Human coronaviruses (HCoV) are single-stranded RNA viruses. There are currently four so-called “classic” or “new” coronaviruses, which circulate in winter. They are the cause of moderate respiratory infections in the general population.

However, infections can be more severe in susceptible populations. In particular, HCoVs are involved in 2 to 7% of hospitalizations consecutive to a respiratory infection, in particular in children and the elderly or immunocompromised.

Therefore, they belong to the panel of respiratory viruses sought during the routine diagnosis of respiratory infections using molecular biology tools. These so-called circulating coronaviruses are to be distinguished from the two emerging coronaviruses, SARS-CoV and MERS-CoV which are associated with more severe respiratory pathologies.

They are distinguished from other HCoVs by their higher epidemic potential, their greater health impact and their atypical mode of circulation. Like paramyxoviruses and Influenza viruses, coronaviruses should be monitored for their risk of emergence into the human population from an animal reservoir.

Introduction Human coronaviruses (HCoV) are the cause of more or less severe respiratory infections depending on the population studied. To date, six human coronaviruses have been described. Among them, two so-called “classic” coronaviruses, the HCoVOC43 and -229E, were identified in the 1960s. The two HCoV-NL63 and -HKU1, are said to be “new” because they were identified more recently, in the early 2000s .

These HCoVs are generally associated with mild respiratory infections. They are to be distinguished from the two emerging HCoVs, SARS-CoV (Severe acute respiratory syndrome associated coronavirus) and MERS-CoV (Middle-East respiratory syndrome coronavirus), which are the only ones to be associated with acute respiratory distress syndrome or ARDS.

Taxonomy and history of coronaviruses

The term coronavirus refers to the subfamily Coronavirinae, belonging to the family Coronaviridae, itself belonging to the order of Nidovirals. Coronaviruses infect many mammalian and avian species. According to current taxonomy, the Coronavirinae are subdivided into four genera named Alpha-, Beta-, Gamma- and Deltacoronavirus. HCoV-229E and -NL63 belong to the genus Alphacoronavirus.

The other four human coronaviruses belong to the genus Betacoronavirus which is itself subdivided into four clades named A, B, C and D. HCoV-HKU1 and –OC43 are included in clade A, SARS-CoV and MERS-CoV belong to clades B and C respectively. Coronaviruses have been known in the veterinary community since the late 1930s. When the first human coronaviruses HCoV-OC43 and -229E were identified in the 1960s, around twenty coronaviruses infecting avian animal species (chicken) and mammals ( dog, cat, pig, cattle, etc.) were already described.

Coronavirinae phylogenetic tree including 51 complete genomes, constructed by the Neighbor-joining method (MEGA6)

When these first HCoVs were identified, the associated respiratory pathologies were considered too moderate to arouse marked interest in the medical community.

In 2003, the identification of a coronavirus as being the etiological agent of Severe Acute Respiratory Syndrome (SARS), circulating in a pandemic since November 2002, generated a new interest for this viral group hitherto little studied in human medicine . Since the identification of SARSCoV, numerous coronaviruses have been described, including two infecting humans, HCoV-NL63 and -HKU1 in 2004. Finally, in 2012, a new human coronavirus, the MERS-CoV, emerged in the Middle East. It is at the origin of a pathology similar to SARS

Clinical manifestations of coronavirus infections

“Classic” and “new” coronaviruses

The “classic” (HCoV-OC43 and HCoV229E) and “new” (HCoV-HKU1 and HCoV-NL63) coronaviruses are generally associated with mild infections of the upper respiratory tract. Coronavirus infections are characterized by non-specific symptoms that vary from patient to patient. In the general population, HCoV infection is most often associated with more or less symptomatic rhinitis or nasopharyngitis. When the infection is symptomatic, the most often described clinical signs are fever, cough, myalgia and nasal congestion.

The pathologies induced by the different HCoVs are similar and the clinical picture alone does not allow them to be distinguished from each other or from other respiratory viruses, such as rhinoviruses, Influenza viruses, metapneumoviruses, respiratory syncytium virus (RSV) or para influenza viruses (PIV).

In the elderly, young children and immunocompromised patients, more severe and even fatal respiratory tract infections may be seen. For example, HCoV-NL63 has been associated with bronchiolitis and broncho-tracheitis, two acute infections of the lower respiratory tract of infants. HCoV-HKU1 was identified for the first time in a patient suffering from pneumonia. Subsequently, it has been associated with community-acquired pneumonia, mainly in the elderly or with an underlying pathology. During an HCoV infection, moderate enteric pathology (gastroenteritis, diarrhea) is sometimes observed in addition to respiratory pathology.

To date, it is not yet clearly defined whether enteric involvement is an indirect consequence of the infection or whether HCoVs have a proven enteric tropism. HCoV have repeatedly been implicated in neurological damage. Several studies already old tend in particular to associate them with multiple sclerosis (MS). The first speculations as to the implication of a coronavirus in MS date back to the 1980s. Studies were then based on the observation of particles similar to coronaviruses in the brains of patients who died of MS or on the detection of antibodies directed against coronaviruses, particularly HCoV-229E and HCoV-OC43.

More recently, molecular studies have detected the RNAs of these coronaviruses in brain-spinal fluids or in the brains of patients, some of whom had MS or other neurological disorders, but also within a control group. These data suggest a neuroinvasive potential of these coronaviruses, but their implication in the development of neurological pathologies is debated.

Severe Acute Respiratory Syndrome or SARS

The term SARS designates the pathology induced by SARS-CoV. This is a coronavirus which emerged in November 2002 and which circulated pandemic until July 2003. SARS-CoV is characterized by an incubation period of 2 to 14 days. The first symptoms observed are a high fever, above 38 ° C, as well as a moderate respiratory syndrome. Coughs, headache or throat pain and general tiredness have also been reported in some patients.

In a few days, the symptoms progress, causing an acute respiratory distress syndrome which may require respiratory aid in the most susceptible patients. During SARS-CoV infection, neutrophilic leukocytes and macrophages infiltrate the lungs and initiate an inflammatory response. The level of pro-inflammatory cytokines increases, while lymphopenia is observed. These phenomena are at the origin of the alterations which occur in the lungs, in particular, of diffuse alveolar damage (DAD).

At the same time, a formation of hyaline membranes and edemas is observed. These morphological alterations result in hypoxia. In a second step, DAD is associated with hyperplasia of type II pneumocytes and with scaly metaplasia, these two characteristics being indicative of a process of scarring of the lungs. The worsening of these histological changes can lead to severe pneumonia and death of the patient. On radiography, unilateral or bilateral condensation of the lungs is observed.

Transmission of SARS-CoV is mainly via respiratory secretions emitted by an infected person. A few cases of asymptomatic infections and mild upper respiratory pathologies associated with SARS-CoV have been detected. In many patients infected with SARS-CoV, digestive disorders most often characterized by watery diarrhea have been described.

The presence of SARS-CoV in the intestinal epithelium has also been highlighted. However, observation of intestinal tissue from colonoscopies and necropsies did not reveal morphological alterations following viral replication of SARS-CoV in the intestine. The highest proportion of digestive disorders associated with SARS-CoV was observed in Hong Kong during a community epidemic that broke out in the Amoy Gardens residential complex. During this epidemic, 73% of the 321 infected patients developed digestive disorders in addition to respiratory symptoms.

This epidemic is believed to have originated in a defect in the wastewater management system within the residence, leading to the emission of contaminated aerosols via the pipes. SARS-CoV is detected in the blood very early after the onset of symptoms. This viremia may explain the presence of SARS-CoV in the intestine and in the stool, but swallowing may also play a role.

SARS-CoV is excreted in the stool up to about 20 days after the onset of symptoms. One of the best markers of infection is the presence of SARS-CoV in the stool. However, attempts to isolate SARS-CoV from stool samples have never been successful.