Infection by viruses including the Middle East respiratory syndrome coronavirus (MERS-CoV) does not always result in obvious sickness. MERS-CoV infection without disease may simply reflect that a healthy human’s immune system is a hard-working and marvellous part of our everyday life.

Immunity is expertise at a cellular level; defences resulting from our body’s many experiences which, mostly, keep us safe from disease. These defences are always on guard which is a good thing because our body has portals to the outside world that are under constant assault from tiny invaders.

We use disease to warn of a virus

Humans have a long history of using the result of infection – disease – to tell us that the cause of that disease is nearby. This approach may be accompanied by laboratory confirmation. Or it may not.

The discovery of MERS-CoV in 2012 was one such search that succeeded.[1,7,8] But if there is no disease, how do we know a virus is circulating among us? The answer is that we don’t know. Unless we test for it. But testing is expensive and there is no clinical need to test a person unless there is an illness in the first place. This is where research can come in handy; breaking a question into chunks for which we can get answers, using funding that is earmarked for that purpose.

A camel virus conundrum

MERS-CoV is a pathogen still attached to a few important unanswered questions. One of these questions asks why there are still cases of disease (MERS), even though the ill person has had no reported contact with the well-known host of the virus, dromedary camels. The patient also hasn’t been in close contact with another known sick person. One answer is that MERS-CoV can be transmitted to the ill person via an intermediary. Perhaps this is another animal or, more likely in my opinion, another person who is infected, shedding virus but not showing any obvious signs of illness.

It’s worth remembering that MERS-CoV infections have occurred mostly in the Kingdom of Saudi Arabia and that the biggest outbreaks of disease have been related to healthcare settings, facilitated by humans and processes that have been insufficient or not implemented correctly. MERS-CoV is a virus that transmits poorly between humans.

A new review

A newly published review seeks to summarize what the current science tells us about MERS-CoV infections that don’t lead to disease, so-called asymptomatic or subclinical infections.[2]

As an aside, the review starts with a reminder that poliomyelitis is a paralytic disease outcome among only 1 in 200 or 0.5% of those infected by poliovirus.[3] This is worth remembering because of another disease in the U.S. news in 2018, acute flaccid myelitis (AFM).

Disease unquestionaably happens as an outcome of infection, but it doesn’t happen every time.

I’ve talked before about some of the 10 studies that the authors reviewed here. One, in particular, identified that asymptomatic infection doesn’t happen (or if so, very rarely) but it lacked evidence to support that finding. Like that paper, another relied heavily on antibody detection which is not very good at detecting past mild or asymptomatic MERS-CoV infections.[4] There is a need for some planned studies.

Asymptomatic infections do happen. They mostly occur in healthier and younger people. It is older people with pre-existing heart, lung and kidney diseases who suffer most from MERS-CoV disease. The review found that between 1 and 4% of contacts of infected cases, tested positive for MERS-CoV.

Asymptomatic infections are sometimes a high proportion of detections

In one of the cited studies, 12 of 280 (4% of those tested) household contacts of known cases, tested positive for MERS-CoV.[6] Those authors suggested these were probable cases of secondary transmission. Importantly 11 of those 12 secondary cases were asymptomatic (91% of the positives) infections. Did the 11 asymptomatic people spread their infection further (contacts-of-contacts)? That was not examined.

In their latest global summary, the World Health Organization noted that 10% (19 of 189) of most recent cases had mild or no symptoms.[5]

The authors also note that despite small studies screening healthy or ill pilgrims over multiple years, only 4 cases of MERS have been reported in association with Umrah and apparently zero in association with the Hajj. Once again, MERS-CoV really doesn’t seem to transmit well despite plenty of opportunities [8] – at least so far as current studies tell us.

Do asymptomatic cases infect new people?

But the authors don’t really give us any data to show that an asymptomatic, laboratory-confirmed MERS-CoV can/cannot transmit to others and because of that, they can’t address their review’s title “Asymptomatic Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection: Extent and implications for infection control: A systematic review“. It also never resolves its early statement that there “are reports of the role of asymptomatic individuals in the transmission of MERS-CoV, however, the exact role is not known”. This shortcoming is reinforced by the conclusion that asymptomatic infection “may contribute to the transmission of the virus“. Or they may not? How will we know? Can we stop it? What are the knoweldges gaps? How do we address them with research?

The review does (inadvertently) highlight the lack of studies looking not at asymptomatic contacts of known cases, but whether asymptomatic case contacts go on to infect more people. This would address the real issue of whether asymptomatic cases contribute to transmission chains and cause trouble for the occult spread of the virus in healthcare settings.

So what if there are asymptomatic infections?

There are a few things to be concerned about when considering the issue of people inadvertently shedding a virus:

• New infections may occur without obvious transmission chains, making infection control in healthcare settings more difficult. Or it may just be that healthcare infections occur so frequently because of early spread prior to adequate ICP is installed.
• Asymptomatic but virus-shedding healthcare workers may expose patients to MERS-CoV. Hospitals already have vulnerable populations in whom MERS-CoV can have a serious clinical impact.
• For a newly discovered or emerging virus, asymptomatic infections and poor laboratory tests and testing can really mess up the understanding of transmission. It’s essential to test cases and all contacts at the outset of studies to characterise viruses, using reliable tools.

Final thoughts

No single technology exists to quickly, sensitively and inexpensively identify all known pathogens from a person of interest. It remains impractical to routinely test everyone for everything using individual tests, just to find asymptomatic cases. So we rely on research to answer the medical mysteries by testing samples. This review outlines that we still don’t understand the importance of asymptomatic infections in the unseen transmission of MERS-CoV.

A finding of MERS in a patient who had no contact with infected camels or sick people shouldn’t leave us flummoxed. It is cause for further investigation. We don’t always have to be sick to pass along viruses, we just have to be infected. But if we’re not sick, then how do we identify infection? With a quality lab test, silly.

Research projects that address the questions around MERS-CoV infection without disease, specifically, whether an asymptomatic person infects others, could include:

1. A cohort study that follows those at risk of acquiring MERS-CoV infection, and enrols them, their contacts and the contacts of those contacts and tests nasal swabs weekly, regardless of symptoms
2. A study that follows laboratory-confirmed MERS-CoV cases and tests the nasal swabs of their contacts and the contacts-of-contacts weekly, regardless of symptoms.
3. Enrolling patients who visit Saudi general practitioners for acute respiratory illnesses (common colds) and screening them, their contacts and the contacts-of-contacts by RT-PCR for MERS-CoV. This would be an interesting way to capture occult community MERS-CoV if it exists.

References

1. NOVEL CORONAVIRUS – SAUDI ARABIA: HUMAN ISOLATE http://www.promedmail.org/direct.php?id=20120920.1302733
2. Asymptomatic Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection: Extent and implications for infection control: A systematic review.
   https://www.ncbi.nlm.nih.gov/pubmed/30550839
3. What Is Polio?
   https://www.cdc.gov/polio/about/index.htm
4. MERS-CoV Antibody Responses 1 Year after Symptom Onset, South Korea, 2015
   https://wwwnc.cdc.gov/eid/article/23/7/17-0310_article
5. WHO MERS Global Summary and Assessment of Risk August 2018
   https://www.who.int/csr/disease/coronavirus_infections/risk-assessment-august-2018.pdf?ua=1
6. Transmission of MERS-Coronavirus in Household Contacts
   https://www.nejm.org/doi/full/10.1056/NEJMoa1405858
7. Middle East respiratory syndrome: An emerging coronavirus infection tracked by the crowd.
   https://www.ncbi.nlm.nih.gov/pubmed/25656066
8. An Opportunistic Pathogen Afforded Ample Opportunities: Middle East Respiratory Syndrome Coronavirus
   https://www.ncbi.nlm.nih.gov/pubmed/29207494

Acknowledgements

With thanks to Dr Katherine Arden for editing contributions.