OVERVIEW: What every clinician needs to know

Pathogen name and classification

Coronaviruses are in the family Nidovirus. There are six species of coronaviruses that infect humans and many others that infect animals.

The coronaviruses that cause human disease are found in two genera: alphacoronaviruses (HCoV-229E, HCoV-NL63) and betacoronaviruses (HCoV-HKU1, HCoV-OC43, and the coronavirus associated with Severe Acute Respiratory Syndrome (SARS)). There is an additional novel betacoronavirus, identified in 2012, that can cause human disease – Middle East Respiratory Syndrome Coronavirus (MERS CoV).

What is the best treatment?

There are currently no recommended antiviral treatments for coronavirus infections in humans.
Supportive care is recommended
During the SARS outbreak from 2002 to 2004, patients were treated with corticosteroids and ribavirin, but there are no data to suggest these therapies were beneficial.
In MERS CoV, studies in non-human primates have shown some efficacy of IFN-alpha-2b plus ribavirin, and a retrospective cohort study of IFN-alpha-2a with ribavirin in humans have shown improved survival at 14 but not 28 days, but there are no prospective trial outcomes of combination in humans.
There are no applicable data on antiviral resistance.

How do patients contract this infection, and how do I prevent spread to other patients?

Epidemiology

In temperate climates, the four non-SARS, non-MERS CoV human coronaviruses (HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1) occur primarily in the winter months. However, infections have been detected throughout the year.

Spread is by contact with infected secretions or by large aerosol droplets, so close contact increases risk of transmission. Caretakers or healthcare workers may spread infections in hospitals or nursing homes.

For the SARS coronavirus, the rapid outbreaks identified in Hong Kong and elsewhere suggested that airborne (e.g., on an airplane or via building ventilation systems) or fecal-oral spread may also be possible.

For MERS CoV, all cases and clusters have either occurred in Saudi Arabia and surrounding countries in the Arabian Peninsula, or have been linked by travel to this area. Current evidence points to camels as primary hosts and a likely animal source for human cases, though bats also are a reservoir. Person to person transmission has been seen in case clusters, mostly in healthcare facilities, and involve close contact in the absence of infection control precautions – the mechanism is felt to be droplet or contact transmission as with other coronaviruses.

Updated information can be obtained via the CDC website. www.cdc.gov/coronavirus/MERS.

Exposure to or eating civet cats in China has been associated with SARS.

Coronaviruses are found throughout the world. The exact prevalence and distribution is unknown because of the variability in assay types and utilization.

It is unknown if there are true increases in prevalence, as testing methods, including polymerase chain reaction (PCR), have rapidly improved following the SARS outbreaks of 2002-2004. The differences in testing methods over time make it difficult to interpret trends in the epidemiology of coronaviruses before 2002.

Infection control issues

Coronaviruses are more easily spread among hospitalized or institutionalized populations or others in closed conditions.

Strict infection control measures, both for airborne droplets as well as surface contact precautions, can reduce the risk of transmission of all coronaviruses.

The U.S. Centers for Disease Control recommend heightened infection control measures including contact and airborne precautions for hospitalized patients with suspected or confirmed MERS CoV infection.

Preventive Measures

There are no vaccines against the non-SARS coronaviruses and no plans to develop them, given antigenic variation within the four known species and the fact that others are likely to be discovered.

There has been strong interest in developing a SARS vaccine, and several candidates are in the stages of animal testing. The primary target of vaccine has been the S surface glycoprotein, which is necessary for neutralizing antibody responses in vitro. There have been no studies in humans.

Monoclonal antibodies against the S glycoprotein on the SARS coronavirus have also shown initial promise in in vitro studies, and further investigation is ongoing.

Candidate vaccines against MERS CoV are under investigation.

There are no recommendations for post-exposure prophylaxis for any of the human coronaviruses.

What host factors protect against this infection?

Knowledge of factors that confer protection against clinical disease with coronaviruses is limited.

In patients who survive SARS, cell mediated and innate immunity both appear to play an important role.

In MERS CoV, increasing age and pre-existing concurrent health conditions are associated with mortality. It is not known what specific host factors may be protective.

What are the clinical manifestations of infection with this organism?

Two of the four non-SARS human coronaviruses (HCoV-229E and HCoV-OC43) can cause symptoms of the common cold in healthy human volunteers, with upper respiratory congestion and rhinorrhea. It is assumed that the other two (HCoV-NL63 and HCoV-HKU1) can do the same, but this has not been experimentally proven.
The clinical syndromes of HCoV-229E and HCoV-OC43 are very similar to rhinoviruses.
In addition to acute upper respiratory tract infections, coronaviruses have also been linked to otitis media, asthma exacerbations, and community acquired pneumonias in children and adults.
There are some studies that link coronaviruses to diarrhea disease in infants; however, no clear causal link has yet been determined.
For SARS, most cases of severe disease occurred among adults, not children.
Those at most risk for severe disease and death from SARS include the elderly, those with diabetes or other comorbid conditions, those with an atypical presentation, and those with high LDH.
Most patients with SARS presented with a nonspecific viral prodrome with malaise, fatigue, and fever. Respiratory symptoms were not initially present, but dyspnea progressing to respiratory distress followed in patients who developed severe illness. This lung disease is the hallmark of SARS, and patients most often died of respiratory distress and multi-organ failure.
As with SARS, the primary clinical feature in MERS CoV has been fever and severe pulmonary disease, including pneumonia and acute respiratory distress syndrome. A subset of cases have additionally developed acute kidney injury. Other less common findings include pericarditis, nausea, vomiting, abdominal pain, diarrhea, and disseminated intravascular coagulation.
There are some indications that mild disease with MERS CoV is underreported and therefore underrepresented in the cases to date.

What common complications are associated with infection with this pathogen?

For the SARS coronavirus, acute respiratory distress syndrome (ARDS) and multi-organ failure were the most common causes of death.
In MERS CoV infection, mortality from reported cases is approximately 40%, primarily due to respiratory failure, shock and multi-organ failure.

How should I identify the organism?

Viral culture is difficult to perform and insensitive for coronavirus.
PCR is the test method of choice in patients with suspected coronavirus infections. However, most patients are not diagnosed outside of research or surveillance studies since there is no specific therapy available.
For suspected cases of SARS, PCR should be performed on two separate specimens, either from the same site (respiratory, stool, serum plasma) or the same specimen type on two separate occasions.
Acute and convalescent serum specimens for SARS enzyme-linked immunosorbent assay (ELISA) or indirect fluorescent antibody (IFA) should also be obtained. Recall that there have been no documented cases of SARS worldwide since 2004.
For diagnosis of MERS CoV, lower tract respiratory specimens (e.g. induced sputum, endotracheal aspirate, bronchoalveolar lavage) should be obtained for real-time reverse transcriptase polymerase chain reaction (rRT-PCR). If lower tract specimens are not feasible, or in mild illness, upper respiratory tract specimens such as nasopharyngeal swabs may be obtained.
Acute and convalescent sera should also be obtained for MERS CoV.
Updated information can be obtained via the CDC website www.cdc.gov/coronavirus/MERS
In the United States, consultation for suspected cases of MERS CoV may be obtained via the CDC Emergency Operations Center (770) 488-7100.

How does this organism cause disease?

The upper respiratory coronaviruses infect nasal epithelium and cause release of cytokines, much as rhinoviruses do, leading to rhinorrhea, congestion, and other symptoms of the common cold. Angiotensin Converting Enzyme 2 (ACE-2) is a receptor for HCoV-N63 and Aminopeptidase N for HCoV-229e.
The SARS coronavirus has an S glycoprotein that mediates infection via attachment to cells in the upper respiratory tract. ACE-2 is a receptor for SARS and is expressed on many cell types. The lungs are the almost exclusive target of infection, with the gastrointestinal (GI) tract second.
Lung pathogenesis is likely mediated by ACE2, which causes diffuse alveolar damage via the angiotensin-renin system. SARS 3a and 7a proteins also contribute to lung damage by inducing apoptosis in alveolar cells.
In SARS, severe cases are found to show a histopathologic pattern consistent with ARDS. As in other causes of ARDS, the initial phase reveals capillary congestion and resultant edema, followed by hyaline and fibroblast proliferation in the alveolar spaces, and finally, in the later organization phase, fibroblast proliferation in the alveolar septa.
DPP4 is the functional cellular receptor for MERS CoV, in contrast to SARS which has ACE-2 as its receptor.
MERS CoV appears to cause disregulation and apoptosis in the antigen presentation pathway compared to SARS, and so likely causes disease via different cellular pathways.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Balboni, A, Battilani, M, Prosperi, S. “The SARS-like coronaviruses: the role of bats and evolutionary relationships with SARS coronavirus”. New Microbiol. vol. 35. 2012 Jan. pp. 1-16. (This source details possible evolution of coronaviruses.)

Hui, DS, Chan, PK. “Severe acute respiratory syndrome and coronavirus”. Infect Dis Clin North Am. vol. 24. 2010 Sep. pp. 619-38. (This is a good review of epidemiology and clinical presentation.)

Prill, MM, Iwane, MK, Edwards, KM. “Human coronavirus in young children hospitalized for acute respiratory illness and asymptomatic controls”. Pediatr Infect Dis J. vol. 31. 2012 Mar. pp. 235-40. (This source attempts to assess how commonly coronaviruses may be the cause of respiratory illness in hospitalized children.)

Tseng, CT, Sbrana, E, Iwata-Yoshikawa, N. “Immunization with SARS coronavirus vaccines leads to pulmonary immunopathology on challenge with the SARS virus”. PLoS One. vol. 7. 2012. pp. e35421(This source highlights challenges of vaccine development for all human coronaviruses.)

Weiss, SR, Leibowitz, JL. “Coronavirus pathogenesis”. Adv Virus Res. vol. 81. 2011. pp. 85-164. (This is a good general overview of pathogenesis.)

Yu, IT, Xie, ZH, Tsoi, KK. “Why did outbreaks of severe acute respiratory syndrome occur in some hospital wards but not in others”. Clin Infect Dis. vol. 44. 2007 Apr 15. pp. 1017-25. (This source reviews epidemiology and infection control.)

“State of Knowledge and Data Gaps of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in Humans”. PLoS Curr. vol. 12. 2013 Nov. pp. 5(This source reviews current scientific and clinical understanding of MERS CoV and the remaining knowledge gaps.)

Rasmussen. (This source reviews epidemiology, diagnosis, and infection control for MERS-CoV for US clinicians.)

Coronaviruses (including SARS)