effort of scientists from around the world, using a combination of: serological techniques, viral culture, electron microscopy, histopathology and molecular methods to narrow the list of potential agents down to the point where the specific coronavirus was known. This was a remarkable case study in the identification of an unknown organism.
Important in the individual patient's diagnosis of SARS was the exclusion of other organisms that could cause similar pathology, as well as the establishment of an epidemiological link:
Serology: presence of antibodies indicated infection, and formed part of the diagnostic criteria (a four-fold rise in titre, or seroconversion).
Isolation: electron microscopy (Fig. 3 ).
Cell culture: vero cells.
(Diagnostic criteria required confirmation by polymerase chain reaction (PCR) to identify the virus as SARS-CoV.)
Molecular: reverse-transcription PCR (two or more primer sets on the same positive sample or two or more positive samples were required in the diagnostic criteria).
Fig. 3.
Coronaviruses as seen under an electron microscope.
(Photo courtesy of CDC/Fred Murphy.)
Specific treatment
Supportive treatment, such as ventilation, was the centrepiece of the management of a SARS patient. Specific treatments, such as steroids, remain controversial regarding their effect, whether adverse or beneficial, on SARS patients. Ribavirin was used, as it is a broad-spectrum guanosine analogue, and appeared to have some benefit, as did other agents that have an effect on the inflammatory response, such as chloroquine and interferon, and agents that interfere with coronavirus protease activity, such as the lopinavir/ritonavir combination used for HIV treatment. SARS-specific immunoglobulin was also tried. The degree to which any of these was successful as treatment is still debated.
Prevention
Isolation of infected patients and quarantine of exposed people, along with disinfection and infection control precautions, were the key to prevention of spread. A vaccine has been investigated, but may be merely an academic measure, relevant to future vaccine research, since the epidemic is over and SARS is no longer circulating.
Stop/Think.
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What other infectious agents cause epidemics and pandemics?
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What clinically relevant new viruses have been discovered recently?
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In which other infections does the immune response play an important role in causing pathology?
Key points.
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Severe acute respiratory syndrome (SARS) is no longer circulating in the human population, but laboratory stocks exist.
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Coronaviruses are common causes of colds in adults and important causes of croup and lower respiratory tract infection in infants.
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Facilities to detect and diagnose coronavirus infection are scarce.