MERS discussion thread

Giuseppe · Apr 27, 2014

Re: MERS discussion thread

The problem is that MERS can attach lower respiratory tract epithelium cells (and many other tissue indeed, except those in the upper respiratory tract) through the DPP-4 protein, thus restricting the way it can be shed through respiration.

The spike protein play an essential role in this mechanism and it is the target of genome sequencing.

No mutation in S-protein would mean someting, at the end!

Although many things remain to be elucidated about viral mechanism, pathogenicity and tissue tropism, some are known.

We have no data about the precise location of some of these patient exposures: long-term care institutions, acute care health services, asylums?

Hospitals may be the culprit but also other health facilities may have trouble in establishing and maintaining proper infection and control measures.

Shannon Bennett · Apr 27, 2014

Re: MERS discussion thread

The spike gene has not changed, at least with those first victims in the Jeddah cluster. But, no one can dispute the fact the number of sick has jumped and the chains are a little longer. So, something has to have changed. If it isn't the spike gene then maybe it is in the other small changes. The report did say the virus was not identical. If it isn't the smaller mutations then what is it? There are only a limited number of options for the increased number of sick and the chain lengthening. Either the sequence changed after the beginning of the cluster, they are missing something vital, an environmental factor is at play (sand storms?), or there are so many subclinical cases infecting others that statistically the lengthening chains are an explainable outcome.

Giuseppe · Apr 27, 2014

Re: MERS discussion thread

The reference about not identical viruses are likely due to different first exposures: ie, the viruses had not passed from h2h, but from animal-to-human. These could be related to index cases.

Shannon Bennett · Apr 27, 2014

Re: MERS discussion thread

Giuseppe, then how do you account for the uptick in numbers and the longer chains? Something has changed. If it had not changed, then the graph that Gaia was kind enough to share would not look any different this month from last month.

http://www.flutrackers.com/forum/showthread.php?t=222322

btw I strongly suspect that graph will look even more stunning after she adds the rest of the months totals.

Giuseppe · Apr 28, 2014

Re: MERS discussion thread

We can't assume that chain of infections exceeded tertiary level, as far as it is known.

The data is murky, mostly because the precise willingness of the saudi govt.

Data must be murky, they should have thought.

There is not a single word about the kind of health care settings patients firstly became infected: acute, long-term, tertiary, insane asylums, disabled people care centres?

The infection control measures differ likely among several kind of health care settings.

Outpatients clinics (for example for cancer patients, multiple chronic diseases (diabetes, blood disorders, mental illneesses)) may act as flashpoint if the overall circulation of the virus increased during April months (obviously, as the H7N9 in China & the lack of a 'smoking chicken', camels are infected but 'there is not convincing evidences of their role in this outbreak!).

I think also that as other samples will arrive to Dr Drosten laboratory, the situation will become more clear about the S & DPP-4 status of MERS.

Drosten is perhaps the expert with largest knowledge on coronavirus of the world.

I would be a little more trustful in his expertise.

Giuseppe · Apr 28, 2014

Re: MERS discussion thread

An example of the first 200 entry in PubMed archive:

1. Amplification of emerging viruses in a bat colony.
Drexler JF, Corman VM, Wegner T, Tateno AF, Zerbinati RM, Gloza-Rausch F, Seebens A, M?ller MA, Drosten C.
Emerg Infect Dis. 2011 Mar;17(3):449-56. doi: 10.3201/eid1703.100526.

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Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response.
Glowacka I, Bertram S, M?ller MA, Allen P, Soilleux E, Pfefferle S, Steffen I, Tsegaye TS, He Y, Gnirss K, Niemeyer D, Schneider H, Drosten C, P?hlmann S.
J Virol. 2011 May;85(9):4122-34. doi: 10.1128/JVI.02232-10. Epub 2011 Feb 16.

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Generic detection of coronaviruses and differentiation at the prototype strain level by reverse transcription-PCR and nonfluorescent low-density microarray.
de Souza Luna LK, Heiser V, Regamey N, Panning M, Drexler JF, Mulangu S, Poon L, Baumgarte S, Haijema BJ, Kaiser L, Drosten C.
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Genomic characterization of severe acute respiratory syndrome-related coronavirus in European bats and classification of coronaviruses based on partial RNA-dependent RNA polymerase gene sequences.
Drexler JF, Gloza-Rausch F, Glende J, Corman VM, Muth D, Goettsche M, Seebens A, Niedrig M, Pfefferle S, Yordanov S, Zhelyazkov L, Hermanns U, Vallo P, Lukashev A, M?ller MA, Deng H, Herrler G, Drosten C.
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Struck AW, Axmann M, Pfefferle S, Drosten C, Meyer B.
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Human coronavirus EMC does not require the SARS-coronavirus receptor and maintains broad replicative capability in mammalian cell lines.
M?ller MA, Raj VS, Muth D, Meyer B, Kallies S, Smits SL, Wollny R, Bestebroer TM, Specht S, Suliman T, Zimmermann K, Binger T, Eckerle I, Tschapka M, Zaki AM, Osterhaus AD, Fouchier RA, Haagmans BL, Drosten C.
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Human coronavirus NL63 open reading frame 3 encodes a virion-incorporated N-glycosylated membrane protein.
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Human coronavirus NL63 replication is cyclophilin A-dependent and inhibited by non-immunosuppressive cyclosporine A-derivatives including Alisporivir.
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Identification and evaluation of coronavirus replicase inhibitors using a replicon cell line.
Scandella E, Eriksson KK, Hertzig T, Drosten C, Chen L, Gui C, Luo X, Shen J, Shen X, Siddell SG, Ludewig B, Jiang H, G?nther S, Thiel V.
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Identification of a novel coronavirus in patients with severe acute respiratory syndrome.
Drosten C, G?nther S, Preiser W, van der Werf S, Brodt HR, Becker S, Rabenau H, Panning M, Kolesnikova L, Fouchier RA, Berger A, Burgui?re AM, Cinatl J, Eickmann M, Escriou N, Grywna K, Kramme S, Manuguerra JC, M?ller S, Rickerts V, St?rmer M, Vieth S, Klenk HD, Osterhaus AD, Schmitz H, Doerr HW.
N Engl J Med. 2003 May 15;348(20):1967-76. Epub 2003 Apr 10.

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Importance of cholesterol-rich membrane microdomains in the interaction of the S protein of SARS-coronavirus with the cellular receptor angiotensin-converting enzyme 2.
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Virology. 2008 Nov 25;381(2):215-21. doi: 10.1016/j.virol.2008.08.026. Epub 2008 Sep 23.

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Investigation of anti-middle East respiratory syndrome antibodies in blood donors and slaughterhouse workers in Jeddah and Makkah, Saudi Arabia, fall 2012.
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Middle East respiratory syndrome coronavirus (MERS-CoV): announcement of the Coronavirus Study Group.
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Middle East Respiratory Syndrome coronavirus (MERS-CoV) serology in major livestock species in an affected region in Jordan, June to September 2013.
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Middle East respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study.
Reusken CB, Haagmans BL, M?ller MA, Gutierrez C, Godeke GJ, Meyer B, Muth D, Raj VS, Smits-De Vries L, Corman VM, Drexler JF, Smits SL, El Tahir YE, De Sousa R, van Beek J, Nowotny N, van Maanen K, Hidalgo-Hermoso E, Bosch BJ, Rottier P, Osterhaus A, Gort?zar-Schmidt C, Drosten C, Koopmans MP.
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Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome.
Kuiken T, Fouchier RA, Schutten M, Rimmelzwaan GF, van Amerongen G, van Riel D, Laman JD, de Jong T, van Doornum G, Lim W, Ling AE, Chan PK, Tam JS, Zambon MC, Gopal R, Drosten C, van der Werf S, Escriou N, Manuguerra JC, St?hr K, Peiris JS, Osterhaus AD.
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A patient with severe respiratory failure caused by novel human coronavirus.
Guberina H, Witzke O, Timm J, Dittmer U, M?ller MA, Drosten C, Bonin F.
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Performance and clinical validation of the RealStar<sup>?</sup> MERS-CoV Kit for detection of Middle East respiratory syndrome coronavirus RNA.
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Plaque assay for human coronavirus NL63 using human colon carcinoma cells.
Herzog P, Drosten C, M?ller MA.
Virol J. 2008 Nov 12;5:138. doi: 10.1186/1743-422X-5-138.

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[Relevance of coronaviruses. The SARS example].
Schmitz H, Drosten C.
Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2004 Jul;47(7):647-52. Review. German.

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Replication of human coronaviruses SARS-CoV, HCoV-NL63 and HCoV-229E is inhibited by the drug FK506.
Carbajo-Lozoya J, M?ller MA, Kallies S, Thiel V, Drosten C, von Brunn A.
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Replicative Capacity of MERS Coronavirus in Livestock Cell Lines.
Eckerle I, Corman VM, M?ller MA, Lenk M, Ulrich RG, Drosten C.
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Retroviral vectors pseudotyped with severe acute respiratory syndrome coronavirus S protein.
Giroglou T, Cinatl J Jr, Rabenau H, Drosten C, Schwalbe H, Doerr HW, von Laer D.
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Reverse genetic characterization of the natural genomic deletion in SARS-Coronavirus strain Frankfurt-1 open reading frame 7b reveals an attenuating function of the 7b protein in-vitro and in-vivo.
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The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors.
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SARS molecular detection external quality assurance.
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Laidback Al · Apr 28, 2014

Re: MERS discussion thread

Giuseppe Michieli said:
We can't assume that chain of infections exceeded tertiary level, as far as it is known.

The data is murky, mostly because the precise willingness of the saudi govt.

Data must be murky, they should have thought.

There is not a single word about the kind of health care settings patients firstly became infected: acute, long-term, tertiary, insane asylums, disabled people care centres?

The infection control measures differ likely among several kind of health care settings.

Even with the knowledge of hospital transmission of this coronavirus, nosocomial infections are still occurring. Among the cases reported by Saudi Arabia Ministry of Health in the past few days, at least four of them from four different hospitals in Jeddah were hospital patients for other reasons and developed symptoms while in the health care facility.

 April 27, 2014
1. Yemeni national, 75 years old, entered Erfan Hospital on March 21,2014, exhibited respiratory symptoms on April 21, 2014 and is now in treatment.
Link: http://www.flutrackers.com/forum/showpost.php?p=532930&postcount=1

April 26, 2014
2. Ethiopian national, 30 years old, entered King Fahd Hospital April 9, 2014, developed respiratory symptoms on April 23, 2014 and receiving treatment for intensive care.
3. Yemeni national, 42 years old, enter the King Fahd Hospital on April 17, 2014, developed respiratory symptoms on April 20, 2014 and is now in stable condition.
4. Saudi resident (?), 60 year old, entered the King Faisal Specialist Hospital on March 13, 2014 and developed respiratory symptoms on April 23, 2014 and is receiving treatment in intensive care.
Link: http://www.flutrackers.com/forum/showpost.php?p=532837&postcount=1

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sharon sanders · May 4, 2014

Re: MERS discussion thread

I think the continued UAE cases represent a wider community spread. We are way beyond the 14 day incubation period since the initial paramedic outbreak on April 6.

Also, in Saudi Arabia, the percentage of health care workers being reported as positive for coronavirus MERS has dipped to between 0 and 11% in the last week. Health care workers were about 50% of the cases announced earlier in this outbreak Spring 2014. Has this disease become a community spread disease, or are health care workers under reported?

Giuseppe · May 4, 2014

Re: MERS discussion thread

Some recent reported KSA cases are long-term multi-medical conditions patients (sometimes in hospital for months before onset of MERS).

I think cases will continue to be reported in some nosocomial settings AND in the community as the source (camels) are well active AND secondary contacts will continue to fall ill.

Continuing reporting of asymptomatic cases are of unclear singificance in current epidemiology undestanding of MERS-CoV.

Laidback Al · May 4, 2014

Re: MERS discussion thread

Giuseppe Michieli said:
. . . Continuing reporting of asymptomatic cases are of unclear singificance in current epidemiology undestanding of MERS-CoV.

From a public relations standpoint it lowers the CFR.

Vibrant62 · May 4, 2014

Re: MERS discussion thread

It also gives a level of 'silent' infections. If there are widespread community infections which are arising and detected as serious cases get referred to hospitals, then there may be a similar number of silent index case infections in the community, which we will be unaware of.

What we dont know is if asymptomatic carriers or mild cases can infect others.

The biggest challenge is how we can break the camel/human interface that creates novel infection chains.

I wonder how far along the development process a camel vaccine might be? And how long it would last before the virus evaded any vaccine that was developed? A camel vaccine has to be the priority right now I would think.

Laidback Al · May 5, 2014

Re: MERS discussion thread

Vibrant62 said:
It also gives a level of 'silent' infections. If there are widespread community infections which are arising and detected as serious cases get referred to hospitals, then there may be a similar number of silent index case infections in the community, which we will be unaware of.

What we don't know is if asymptomatic carriers or mild cases can infect others. . . .

We just don't know how these asymptomatic cases are being identified. It is doubtful that serological studies are being conducted. It is likely that all of these asymptomatic cases are identified through contact tracing after a serious case has been hospitalized. The hospitalized patient may or may not be the index case in these local clusters.

It would be hard to quantify the number of MERS spreaders or super-spreaders based on these data.

Emily · May 5, 2014

Re: MERS discussion thread

Vibrant62 said:
It also gives a level of 'silent' infections. If there are widespread community infections which are arising and detected as serious cases get referred to hospitals, then there may be a similar number of silent index case infections in the community, which we will be unaware of.

What we dont know is if asymptomatic carriers or mild cases can infect others.

The biggest challenge is how we can break the camel/human interface that creates novel infection chains.

I wonder how far along the development process a camel vaccine might be? And how long it would last before the virus evaded any vaccine that was developed? A camel vaccine has to be the priority right now I would think.

People are the ones getting sick, so I think a human vaccine and/or treatment should be the research priority even if it is proven that camels or camel products are transmitting the disease to humans. The disease is not a health problem for camels, and if you attempt to eradicate a mild virus in a species, you could drive the evolution of a more dangerous virus for that species, or worse - for us.

My sense is that in recent years popular press attention to promising scientific research into anti-cancer properties, (among other chronic illness benefits), of camel milk and urine caused immune-suppressed people to seek these alternative biological treatments in greater numbers than ever before. Then when infected, the disease is brought by them back into modern hospitals.

http://www.flutrackers.com/forum/showthread.php?t=222354

I read in one of the old texts online that hundreds of years ago camel urine was boiled prior to medicinal use, so they knew back then that camel urine could carry disease to sick people, but I don't get the impression that this is always done today with the market for treatment getting so large. I think novices are providing the products in some cases.

It doesn't seem impossible to me to get the word out to pasteurize not just camel foods, but camel-derived medicinal biologicals. But then it has been difficult to get infection control in place, too, for some reason.

This article has some information about the hurdles a camel vaccine program would face:

http://www.sciencemag.org/content/343/6178/1422.full.pdf%28paywall%29

Science 28 March 2014:
Vol. 343 no. 6178 pp. 1422-1425
DOI: 10.1126/science.343.6178.1422

Vibrant62 · May 5, 2014

Re: MERS discussion thread

Good article.

However, I think it highlights just how difficult it is going to be to make a vaccine for camels or humans.

For me the central issue is that if we dont break the camel/human interface then the problem is not going to go away, as unlike SARS where it was relatively easy to break the Civet cat/ human interface, camels are an integral part of society in many countries. Its not like chickens which you can cull; the societies that have/ use camels would never permit this.

Without finding a way to control this in camels, we are accepting that MERS WILL go to a global pandemic at some point.

If we take the human only approach, then an annual (depending on mutation rates and how long vaccine coverage would last for) MERS vaccine would be needed in humans, just to protect if from novel re-introductions and or mutations. We could no more vaccinate all at risk people in the Middle East/ Africa than we could camels, and the same safety and development hurdles exist for both animals and humans.

This assumes that the hurdles over developing ANY vaccine can be overcome. I think I would rather have an animal model to test in first, as there are some significant safety issues here.

Given the issues with developing an animal model, I think we just need some labs capable of handling camels brought into existance ASAP!

Shannon Bennett · May 5, 2014

Re: MERS discussion thread

I wonder how long this disease was in camel herds? Was it, two years, 6 years, always? Why is it now affecting humans? Why is the number of sick humans escalating so fast as the virus has remained essentially unchanged over the last two years? I have trouble believing chronically sick people are still using camel urine. So many questions and so few answers.

Shannon Bennett · May 5, 2014

Re: MERS discussion thread

Well I was able to find the answer to one of the above questions. MERS was found in camel herds at least as far back as 2003. Although we still don't know if the virus has changed to something more 'human' since then.
http://www.flutrackers.com/forum/sh...hlight=Study:+MERS-CoV-like+virus+camels+2003

Vibrant62 · May 5, 2014

Re: MERS discussion thread

We were picking up reports of abnormal pneumonia related camel deaths on FT as far back as 2010. Perhaps this was when the virus completed its adaptation to camels??

http://www.flutrackers.com/forum/showthread.php?t=209973

Emily · May 5, 2014

Re: MERS discussion thread

The estimate of how long MERS-like viruses have infected camels was updated since the CIDRAP article referenced above:

http://news.sciencemag.org/health/2014/02/deadly-mers-virus-has-infected-camels-least-1992

The researchers also looked at more than 100 camel serum samples from an archive going back to 1992 and found antibodies against MERS in almost all of them. "This virus has clearly been in camels since at least 1992," Lipkin says.

The paper adds to the growing evidence on the animal reservoir of MERS, says Marion Koopmans, an infectious disease researcher at the National Institute of Public Health and the Environment in Bilthoven, the Netherlands. "It is now undisputable that these viruses circulate among dromedary camels," she writes in an e-mail.

Bart Haagmans, a virologist at Erasmus MC in Rotterdam, the Netherlands, says he is surprised that viral RNA could be found in so many of the animals. "You don't expect to find a virus for a respiratory infection in almost one in four animals," he says. It suggests that the virus knows how to maintain itself in the camel population very well. It's not clear whether the virus actually makes camels sick, but it seems to infect many camels at a young age, Haagmans says. Most scientists agree that studies looking at infected camels over time are needed to find out how long they can harbor the virus.

Couldn't that also suggest cross-contamination of samples?

Emily · May 5, 2014

Re: MERS discussion thread

Shannon said:
I wonder how long this disease was in camel herds? Was it, two years, 6 years, always? Why is it now affecting humans? Why is the number of sick humans escalating so fast as the virus has remained essentially unchanged over the last two years? I have trouble believing chronically sick people are still using camel urine. So many questions and so few answers.

Shannon, I have observed that when faced with a terminal or disabling/painful/disfiguring disease and no hope for cure or relief from suffering, the normal drive to survive and/or find relief from suffering will lead people to take risks with CAM just as they do with conventional treatments. Also there has been a widely held belief that urine is sterile. I see people telling each other that on the Internet.

Even western doctors thought urine of healthy women was sterile and that contamination occurred during collection:
http://www.medscape.com/viewarticle/762048

Medscape Medical News
Urine is Not Sterile, PCR Analysis Shows

Jenni Laidman
April 13, 2012
...
"The punch line is, there really are bacteria in the bladders of a lot of women between the ages of 35 and 82. We don't know how it got there. We don't know what it's doing there. We don't know whether it's related to disease, or if it's related to health," Dr. Wolfe told Medscape Medical News. "Now it's time to figure out what they're doing."

"This is going to redefine the way we look at disease," Deborah Lightner, MD, professor of urology, Mayo Clinic, Rochester, Minnesota, said. "It's going to produce a great flurry of research activity...

Even if it turns out that camels are not the source of human MERS disease, the word needs to get out about CAM use of urine. I get the impression that the active constituents are not heat sensitive, so any effectiveness would not seem diminished if heat treated to make it biologically safe.

Emily · May 5, 2014

Re: MERS discussion thread

Vibrant62 said:
Good article.

However, I think it highlights just how difficult it is going to be to make a vaccine for camels or humans.

For me the central issue is that if we dont break the camel/human interface then the problem is not going to go away, as unlike SARS where it was relatively easy to break the Civet cat/ human interface, camels are an integral part of society in many countries. Its not like chickens which you can cull; the societies that have/ use camels would never permit this.

Without finding a way to control this in camels, we are accepting that MERS WILL go to a global pandemic at some point.

If we take the human only approach, then an annual (depending on mutation rates and how long vaccine coverage would last for) MERS vaccine would be needed in humans, just to protect if from novel re-introductions and or mutations. We could no more vaccinate all at risk people in the Middle East/ Africa than we could camels, and the same safety and development hurdles exist for both animals and humans.

This assumes that the hurdles over developing ANY vaccine can be overcome. I think I would rather have an animal model to test in first, as there are some significant safety issues here.

Given the issues with developing an animal model, I think we just need some labs capable of handling camels brought into existance ASAP!

Vibrant,
You make a good point about the vaccine risk for humans. If we were 100% sure that camels were the source of human infections and that people were being infected in a way that was not controlled with basic public health measures, a camel vaccine could be the solution, especially if progress into finding treatments doesn't progress. (My favorite camel vaccine idea from the Science article is the one that would prevent camelpox at the same time.)

But the questions that you and Shannon are raising about why are people getting MERS now if camels have carried the disease for so long are good questions that remain unanswered. I think part of the problem is that researchers do not have access to most of the human samples.

I don't think it is certain that even if camels are the source of human infections, MERS will become a global pandemic even if it is not eradicated in camels. It seems possible that this one genotype could disappear, or lose its ability to infect humans:

http://www.flutrackers.com/forum/showthread.php?t=222419

However, in contrast to individual human cases, where only clonal genomic sequences are reported, detailed population analyses revealed the presence of more than one genomic variant in individual dromedaries. If humans are truly infected only with clonal virus populations, we must entertain a model for interspecies transmission of MERS-CoV wherein only specific genotypes are capable of passing bottleneck selection.

Briese T, Mishra N, Jain K, Zalmout IS, Jabado OJ, Karesh WB, Daszak P, Mohammed OB, Alagaili AN, Lipkin WI. 2014. Middle East respiratory syndrome coronavirus quasispecies that include homologues of human isolates revealed through whole-genome analysis and virus cultured from dromedary camels in Saudi Arabia. mBio 5(3):e01146-14. doi:10.1128/mBio.01146-14.

Also, more research into transmission modes could be done and basic public health changes made as a result:
http://virologydownunder.blogspot.com/2014/04/mers-and-camelsurine-drinking-seems-to.html
MERS and camels....urine drinking seems to be a very wide ranging thing...

MERS discussion thread

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