Middle East Respiratory Syndrome

Abstract

Between September 2012 and January 20, 2017, the World Health Organization (WHO) received reports from 27 countries of 1879 laboratory-confirmed cases in humans of the Middle East respiratory syndrome (MERS) caused by infection with the MERS coronavirus (MERS-CoV) and at least 659 related deaths. Cases of MERS-CoV infection continue to occur, including sporadic zoonotic infections in humans across the Arabian Peninsula, occasional importations and associated clusters in other regions, and outbreaks of nonsustained human-to-human transmission in health care settings. Dromedary camels are considered to be the most likely source of animal-to-human transmission. MERS-CoV enters host cells after binding the dipeptidyl peptidase 4 (DPP-4) receptor and the carcinoembryonic antigen–related cell-adhesion molecule 5 (CEACAM5) cofactor ligand, and it replicates efficiently in the human respiratory epithelium. Illness begins after an incubation period of 2 to 14 days and frequently results in hypoxemic respiratory failure and the need for multiorgan support. However, asymptomatic and mild cases also occur. Real-time reverse-transcription–polymerase-chain-reaction (RT-PCR) testing of respiratory secretions is the mainstay for diagnosis, and samples from the lower respiratory tract have the greatest yield among seriously ill patients. There is no antiviral therapy of proven efficacy, and thus treatment remains largely supportive; potential vaccines are at an early developmental stage. There are multiple gaps in knowledge regarding the evolution and transmission of the virus, disease pathogenesis, treatment, and prospects for a vaccine. The ongoing occurrence of MERS in humans and the associated high mortality call for a continued collaborative approach toward gaining a better understanding of the infection both in humans and in animals.

MERS-CoV was first identified in September 2012 in a patient from Saudi Arabia who had hypoxemic respiratory failure and multiorgan illness. Subsequent cases have included infections in humans across the Arabian Peninsula, occasional importations and associated clusters in other regions, and outbreaks of nonsustained human-to-human transmission in health care settings (Fig. 1).

Figure 1. Confirmed Cases of the Middle East Respiratory Syndrome.

Data are from the World Health Organization (www.who.int/emergencies/mers-cov/en) and were collected through December 31, 2016.

Figure 2. Geographic Distribution of the Middle East Respiratory Syndrome.

Data are from the World Health Organization (www.who.int/emergencies/mers-cov/mers-summary-2016.pdf) and were collected through December 2, 2016. At that time, the total number of cases was 1841.

Figure 3. Transmission Patterns and Pathogenesis of the Middle East Respiratory Syndrome Coronavirus.

Panel A shows the structure, ecologic features, and transmission patterns of the Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV). The virion surface is covered with the spike glycoprotein, a 149 kDa glycoprotein that extends outward to create a crownlike appearance. The spike glycoprotein is critical for binding the host-cell receptor, dipeptidyl peptidase 4 (DPP-4), to initiate infection. Dromedary camels are infected with the virus and are believed to be the most likely source of animal-to-human transmission. Human-to-human transmission in household and health care settings has also occurred. Panel B shows the current understanding of key events in MERS pathogenesis, which is based on limited observations in patients and data from animal and cell-culture model systems. After intratracheal inoculation of MERS-CoV in nonhuman primates, the virus infects bronchial epithelial cells through DPP-4 before spreading to lung parenchymal cells, including type I and type II alveolar pneumocytes and endothelial cells. Viral entry is facilitated by another cell-surface protein, carcinoembryonic antigen–related cell-adhesion molecule 5 (CEACAM5), which is also expressed in lung tissue. Inflammatory signaling molecules that are released by infected cells, alveolar macrophages, and neutrophils recruited to infected tissue have been detected in infected patients (black text) and animal models (blue text). A host antiviral type I and type III interferon response occurs, with systemic release of proinflammatory cytokines and chemokines., The virus may spread into the circulation, possibly from lung parenchyma or through infected endothelial cells. In humans, a high viral copy number has been detected in the lower respiratory tract, including tracheal aspirates and bronchoalveolar lavage specimens, as well as in peripheral blood. In advanced disease, diffuse alveolar damage is seen, with extensive hemorrhagic edema and hyaline membrane deposition. CXCL10 denotes C-X-C motif chemokine 10, IL interleukin, IL-1RA IL-1 receptor antagonist, IFN interferon, and MCP monocyte chemotactic protein.