,

SUBMITTED:

November 2021

Accepted:

March 2022

W.M.J. Pelt, C. Nederstigt, J. van Paassen, D.J. van Westerloo

Department of Intensive Care, Leiden University Medical Centre, Leiden University, Leiden, the Netherlands

Correspondence:

W.M.J. Pelt - w.m.j.pelt@lumc.nl
Special Review

Potential pandemic pathogens series: MERS virus

Keywords:

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In the last two years we have experienced the effects of the COVID-19 pandemic in our lives and hospitals. Pandemics are part of the history of humanity and we can be certain that in the future new pandemics will appear. In fact, due to the growth in the human population, increased travel and global warming, it is to be expected that new pandemic pathogens will arise more frequently than before. Additionally, decreased barriers between animals and humans will give rise to spillover events, which will result in the introduction of new zoonotic pathogens in humans. In each of the parts of this series we will, in a short format, highlight a potential pandemic pathogen and describe its characteristics, history and potential for global pandemics. This part of the series focusses on MERS-CoV infection which, up until now, has been fairly contained in a small part of the world but definitely has traits that make it a pathogen to watch. As in previous parts of this series, we will highlight its clinical picture and explain why it should not be underestimated.

History of MERS virus
In June 2012, a 60-year-old man died of progressive respiratory and renal failure in the ICU of a hospital in Saudi Arabia.[1] Meticulous investigation of the respiratory samples led to the discovery of a novel coronavirus, named HCoV-EMC (for Erasmus Medical Centre in the Netherlands, where sequencing took place) as the most probable culprit. There was no evidence that other humans were infected at that point. Although it was suspected that bats might play a role in transmission, it remains unclear where this first patient contracted the virus. A few months later another previously healthy 49-year-old man was admitted to a Qatari and later a London hospital with predominantly pulmonary failure due to the same virus.[2] Other than a recent visit to Saudi Arabia there was no proven link with the first patient.

Following the case reports mentioned above, a hospital in Jordan decided to reinvestigate a cluster of patients who suffered from severe respiratory illness in April 2012, who in hindsight had been infected with the same virus.[3] Moreover, as multiple healthcare workers were infected during this outbreak, there was evidence for human-to-human transmission. Following these initial reports the virus kept popping up, but only in the Middle Eastern region, until 2015 when it surfaced in Korea. During the outbreak in Korea evidence for human-to-human superspreading events was identified.[4] By that time, in May 2015, the number of cases that were reported to the WHO had risen to 1180, of which 40% had died due to the infection.[5] As most cases where in that region (figure 1), the virus was renamed Middle East Respiratory Syndrome (MERS-CoV).[6]

MERS-CoV belongs to the family of beta coronaviruses, quite closely related to the also well-known Severe Acute Respiratory Syndrome (SARS-CoV)[1] and indeed COVID-19 (SARS-CoV-2). The danger of this particular virus was already very clear after the global outbreak of SARS-CoV in 2003, where it affected more than 8000 people in 25 countries and killed almost 800 people within a few months.[7] Even though coronaviruses were already first identified in 1960,[8] up until the SARS-CoV outbreak they were considered relatively simple, nonfatal illnesses, usually presenting as a common cold.[9] Nowadays, we have found out that indeed coronavirus outbreaks are very serious and may result in global pandemics and an astounding number of casualties illustrated by the fact that up until today more than 5 million people have died due to SARS-CoV-2 infection.

Similar to other coronaviruses, MERS-CoV is a virus with a zoonotic nature that probably originates from bats.[10] What makes the virus quite unique is the finding that dromedary camels can be intermediate hosts (figure 2). First evidence of this was in a case report of a 43-year-old Saudi male who died of the virus after he had contact with his sick camels. His nine camels were tested as well, one of them turned out to be infected with the same virus. Because this camel had been ill, the patient had applied a topical medicine in its nose seven days before he fell ill himself.[11] A study in 2018 found that 55% of 348 primary cases had contact with dromedaries, either directly or indirectly through consumption of animal products.[12] Further research has shown that the virus can also been found in other animals such as alpacas, llamas and Bactrian camels.[13] Despite this quite extensive research, the precise mode of transmission remains unclear, however.

Figure 1 NJCC V30-5

Clinical presentation
MERS-CoV has a median incubation period for human-to-human transmission of 5-7 days, with a range of 2-14 days.[9,14,15] However, in immunocompromised patients, incubation periods up to 20 days have been described.[16] It is thought that MERS-CoV enters host cells via a cellular receptor dipeptidyl peptidase 4 (DPP4). This receptor can be found most abundantly in human lower airways but also in, for example, epithelial cells and other organs such as the kidneys, intestine and liver.[17] This distinguishes the virus from SARS-CoV and SARS-CoV-2, as they both use the angiotensin-converting enzyme 2 (ACE2).[18] Although all three corona viruses lead to production of a wide array of pro-inflammatory cytokines and chemokines, in MERS-CoV their level is higher, most likely because of the wider distribution of DPP4 in the body.[19] Even though it is uncertain whether asymptomatic household transmissions occur, leading to underreporting of milder cases,[20] it is thought that the difference in pathogenesis leads to a more severe cytokine storm and thus a more severe clinical picture.

Although the classical initial presentation is with fever, headache, non-productive cough, sore throat, arthralgia and myalgia, it is thought that asymptomatic or mild infection rates might be as high as 25-50%.[14] Involvement of the central nervous system can lead to confusion, and gastrointestinal symptoms such as nausea, vomiting and diarrhoea may be present.[14] MERS-CoV causes, more often than in SARS-CoV and SARS-CoV-2, respiratory failure due to acute respiratory distress syndrome.[21] Additionally, the incidence of acute kidney injury is higher, most likely due to a higher incidence of multiorgan failure, through a more severe cytokine storm than seen in SARS-CoV or SARS-CoV-2.[18,21] In severe cases there is respiratory, liver and/or renal failure, culminating in multiorgan failure and death.[14] It remains difficult to distinguish between the viruses on clinical grounds.

In older patients, immunocompromised patients and patients with comorbidities, prolonged viral shedding and increased mortality have been described.[16,22] Severe infections in children remain rare and are mostly reported in children with comorbidities.[23,24] Up to 2021, 2574 laboratory confirmed cases of MERS infection have been reported worldwide, with a case fatality rate of about 35%.[25]

Figure 2 NJCC V30-5

Diagnosis, prevention and treatment
Testing for MERS-CoV takes place via real-time reverse-transcription polymerase chain reaction (rRT-PCR), of which three assays are currently available.[26] Samples should be collected from the upper or lower respiratory tract.[26] So far there has not been any cross-reactivity with other respiratory viruses.[26] Serological testing is also possible, but only advised in specific situations, for example the investigation of an outbreak.[26]

Transmission from dromedary camels as well as their products, such as unpasteurised camel milk, to humans has been described. Therefore, an obvious and important way to prevent infection with MERS-CoV is to avoid contact with camels as well as consumption of their products.[11,12] To prevent human-to-human transmission, home isolation and measures such as hand hygiene and face masks are advised.[27] In-hospital transmission has been documented,[20] early detection and isolation preferably in negative pressure isolation rooms are therefore important.[14] Other important measures include contact tracing and quarantine of close contacts.[14]

Multiple vaccine candidates for use in camels as well as humans are in development, phase I and II trial studies on more than 20 vaccines (inactivated whole virus / live attenuated virus / subunit / DNA / viral vector vaccines) are being done.[14,28] In fact, research already available on SARS-CoV and MERS-CoV vaccine development aided the fast design of vaccines for SARS-CoV-2.[29] Although these vaccines appear to protect against variants of SARS-CoV-2, they do not prevent infection with MERS-CoV.[19] In theory, for example RNA vaccines could be redesigned for use in MERS-CoV. However, likely due to considerably less funding as a result of the relatively small outbreaks of MERS-CoV so far, no vaccines have been approved for use in humans at the moment.

A wide variety of treatment options have been proposed, ranging from antiviral therapy to antibody-based interventions, interferons and host-directed therapies.[14,30] The most relevant option so far is treatment with interferon beta-1b combined with lopinavir-ritonavir, which led to a reduction in mortality among hospitalised patients, when compared with placebo (relative risk 0.19; 95% CI 0.05-0.75).[31] In contrast to SARS-CoV-2, administration of corticosteroids did not affect mortality but was associated with delay in virus clearance and is therefore not recommended.[32] Because the inflammatory response is more pronounced than with SARS-CoV and SARS-CoV-2, treatment just aimed at IL-6 most likely has less effect than it has in SARS-CoV-2. Other systemic anti-inflammatory treatment has not been of benefit so far.[14] The mainstay of treatment continues to be supportive care.[14,30,33]

Of the patients admitted to hospital, 53-89% are admitted to intensive care, of whom about 85% need invasive ventilation.[34] Non-invasive ventilation is associated with a high failure rate. Other supportive therapy consists of renal replacement therapy, antimicrobial therapy in case of co-infections and inotropic support.[14] Survivors of these severe infections report a similar long-term quality of life compared with others that survived comparable illness due to, for example, influenza.[35]

Pandemic threat potential
Even though MERS-CoV has not yet spread as fast as its family members SARS-CoV and SARS-CoV-2, it does have some worrisome attributes. Coronaviruses are known to mutate easily, as history has already made abundantly clear.[1,7,10] Like SARS-CoV-2, it has a relatively long incubation time and a large group of people appear to be asymptomatic. Therefore, it can spread relatively unnoticed. Its symptoms are not very specific and could be mistaken for common flu or pneumonia, which has already led to infection of several health workers in the past.[3] Although the reported reproduction number (R0) ranges widely, from 8.1 to 0.45, especially in healthcare-related outbreaks superspreader events have been reported.[36] On top of that, the reported case fatality rate of MERS-CoV is much higher than that of SARS-CoV and SARS-CoV-2.[18]

Fortunately, up until now, MERS-CoV has had a lower transmissibility than SARS-CoV or SARS-CoV-2, possibly partly explained by the fact that its clinical picture is more severe.[18] Additionally, its intermediate host, the camel, is an animal predominantly kept in a limited area in the world and not many humans have intensive contact with camels. However, the fact that neither vaccine nor treatment are available at the moment and the possibility of mutation leading to higher transmissibility is very worrisome.

Conclusion
MERS-CoV is an RNA virus quite closely related to SARS-CoV and SARS-CoV-2, two viruses that have already proven to be causes of pandemics. The fact that MERS-CoV has not caused a pandemic yet is attributable to the circumstance that so far its spread has been mostly through dromedary camels and less often through human-to-human transmission. However, its clinical presentation is more severe than the other two coronaviruses and neither vaccines nor treatment are available at the moment. Combined with the potency of mutation, this makes MERS-CoV a virus to be closely watched and the WHO has rightfully classified it as one of the priority pathogens for research and development.

Disclosures
All authors declare no conflict of interest. No funding or financial support was received.

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