MERS-CoV in the blood....

The Middle East respiratory syndrome coronavirus (MERS-CoV) is, at its core, a respiratory virus. Well, as far as we know it is anyway. But, like other respiratory viruses (see an earlier post on rhinoviruses), MERS-CoV can be detected in the blood....a so-called "viraemia". In some cases this is identified in other virus infections in parallel with the viral load being generally high, perhaps indicating that virus is replicating beyond the body's ability to contain and control it at the site of initial replication. 

Perhaps, and MERS-CoV may be a good example of this, so-called extra-respiratory spread of a respiratory virus occurs when it has a penchant for blood vessel cells (they present its receptor in their surface, or have something in their cellular machinery that aids virus replication) or some other ability to specifically get beyond the respiratory tract. 

However it occurs, the result is a much wider spread of the virus around the body; blood being something that is widely traveled! We already know that MERS-CoV has a love for growing in kidney cells so extra-respiratory spread may create a perfect storm for delivering this little bomb to a site where it can create even more havoc than in our airways. If those kidneys are already a bit bashed about, say by diabetes, then the blast radius is perhaps increased that much more.

A new paper just out in Emerging Infectious Diseases [1] is the latest to highlight viraemia, or pedantically because its viral RNA in the blood, RNAemia and its role in detection of MERS-CoV.

A lower respiratory tract (LRT) sample (bronchoalveolar lavage; BAL) was collected from a 66-year old man (66M) who returned to Tunisia after after a 5-week visit (20-March to 28-April) with his daughter in Qatar, interspersed with a pilgrimage to Mecca (Makkah; 27-March to 04-April) in the Kingdom of Saudi Arabia (KSA). 

66M arrived back in Tunisia 28-April with an acute respiratory illness which progressed and from which the LRT sample was collected. A subsequent X-Ray identified cellular infiltrates in his lungs. His 30-year old daughter (30F) stayed in Qatar. His 34-year old son (34M), a nurse, cared for him both at home and later in the intensive care unit as his disease progressed, eventually ending in his death from multi-organ failure. He was buried 13-May and his daughter returned from Qatar for the funeral. 66M's LRT sample was not positive for MERS-CoV and he had no other respiratory viruses (not detected using PCR testing which may have been more appropriate). His daughter and son were positive for MERS-CoV so 66M was described as a "probable" case (travel, signs & symptoms, and at least subsequent contact with MERS-CoV cases). The incubation period for his illness placed 66M in Qatar at the likely time of acquisition of virus and his son was likely to have acquired his infection from his father in Tunisia. The daughter may have acquired the virus from her father while he was in Qatar or from a related source in Qatar (but seems to have been a Qatar-related acquisition of some sort). 66M's wife, 2 other well children and his son's wife were not MERS-CoV positive 5-weeks later (but then they were unlikely to have tested positive so far out from the event). 

Afterwards the US CDC tested a serum sample (tested 5-August-2013, blood taken 9-May-2013) by reverse transcription real-time polymerase chain reaction (RT-rtPCR), and it was positive. Thus - the cluster is resolved. Got a better appreciation for the amount of work that goes into tracking this stuff down in detail?

But this was not the first time a MERS-CoV diagnosis was obtained retrospectively, or as part of a study, using RT-PCR (conventional or real-time) on serum (cell free blood) rather than a respiratory tract sample. Yet remember that the presence of viral genome (or bits thereof) identified by RT-PCR does not guarantee that infectious virus was in the blood, only that viral RNA could be detected there.

• Case No. 1 from the original hospital cluster of MERS cases in Al-Zarqa, Jordan in March-May 2012, was identified thanks to retrospective RT-rtPCR (CDC version) on a convalescent serum sample.[2] 
• The 2 French MERS cases (1 imported, 1 locally acquired from contact) had RNA in their blood (UpE RT-rtPCR); the patient who died was positive for at least 4-weeks while the surviving patient cleared viral RNA in the 1st week after symptom onset.[3] 
• Two cases imported into the Netherlands from the KSA were found to have viral RNA in their blood for days; Case #1 from day-0 after diagnosis until at least day-9 and Case #2 from day-1 until at least day-5.[4] In this study viraemia outlasted virus detectability in the faeces but was detected for as long as virus in throat swabs of Case #1. RNA was not detected in the urine.[4]

Serum may be a useful sample, not just to determine whether antibodies to MERS-CoV develop(ed), but to help detect MERS-CoV RNA, as a surrogate for infectious virus, when a respiratory sample is not available. 

The finding of MERS-CoV RNA in the blood so frequently, among those studies that have looked, may also indicate it is a useful marker of disease severity as seen in the French cases. Serum is already a sample recommended for collection for antibody studies.[5] Let's see if these papers can trigger a little more looking back at those samples, which are hopefully stored in freezers somewhere. 

Anything that helps nail down "probable" cases and better define the pathogenesis of MERS-CoV is a good thing. 

Some typos & grammar corrected 05MAR2015

References.... 

1. Family Cluster of Middle East Respiratory Syndrome Coronavirus Infections, Tunisia, 2013 http://wwwnc.cdc.gov/eid/article/20/9/14-0378_article.htm
2. Novel coronavirus infections in Jordan, April 2012: epidemiological findings from a retrospective investigation
   http://applications.emro.who.int/emhj/v19/Supp1/EMHJ_2013_19_Supp1_S12_S18.pdf
3. Distinct Immune Response in Two MERS-CoV-Infected Patients: Can We Go from Bench to Bedside?
   http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0088716
4. Middle East respiratory syndrome coronavirus (MERS-CoV) infections in two returning travellers in the Netherlands, May 2014
   http://www.eurosurveillance.org/images/dynamic/EE/V19N21/art20817.pdf
5. http://who.int/csr/disease/coronavirus_infections/MERS_Lab_recos_16_Sept_2013.pdf?ua=1

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Wrapping up in Uganda - Chronic HBV infection research

Hi again, from Mbarara, Uganda! I am leaving for the airport shortly to return to Boston, and am sad to leave.

In terms of updates, I completed a week full of interesting meetings at MGH-MUST. From meeting with research coordinators in charge of other studies, I learned of the impressive commitment to research. We went on a UARTO field visit, specifically looking for a patient who had been noncompliant (as measured by the Wisepill). As part of this study, there are patient trackers who try to locate the patients at least twice a week, to understand whether the patient was noncompliant or whether there was an issue with the device. We loved being able to leave Mbarara and visit a nearby village, with a small trading post surrounded by large farms.

I also met with several important collaborators, including Dr. Yap Baum, director of Epicentre, and Dr. Winnie Muyindike, director of the Immune Suppression Syndrome (ISS) clinic. I was very impressed with Dr. Yap�s knowledge and expertise, and most importantly, his commitment to capacity-building. He quickly identified a student who is interested in studying viral hepatitis, and arranged for a joint meeting so she could become involved in our project. Dr. Winnie has spearheaded our proposed study, and it was wonderful to meet with her and discuss logistics (including study procedures, reserving temporary space in the ISS clinic, and working with the Voluntary Counseling and Testing Centre and the medical wards to help recruit potential patients). Dr. Winnie�s commitment to her patients is inspiring �- and I feel so lucky to work with her.  I am including a picture of the 2 of us, standing in her office at the ISS clinic.

Finally, my husband and I were able to see more of Uganda, specifically visiting Queen Elizabeth National Park and Lake Mburo. I am including a picture of myself in front of one of the crater lakes at Queen Elizabeth National Park � simply stunning. I am in awe of the landscape here � beautiful, lush tea fields as well as stunning lakes and channels. We were able to see several animals, including leopards, lions, hyenas, and a myriad of birds that I have already forgotten the names for.   

I feel so fortunate to have been able to experience this trip -- it has been extremely memorable, and I am looking forward to returning very soon.

Thanks again for reading,
Jennifer Y. Chen
MGH Gastroenterology and Hepatology Fellow

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Mbarara, Uganda: A study to diagnose and treat chronic HBV infection

Greetings from Mbarara, Uganda!

After a 16-hour flight from Boston to Entebbe (via London), a quick overnight stay at the Karibu Guest House in Entebbe (with a fantastic breakfast), and a 6-hour drive, my husband and I arrived safely to the MGH Guest House in Mbarara.

I have been here for 3 days, and have had a wonderful experience thus far. It has been about 5 years since I have traveled to Africa, and I wish I had been able to come back sooner. I worked in Gaborone, Botswana in 2008-2009 with Dr. Roger Shapiro on a study analyzing birth outcomes among HIV-infected pregnant women, which was a phenomenal experience. So arriving in Uganda, I did not know what to expect.

After just a few days here in Mbarara, I have been extremely impressed with the research infrastructure of the MGH-MUST collaboration. My collaborators and I are hoping to introduce a study to diagnose and treat chronic HBV infection according to a simplified algorithm, and my main goals of this trip were to learn about the research infrastructure and to learn how we can best implement this study. I have met with the directors of the MUST Grants Office (specifically, from the Finance, Administration, and the Human Resources divisions), and found these meetings to be very helpful. With several studies ongoing, including the large UARTO study, it quickly became clear that this office knows how to effectively manage research studies � from budgetary concerns to hiring new research staff. Interestingly, when I met with James from the Human Resources Division, I asked whether they gave preference to applicants who had worked for MUST before. He said that although some principal investigators preferred this, as it reduces the amount of training needed, he prefers to hire individuals based on merit � as there may be highly qualified applicants who have not worked or volunteered at MUST in the past. I told my husband, �I can�t believe I have to go all the way to Uganda to find a merit-based system!�

Thanks for reading my first blog entry, and I�ll be back soon with another one.

Jennifer Y. Chen

MGH Gastroenterology and Hepatology Fellow

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