EBOLA UPDATE (41): BIOMARKERS, DIAGNOSTICS, NEWS

Posted on 19TH NOV 2017
tagged Ebola, Worldwide

A ProMED-mail post
http://www.promedmail.org
ProMED-mail is a program of the
International Society for Infectious Diseases
http://www.isid.org

In this update:
[1] Biomarkers of severe disease
[2] Diagnostic approach
[3] News scan
[4] News scan 2

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[1] Biomarkers of severe disease
Date: Thu 16 Nov 2017
Source: Eureka Alert [edited]
https://www.eurekalert.org/pub_releases/2017-11/uow-ith111417.php

In a comprehensive and complex molecular study of blood samples from Ebola patients in Sierra Leone, published today [Thu 16 Nov 2017] in Cell Host and Microbe, a scientific team led by the University of Wisconsin-Madison has identified signatures of Ebola virus disease that may aid in future treatment efforts.

Conducting a sweeping analysis of everything from enzymes to lipids to immune-system-associated molecules, the team -- which includes researchers from Pacific Northwest National Laboratory (PNNL), Icahn School of Medicine at Mount Sinai, the University of Tokyo and the University of Sierra Leone -- found 11 biomarkers that distinguish fatal infections from nonfatal ones and 2 that, when screened for early symptom onset, accurately predict which patients are likely to die.

With these results, says senior author Yoshihiro Kawaoka, a virology professor at the UW-Madison School of Veterinary Medicine, clinicians can prioritize the scarce treatment resources available and provide care to the sickest patients.

Studying Ebola in animal models is difficult; in humans, next to impossible. Yet, in Sierra Leone in 2014, a natural and devastating experiment played out. In September of that year, an Ebola outbreak like no other was beginning to surge in the West African nation. By December, as many as 400 Ebola cases would be reported there each week.

That fall, Kawaoka sought access to patient samples. He has spent a career trying to understand infectious diseases like Ebola -- how do they make people sick, how do bodies respond to infection, how can public health officials stay at least a step ahead? "Here, there is a major outbreak of Ebola. It is very rare for us to encounter that situation," says Kawaoka, who is also a professor of virology at the University of Tokyo.

Yet blood samples were proving difficult to obtain and people continued to die.

Then, just weeks before Christmas, Kawaoka learned about a colleague in his very own department at UW-Madison, a research fellow from Sierra Leone named Alhaji N'jai, who was producing radio stories for people back home to help them protect themselves from Ebola. The pair forged a fortuitous partnership.

"He knows many people high up in the Sierra Leone government," says Kawaoka. "He is very smart and very good at explaining things in lay terms."

By Christmas, Kawaoka, N'jai and Peter Halfmann, a senior member of Kawaoka's team, were in Sierra Leone.

"On the 1st trip, Alhaji took me to Parliament and we talked to a special advisor to the president, then the vice chancellor of the University of Sierra Leone," says Kawaoka. "We got the support of the university, which helped us identify military hospitals and provided space. We went to the Ministry of Health and Sanitation and the chief medical officer and we explained what we hoped to do."

By February of 2015, Kawaoka and other select senior researchers on his team, including Amie Eisfeld, set up a lab in a military hospital responding to the outbreak in the capital city of Freetown (the researchers never entered patient wards). With the approval of patients and the government of Sierra Leone, health workers collected blood samples from patients after they were diagnosed with Ebola and at multiple points thereafter.

They obtained 29 blood samples from 11 patients who ultimately survived and 9 blood samples from 9 patients who died from the virus. The samples were transported to the lab where Kawaoka's experienced and expertly trained team inactivated the virus according to approved protocols. Blood samples were subsequently shipped to UW-Madison and partner institutions for analysis.

For comparison, the research team also obtained blood samples from 10 healthy volunteers with no exposure to Ebola virus.

"Our team studied thousands of molecular clues in each of these samples, sifting through extensive data on the activity of genes, proteins and other molecules to identify those of most interest," says Katrina Waters, a biologist at PNNL and a corresponding author of the study. "This may be the most thorough analysis yet of blood samples of patients infected with the Ebola virus."

The team found that survivors had higher levels of some immune-related molecules, and lower levels of others compared to those who died. Plasma cytokines, which are involved in immunity and stress response, were higher in the blood of people who perished. Fatal cases had unique metabolic responses compared to survivors, higher levels of virus, changes to plasma lipids involved in processes like blood coagulation, and more pronounced activation of some types of immune cells.

Pancreatic enzymes also leaked into the blood of patients who died, suggesting that damage from these enzymes contributes to the tissue damage characteristic of fatal Ebola virus disease.

And, critically, the study showed that levels of 2 biomarkers, known as L-threonine (an amino acid) and vitamin D binding protein, may accurately predict which patients live and which die. Both were present at lower levels at the time of admission in the patients who ultimately perished.

"We want to understand why those 2 compounds are discriminating factors," says Kawaoka. "We might be able to develop drugs."

When Ebola virus leads to death, experts believe it is because of overwhelming viral replication. Symptoms of infection include severe hemorrhaging, vomiting and diarrhea, fever and more.

Kawaoka and his collaborators hope to better understand why there are differences in how patients' bodies respond to infection, and why some people die while others live. The current study is part of a larger, multicenter effort funded by the National Institutes of Health.

"The whole purpose is to study the responses of human and animal bodies to infection from influenza, Ebola, SARS and MERS, and to understand how they occur," Kawaoka explains. "Among the various pathways, is there anything in common?"

In the current Ebola study, the team found that many of the molecular signals present in the blood of sick, infected patients overlap with sepsis, a condition in which the body -- in response to infection by bacteria or other pathogens -- mounts a damaging inflammatory reaction.

And the results contribute a wealth of information for other scientists aimed at studying Ebola, the study authors say....-more

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Communicated by:
ProMED-mail from HealthMap Alerts

[Citation. Eisfeld et al., Multi-platform 'Omics Analysis of Human Ebola Virus Disease Pathogenesis, Cell Host & Microbe
(2017), https://doi.org/10.1016/j.chom.2017.10.011

Supplemental Information includes 7 figures and 7 tables and can be found with this article online at https://doi.org/10.1016/j.chom.2017.10.011.

Summary
"The pathogenesis of human Ebola virus disease (EVD) is complex. EVD is characterized by high levels of virus replication and dissemination, dysregulated immune responses, extensive virus and host-mediated tissue damage, and disordered coagulation. To clarify how host responses contribute to EVD pathophysiology, we performed multi-platform 'omics analysis of peripheral blood mononuclear cells and plasma from EVD patients. Our results indicate that EVD molecular signatures overlap with those of sepsis, imply that pancreatic enzymes contribute to tissue damage in fatal EVD, and suggest that Ebola virus infection may induce aberrant neutrophils whose activity could explain hallmarks of fatal EVD. Moreover, integrated biomarker prediction identified putative biomarkers from different data platforms that differentiated survivors and fatalities early after infection. This work reveals insight into EVD pathogenesis, suggests an effective approach for biomarker identification, and provides an important community resource for further analysis of human EVD severity."

(See full article for figures and discussion.)

This paper is highly recommended reading. The development of human disease-specific biomarkers for the early diagnosis and prediction of disease severity is a new frontier in science. Using multi-platform 'omics analysis of peripheral blood mononuclear cells and plasma from EVD patients, this work contributes significantly to our understanding of virus-host interactions increasing our knowledge base on pathophysiology of Ebola infection. A panel of biomarkers could assist evaluation of new treatments to improve the outlook for those who may develop severe disease. If the biomarker could be monitored over time, it could be a powerful tool to monitor the impact of treatment in real time. - Mod.LK]

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[2] Diagnostic approach
Date: Sat 11 Nov 2017
Source: The Lancet [edited]
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31224-2/fulltext?elsca1=etoc

Citation. MD Perkins et al. Diagnostic preparedness for infectious disease outbreaks. The Lancet 390 (10108): 2211-2214, 11 November 2017. DOI: http://dx.doi.org/10.1016/S0140-6736(17)31224-2

Summary
Diagnostics are crucial in mitigating the effect of disease outbreaks. Because diagnostic development and validation are time consuming, they should be carried out in anticipation of epidemics rather than in response to them. The diagnostic response to the 2014-15 Ebola epidemic, although ultimately effective, was slow and expensive. If a focused mechanism had existed with the technical and financial resources to drive its development ahead of the outbreak, point-of-care Ebola tests supporting a less costly and more mobile response could have been available early on in the diagnosis process. A new partnering model could drive rapid development of tests and surveillance strategies for novel pathogens that emerge in future outbreaks. We look at lessons learned from the Ebola outbreak and propose specific solutions to improve the speed of new assay development and ensure their effective deployment. ...

We propose to set up a dedicated diagnostic product development effort, coordinated by the Foundation for Innovative New Diagnostics (FIND) and based on collaborations with key diagnostic partners, which would work under the auspice of the Coalition for Epidemics and Preparedness Innovations (CEPI)16,17 with the specific goal of ensuring that diagnostic outbreak needs are comprehensively addressed. Such a partnering model between CEPI, FIND, and other key diagnostics players such as Institut Pasteur (CEPIdx) would need to have a unified vision for achieving diagnostic preparedness and response. ...

The formation of CEPIdx would improve coordination, collaboration, and accountability for diagnostic preparedness. It would focus on the pragmatic issues that need to be addressed to achieve success, and leverage multi-disciplinary experts across research and development, clinical trials, ethics, sociology and anthropology, regulation, manufacturing, and product delivery. Additionally, it could play an instrumental role in designing and managing the finance and coordination mechanisms needed to overcome weak market forces.

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Communicated by:
ProMED-mail Rapporteur Mary Marshall

[Too often public health is responsive rather than preventive, with the exception of those diseases for which vaccines exist, such as measles, mumps, rubella, flu, polio, small pox, yellow fever and more. The collaborative approach described in the report above should assist in changing this paradigm for novel pathogens. - Mod.LK]

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[3] News scan
Date: Tue 31 Oct 2017
Source: Cidrap [edited]
http://www.cidrap.umn.edu/news-perspective/2017/10/news-scan-oct-31-2017

Greater participation in funerals may be one reason Ebola case-fatality rates are higher in elderly people, compared to their younger adult counterparts, researchers from Guinea reported yesterday [Mon 30 Oct 2017] in the American Journal of Tropical Medicine and Hygiene [see citation below].

They looked at patterns in adults age 20 and older who were admitted to Ebola treatment centers in Guinea between Jan 2014 and Dec 2015. The group included 2004 adults, which included 309 people who were elderly (age 60 and older).

Funeral participation, including washing and handling the dead body, was found to be a risk factor in West Africa's Ebola outbreak, and according to the authors, older people play a key role in funeral activities, including leading ceremonies and performing rituals and burial.

Their analysis found that the proportion of funeral participation was higher in the elderly group, compared to the younger adults. Also, duration between symptom onset and treatment center admission was significantly longer in the older group, which the team said could also play a role in the higher case-fatality rate, which was 80.6 percent in the elderly group, compared to 66.2 percent in the adult group.

Citation.
MS Cherif et al. Prognostic and Predictive Factors of Ebola Virus Disease Outcome in Elderly People during the 2014 Outbreak in Guinea . Am J Trop Med Hyg. 2017 Oct 30. doi: 10.4269/ajtmh.17-0372. [Epub ahead of print]

Abstract. Elderly people occupy a prominent position in African societies; however, their potential linkage to high case fatality rate (CFR) in Ebola virus disease (EVD) was often overlooked. We describe the predictive factors for EVD lethality in the elderly. A total of 2004 adults and 309 elderly patients with confirmed EVD were included in the analysis. The median age (interquartile range) was 35 years (23-44) in adults and 65 years (60-70) in the elderly. The proportion of funeral participation was significantly higher in the elderly group than in the adult group. Duration (in days) between the onset of symptoms and admission was significantly longer in elderly. CFR in the elderly people was also significantly higher (80.6 percent) than in the adult group (66.2 percent). Funeral participation constituted a risk factor for the transmission of EVD in elderly people.

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Communicated by:
ProMED-mail

[Funeral participation as a major risk factor for severe disease and high rate of mortality from Ebola should be able to be addressed in future outbreaks with education, particularly of the segment of the population over 60 years old. - Mod.LK]

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[4] News scan 2
Date: Tue 31 Oct 2017
Source: Cidrap [edited]
http://www.cidrap.umn.edu/news-perspective/2017/10/news-scan-oct-31-2017

In another Ebola research development, recent deforestation in Central and West Africa may increase the probability of an Ebola outbreak, an international research team reported yesterday [Mon 30 Oct 2017] in the latest issue of Scientific Reports [see citation below]. Deforestation is thought to increase contacts between humans and animals, a factor thought to increase the zoonotic disease threat.

They examined deforestation data between 2001 and 2014, focusing on 27 Ebola outbreak sites since 1976 where index cases were identified. With a modeling tool, they looked at variables to discriminate Ebola outbreak sites from 280 randomly selected control sites where humans lived but no Ebola outbreaks had occurred.

They found that outbreaks along the limits of the rainforest biome were associated with forest losses over the previous 2 years, a connection that was strongest for closed forests across a range of tree heights. Curbing forest losses could reduce the likelihood of future outbreaks, researchers concluded.

Citation. Olivero J et al. Recent loss of closed forests is associated with Ebola virus disease outbreaks. Sci Rep. 2017 Oct 30;7(1):14291. doi: 10.1038/s41598-017-14727-9.

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Communicated by:
ProMED-mail

[The investigators considered different sets of predictors to model, i.e., the spatio-temporal pattern of EVD outbreak occurrences, spatio-temporal association between forest loss and EVD outbreaks, and the association of other environmental factors and EVD outbreaks. Then they estimated the relative contribution of each of those 3 factors in explaining where and when EVD outbreaks occur, by integrating their predictor variables into a single favorability model. See the paper for a full discussion of the importance of each of these sets of variables.- Mod.LK]

[Maps of the West African countries affected by the 2014 Ebola outbreak can be accessed at
Liberia http://healthmap.org/promed/p/54
Guinea http://healthmap.org/promed/p/45
Sierra Leone http://healthmap.org/promed/p/46. - Mod.LK]

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