Global Alert and Response (GAR)

Novel coronavirus summary and literature update – as of 25 April 2013

This update has been changed to reflect a correction in the number of deaths.

As of 25 April 2013, 17 cases of human infection with novel coronavirus (nCoV) have been reported to WHO: two from Jordan, two from Qatar, 10 cases from Saudi Arabia, two from the United Kingdom (UK), and one from the United Arab Emirates. Most patients are male (81.3%; 13 of 16 cases with gender reported) and range in age from 25 to 73 years old (median 45 years old). The first cases had onset of illness in late March or early April 2012, the most recent case reported had onset on 8 March 2013. Most patients presented with severe acute respiratory disease requiring hospitalization, and at least 11 have required mechanical ventilation or other advanced respiratory support. Only 2 of the 17 presented with mild disease. Eleven patients have died. One was co-infected with influenza A virus.

Four clusters of cases have been identified. The first occurred in April 2012 in a health care setting in Jordan, with 2 confirmed cases, and 11 probable cases. Both of the confirmed cases died. Ten of the 13 persons in this cluster were health care workers. Two additional clusters occurred among family contacts of cases in Saudi Arabia and one among family members of a resident of the United Kingdom who had recently visited Saudi Arabia. Human-to-human transmission can be confirmed only in the latter as none of the family members who were infected had recently been outside of the United Kingdom and their only known exposure was to the first case (see UKHPA reference below). No sustained community transmission was observed in any of the clusters.

Although some of the cases may have become infected from animal exposures and zoonotic transmission, information on animal exposures is limited. An animal reservoir has not been identified. Investigations into animal sources are on-going.

Four viruses from the United Kingdom (n=2), Saudi Arabia (n=1) and Jordan (n=1) have been cultured and complete genome sequences have been posted to GenBank, a public database. All four of the viruses have a high degree of genetic similarity. Analyses show that the viruses are similar to a bat virus. It should be noted, however, that the similarity of the human virus to the bat virus does not necessarily imply that bats are the reservoir for the human virus. Given the living environment of most of the patients, direct exposure to bats appears unlikely.

Recent publications

  • Detailed descriptions of some of the patients can be found in the following:
    • Zaki AM et al. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. New England Journal of Medicine, 8 Nov 2012, 367(19):1814-20.
    • Pebody RG et al. The United Kingdom public health response to an imported laboratory confirmed case of a novel coronavirus in September 2012. Eurosurveillance, 4 Oct 2012, 17(40):20292.
    • Bermingham A et al. Severe respiratory illness caused by a novel coronavirus, in a patient transferred to the United Kingdom from the Middle East, September 2012. Eurosurveillance, 4 Oct 2012, 17(40):20290; and
    • Albarrak AM et al. Recovery from severe novel coronavirus infection. Saudi Medical Journal, Dec 2012, 33(12):1265-9.
  • An investigation of 123 hospital and out-of-hospital contacts of the first nCoV case identified in Germany was conducted to evaluate human-to-human transmission. 86 contacts provided a blood sample. Analysis was performed using a two-stage serologic testing approach. None of the contacts tested positive for antibodies of the nCoV, indicating that no transmission had occurred. Reference: Buchholz U et al. Contact investigation of a case of human novel coronavirus infection treated in a German hospital, October-November 2012. Eurosurveillance, Feb 2013, 18(8):pii=20406. Available online at:
    http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20406
  • The UK Health Protection Agency (now known as Public Health England) investigated contacts of a nCoV case returning from Pakistan and Saudi Arabia. The investigation found two secondary cases (of 135 contacts tested) among family members, one of whom died, and one of which was mild. As the secondary cases had not travelled outside of the United Kingdom, this cluster provides the first definitive evidence of human-to-human transmission. It is also the first report of a co-infection, as the first case in the cluster was also infected with influenza type A. Reference: The Health Protection Agency (HPA) UK Novel Coronavirus Investigation team. Evidence of person-to-person transmission within a family cluster of novel coronavirus infections, United Kingdom, February 2013. Eurosurveillance, March 2013, 18(11):pii=20427. Available online at:
    http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20427
  • Munster et al recently described a nonhuman primate disease model for hCoV-EMC/2012 using rhesus macaques. The study demonstrated a causal relationship between hCoV-EMC and respiratory disease. Reference: Munster VJ, de Wit E, Feldmann H. Pneumonia from Human Coronavirus in a Macaque Model. New England Journal of Medicine, 3 April 2013 [Epub ahead of print]. Available online at:
    http://www.nejm.org/doi/full/10.1056/NEJMc1215691
  • Several laboratories are working to develop and validate serologic assays for nCoV. Two approaches for serologic testing have recently been published:
  • A study at the University of Bonn found that the cellular receptor for novel coronavirus is different from that used by the coronavirus SARS-CoV, which causes Severe Acute Respiratory Syndrome. In addition, the investigators found that the virus is capable of infecting human, pig, and bat cells. Reference: Müller MA et al. Human coronavirus EMC does not require the SARS-coronavirus receptor and maintains broad replicative capability in mammalian cell lines. mBio 2012, 3(6):e00515-12. doi:10.1128/mBio.00515-12.
  • Investigators at the Institute of Immunology in St. Galen, Switzerland, found that human bronchial epithelia are highly susceptible to infection with the novel coronavirus. In addition, they found that type I and type III interferon treatment can efficiently reduce replication of the virus in cell cultures of human airway epithelium, suggesting a direction for future clinical research. Reference: Kindler E et al. Efficient replication of the novel human betacoronavirus EMC on primary human epithelium highlights its zoonotic potential. mBio 2013, 4(1):e00611-12. doi:10.1128/mBio.00611-12.
  • The United States of America National Institutes of Health have found that a combination of two licensed antiviral drugs, ribavirin and interferon-alpha 2b, can inhibit replication of the virus in cell cultures. Reference: Falzarano et al. Inhibition of novel human coronavirus-EMC replication by a combination of interferon-alpha2b and ribavirin. Scientific Reports 2013, doi: 10.1038/srep01686.

Summary

The available evidence related to novel coronavirus continues to suggest a zoonotic origin for the virus. However, the cluster of cases reported by the United Kingdom provides strong evidence of human-to-human transmission, confirming suspicions that were raised in the previously reported clusters. Investigations around cases have not thus far uncovered evidence of sustained transmission in the community, and transmission between humans appears to be relatively uncommon. The availability of serological tests and the recently acquired capacity to test for the virus using sensitive PCR techniques provide an opportunity to expand our knowledge of the occurrence of the virus in the community.

Many questions remain to be answered. The most important are the source of the virus, the exposures that result in human infection, and the mode of transmission. Some features of the cases such as the predominance of males among the confirmed cases may provide important clues to relevant exposures. In addition, although all cases to date have had some connection with the Arabian peninsula, more information is needed about the true geographic extent of the virus. Available evidence suggests that the virus may have its origin in bat species. However, experience with Nipah virus in Malaysia and SARS in China both illustrate that intermediate hosts may sometimes play an important role in transmission to humans and that direct exposure to reservoir species is not needed for infection. The experience of Nipah virus in Bangladesh, in which consumption of raw palm sap contaminated by bat feces has been identified as the mode of transmission, also illustrates the sometimes complex route by which virus may be transmitted from source to human. Finally, if more cases occur, it will be important to study clinical management methods in light of new research demonstrating the effect of certain antiviral agents on laboratory growth of the virus. Protocols for clinical management trials should be developed in anticipation of future cases.

In addition to the kinds of investigations described above, there continues to be a need for vigilance and surveillance, both within the affected area and for unusual clusters of respiratory disease in other parts of the world.

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