Happy 3rd birthday Middle East respiratory syndrome coronavirus (MERS-CoV)...

It has been 3-years since Prof. Ali Mohamed Zaki sent his email to ProMED notifying them, and the world, of a novel coronavirus (15-Sept-2012). That email was published 20-Sept 2012.[1,7,8] 

Two years ago at this time we had 138 cases and 58 deaths, last year 856 cases with perhaps 306 fatal (36%). Today, we have heard of 1,588 cases worldwide of which at least 551 (35%) have been fatal.[2,3] A higher proportion of fatal cases occur in the Kingdom of Saudi Arabia (KSA) than were recorded in the 2015 South Korean outbreak. The type and extent of a nation's community that has comorbidities may play a role in these differences. The young seem nearly untouched by MERS. To date, 26 countries have harboured a MERS-CoV infected person and 13 of those have hosted ongoing transmission.[4]

Thankfully, the diagnostic tools described very early on are as useful today as they were in 2012.[5,6]

Three years on we still see no sign of that virus patenting issue manifesting into a real problem.[3] 

For me, this past year in MERSville has been about:

• How amazing it was that MERS cases didn't occur during or as a result of one of the world's largest mass gatherings, the Hajj. Really. Amazing.
• The absence of asymptomatic cases included in reporting from KSA. The World Health Organization's (WHO) definition of a case does not rely on the presence of symptoms but on the presence of virus or past viral infection. Withholding or not seeking these data produces an overstated value for the proportion of cases that die from infection and could confound efforts to interrupt transmission during an outbreak. In reality, the higher percentages may just be what we should expect among infection of older males and females with one or more comorbidities
• The continuing appearance of large hospital-based MERS-CoV outbreaks driven by circumstances we create through unsatisfactory understanding of respiratory viruses, as well as poor preparation for their arrival in an emergency department. This occurred again in South Korea and Riyadh over the past year as it did in Jeddah the year before. In South Korea, the financial, economic, social and trust impacts were significant; communication once again a big loser from public health authorities and governmental agencies
• The big question over our MERS-CoV antibody detection tools' capabilities. Can they detect the prior presence of a MERS-CoV infection when that infection did not result in symptoms in its human hosts, or caused only very mild symptoms? A 4-week study enrolling the contacts of confirmed cases and collecting daily nose/throat swabs, weekly bloods, filling in a daily symptom and temperature diary, followed by an 8-week blood sample, would help address this I think
• Slow acceptance that camels are the main, albeit sporadic, source of MERS-CoV spillover infections of humans. Bats may have been involved in the distant past but for 30 or more years we have strong data to say that a MERS-CoV (or closely related virus) has resided in and spread among dromedary camels in Africa and or the Arabian peninsula causing mostly a 'common cold' like upper respiratory tract illness. The precise role of importation on moving MERS-CoV around the region remains poorly explored
• Other animals, on paper, look like they could host MERS-CoV, but experimental infection studies are still lacking. Similarly, a camel birth cohort study (h/t @newprof1) would add additional information to the story of how this virus spreads between camels in herds or holding pens after importation or during festivals
• We did not see any resolution to the missing data from 2014 - despite assurances from the KSA MOH.[12] Comprehensive data on cases that were just 'found' - remained incomplete.[11] Also, trying to identify deaths from among previously announced MERS cases is a task fraught with frustration, despair and dismay. And then there are the unexplained errors and differences in reporting when comparing MOH data to World Health Organization data. Yes, those cases that are reported are likely to be the tip of an iceberg of indeterminate size, but at least get right what is being reported-or...GASP...fix it up later
• It was reported that among those humans listed as being 'asymptomatic' - over three quarters of such cases, when later interviewed, recalled having symptoms.[6] This, to me, casts a darker shadow over the quality of other clinical and epidemiology data too
• We still have not seen any data from the testing of human samples, prospectively or retrospectively, from non-Arabian countries that play host to high numbers of MERS-CoV antibody-positive camels, for example, Egypt, Sudan, Somalia or Ethiopia
  
• In the past year we learned that MERS-CoV variants, like other CoV variants, can recombine when multiple variants co-infect the same host (probably in camel herds but perhaps in crowded hospital outbreaks in places like Riyadh which appears to be a nexus for mixing of variants [13,14]) producing a new variant.[9,10] To date there has been no proven impact on clinical presentation or course, virus reproduction or immunomodulation or transmission. But have wee looked hard enough lately? While it is not immediately obvious from observing whole genome sequences - most of the kind of sequencing produced since MERS-CoV was discovered - sites of recombination can be predicted when we look with more specific software tools. Yet, what happens if this recombination happens between a contemporary human/camel variant and a more ancestral camel variant? Could the resultant recombinant virus change in transmissibility or become more or less clinically severe? Is that recombination scenario even possible? Are even older bat variants too genetically distinct to allow easy recombination? It is important we find out more about the diversity of MERS-CoV and CoVs among camels outside the Arabian Peninsula and seek them out in other animals there too. Just as it is important to measure what is happening in people there
• Advances in therapeutic antibody preparations and in vaccine candidates. It remains to be seen whether camels will respond as immunologically required for a camel-based vaccine to prove effective, but as Ebola virus disease showed us, there is obvious benefit to having a ready-to-deploy arsenal of weapons in case of invasion by a viral foe that just 'shouldn't be capable of doing that thing'

It would be stupid to predict what will happen with MERS and MERS-CoV in the next 12 months. We can take some educated guesses though. 

But for now the focus is still largely on what the KSA will do about the problem on their doorstep. It may also be that MERS-CoV cases are percolating outside the Arabian Peninsula without our knowledge. Let's not leave this virus to its own device any longer. Let's act to make sure it doesn't comes back to bite us. The clues are all there. There are patterns that are clearly visible. Let's get the work done ahead of the panic for a change. How about we meet back here this time next year, same batch channel, same camel topic?

References...

1. http://www.promedmail.org/direct.php?id=20120920.1302733
2. https://flutrackers.com/forum/forum/novel-coronavirus-ncov-mers-2012-2014/146270-2012-2015-case-list-of-moh-who-novel-coronavirus-mers-ncov-announced-cases?t=205075
3. http://www.who.int/csr/don/17-september-2015-mers-saudi-arabia/en/
4. http://virologydownunder.blogspot.com.au/2015/09/mers-around-world.html
5. http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20285
6. http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20334
7. Happy 1st birthday Middle East respiratory syndrome coronavirus (MERS-CoV)
   http://virologydownunder.blogspot.com.au/2013/09/happy-1st-birthday-middle-east.html
8. Happy 2nd birthday Middle East respiratory syndrome coronavirus (MERS-CoV)...
   http://virologydownunder.blogspot.com.au/2014/09/happy-2nd-birthday-middle-east.html
9. http://biorxiv.org/content/early/2015/06/12/020834
10. http://mbio.asm.org/content/6/5/e01280-15
11. http://virologydownunder.blogspot.com.au/2015/03/where-did-mers-cov-comorbidity-and.html
12. http://virologydownunder.blogspot.com.au/2014/09/mers-cov-data-request-response-from.html
13. http://www.ncbi.nlm.nih.gov/pubmed/24055451
14. http://mbio.asm.org/content/5/1/e01062-13.abstract

Influenza A(H7N9) virus case accumulation for 2013...

Click on image to enlarge.

Sure a full 12-months of H7N9 in humans hasn't passed yet, but 2013 is coming to a close. 

I have 148 H7N9 cases worldwide including deaths and the asymptomatic boy from Beijing who seems to still be off the official tallies for some reason. WHO have not had an official tally of fatal cases in their recent 2 disease outbreak news posts, the last with a tally was 6-Nov in which 45 deaths were recorded with 6 cases remaining in hospital and 88 having been discharged. Hong Kong's Centre for Health Protection (CHP) maintains a running tally of mainland China cases With the recent death of a Hong Kong man the tally of fatal cases rest around 46 (PFC of 31.1%).

I've just changed my spreadsheet to a weekly format from the daily version and the first chart it reveals is shown above. 

This includes the lay of the land for all H7N9 cases from the beginning of the outbreak, 11-Feb (date of pneumonia for son of index case), through to 29-Dec. Date data employ dates of reporting if no date of illness onset could be found.

We can see from this 47-week inclusive dataset that the principle period of activity was in late March to late April. Whether that will also be the case in the new year is anyone's guess really.

What we can say from the vast amount of influenza virus research data in the scientific literature, is that each and every new combination of 8 gene segments that comprise a distinct influenza A virus seem capable of their own distinct "personality".

Concise overview of MERS from mid-2013...

Publishing in the Oman Medical Journal, Blakhair and colleagues summarized the state of play for MERS back in July 2013.

While the numbers may have changed since then, the article is as relevant now as it was. Not much new data has been accrued to address the knowledge gaps listed in July despite 3-months and about 50 papers having passed.

The final summary is particularity useful I thought...

The fact that our current knowledge on this virus is sparse should not induce unnecessary panic or fear, instead it should promote vigilance and a state of preparedness. Over reaction to the current situation may lead to significant clinical, economic and epidemiological impacts among others.

The article also provides VDU's first ever citation in the scientific literature. Cool.

Reference...

1. The Struggle Against MERS-CoV (The Novel Coronavirus). Oman Medical Journal. 2013. 28(4):226-7
   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725253/pdf/OMJ-D-13-00242.pdf

Dr Ziad Memish discusses MERS in the Kingdom of Saudi Arabia (KSA)

Insights from the Front Lines. UPMC Center for Health
Security presentation by Dr Ziad Memish on MERS-CoV.
August 21, 2013

University of Pittsburgh Medical Center (UPMC) Center for Health Security recently organized a seminar by Dr Memish in which he discusses the Saudi experience with the Middle East respiratory syndrome outbreak. 

Dr Memish, is among the most important health professionals in the world on this topic and he is located at the front-line of understanding the behaviour of this new virus and its ongoing outbreak in humans.

I've distilled some quotes (with some of my additions in brackets) and points that I found interesting during his 30-min presentation:

• In addition to his many awards and roles in consultancy and medicine (including roles as Deputy Minister of Health for Public Health (KSA), Director for WHO collaborating centre for Mass Gathering Medicine; consultant for infectious diseases at King Fahd medical city, Faculty of College of Medicine at Alfaisal University/King Saud University/Emory University/Liverpool School of Medicine and on committees (Executive Board of the WHO), Dr Memish also has >300 peer-reviewed publications and chapters. I recently summarized a few of the MERS-CoV-related ones here.
• Dr Memish and the KSA Ministry of Health (MOH) have a "huge public health team" investigating the new virus (currently 96 cases and 47 deaths worldwide; 76/39 in KSA)
• More and more mild and symptomatic cases being detected - more extensive testing on contacts
• Healthy and well MERS-CoV infectees do better than those with underlying conditions
• Dr Memish saw the Prof Ali Zaki report of the first MERS-CoV case in Bisha/Jeddah, on his Blackberry, and an MOH team was then immediately dispatched and communication with WHO, CDC, Columbia University and the EcoHealth alliance to work with the KSA MOH including extensive investigation of at least 29 family members and 100 employees in Bisha and the hospital in Jeddah - none of whom were MERS cases (around 7min in the video)
• Reminder of the 2002/2003 8,098 probable SARS-CoV cases and 774 deaths over 5-7-months, costing the economy >$30-billion. SARS differs from MERS in the lower proportion of cases of severe disease linked to an underlying condition
• Between Jan and end of July - there were close to 8-million umrah visitors. The month of Ramadan had almost 15-million people perform the hajj (5-million from outside KSA)
• We think there is a some sort of pre-existing genetic underlying disease predisposing to MERS; based on studies of family clusters (late 18min)
• The Al-Ahsa hospital cluster
• Al-Ahsa represents 25% of the area of KSA; population 1.3-million
• No increase in mortality, but local infection control team noted a shift in mortalities from the "usual" causes towards pneumonia 
• The hospital cares of the elderly (a geriatric hospital)
• Very good documentation at this hospital which helped track infection
• Had to stop shared transport (ambulance) system for dialysis patients coming to hospital, stopping  those with suspected disease from coming to the dialysis unit, enhancing cleaning and excluding visitors and non-essential staff
• 10/30 had animal exposures of any sorts (birds, bats, camels, cats etc). Hard to get families to recall exposures-problem for animal source tracking.
• Lesson learned include
• MERS-CoV can causes healthcare-associated infections
• Early symptoms of MERS can be mild and non-specific and can be missed
• 1/3 of patients have gastrointestianl symptoms
• Human-to-human transmission does occur but how is not clear
• Droplet and contact precaution are essential
• Don't know if asymptomatic but MERS-CoV PCR positive patients can transmit virus
• PCR is the gold standard testing method
• Deeper airway samples give better results - repeat sampling required if negative on first sampling, when MERS is clinically suspected
• Collaborating with international groups (CDC, NIH etc) to standardise and validate antibody testing methods
• Potential sources includes dates, bats, livestock, stray cats and dogs, pet birds and camels (antibody-positive in Oman despite absence of human cases there)
• >1000 bat samples collected but relationship between bats and patients is undocumented
• Transmission routes include:
• Sporadic community cases with non-human exposures (animals or environmental)
• Family clusters
• Healthcare clusters
• Travel-related/workplace transmission
• Clinically, MERS-CoV can cause severe disease on older, immunocompromised patients, those with underlying conditions, and primary index cases but also causes mild or asymptomatic disease in the previously healthy, young and secondary cases; most HCW infections were in teh young and healthy. Standard acute (48-hour) fever and myalgia in the healthy cases.
• Risk for HCWs was related to invasive procedures (see WHO IPC linked and discussed in previous post on this). Diabetes and obesity is relatively high in KSA so need more cases to determine risks.
• Looking at therapeutics that have and have not worked for SARS infections
• MOH website adds cases daily at 5 o'clock
• Reservoir needs to be determined
• Sample type, false negatives and lack of serology are diagnostic challenges
• MERS-CoV has limited transmission

In follow-up questions, Dr Memish noted that the first the KSA MOH knew of the new CoV was when they read Dr Zaki's eMail to ProMED. Since then, surveillance testing of anyone at key sites, with pneumonia admitted to an intensive care unit was extrapolated post-hajj 2012, to all of the KSA. Other patients can get tested. MERS-CoV testing is centralised - 3 KSA labs now test, 24/7.

70 suspected cases are reported per day. Most testing is on those who are hospitalised.

The KSA is working with Sanger Institute in the UK for sequencing. All samples are being sent there. Not every case yields a full genome (real-time PCR threshold cycle values >30-35 may fail). 21 more genomes are being finalised-coming out in the next few days-to add to the existing 9. KSA also works with other institutes worldwide and it seems that local capacity for virus discovery and genome sequencing is lacking at this stage. This means delays due to forging new international alliances and in getting materials out of the KSA and into other countries, with strong biohazard importation borders to cross and regulations to satisfy, will probably continue. But things should speed up as the process becomes more familiar to all parties.


Dr Memish, supporting comments he has made previously, still suspects that other countries both in the region and globally, would find more MERS-CoV cases if they looked as hard and as proactviely as the KSA is doing. 

At around 48-40min Dr Memish made an important comment about epidemiology:

Epi 101. If you don't look for something you will not find it. You have to look for the disease and if you're not testing and you are not doing anything you will not pick it up.

I only got to 50-min, so feel free to follow the link and hear more. 

A great summary of the situation so far from the country at the center of the emergence of this new virus.