A Brief History Of Ebola

Range of Reported Ebola Outbreaks 1976-2014 – Credit WHO

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Nearly 10 days ago FluTrackers began to compile and translate a series of vague reports out of the West African nation of Guinea of an unidentified hemorrhagic fever.  Early media reports speculated on Lassa fever as a potential cause. Last week Crof at Crofsblog began to cover these reports as well (see Guinea: Unknown disease evokes Ebola and yellow fever).

 

Yesterday, with the death toll approaching 60,  it was widely reported that this outbreak was due to one of the Ebola virus strains (see Crof’s coverage here, here, and here). 

 

Overnight ProMed Mail published a statement from the National Reference Center for Viral Hemorrhagic Fevers - Institut Pasteur in Lyon, France  (see EBOLA VIRUS DISEASE - WEST AFRICA: GUINEA, ZAIRE EBOLAVIRUS SUSPECT) where testing of samples is ongoing, and they report a `strong homology to Zaire Ebolavirus’, considered to be the deadliest strain.

 

Ebola was first discovered in Zaire and Sudan in 1976 and since then has become almost legendary for its incredibly high fatality rate and gruesome hemorrhagic symptoms.

 

As a public health threat, Ebola – which has been blamed for fewer than 2,000 deaths over the past 30+ years - pales in comparison to most of the world’s less feared infectious diseases. Simple childhood pneumonia, claims 1.8 million lives each year (cite) and Malaria claims between one half, to one million lives a year (cite).

 

Despite its rarity, movies like 1995’s Outbreak with Dustin Hoffman, and books like Tom Clancy’s Executive Orders and The Hot Zone by Richard Preston, have helped to turn Ebola into the ultimate nightmare disease in the eyes of the public.

 

Fortunately, the spread of these African Viral Hemorrhagic Fevers (VHFs which includes Ebola, Marburg & Lassa) has thus far been geographically limited. The illness strikes quickly, with profound and debilitating symptoms, and that helps to limit human-to-human spread.

 

But as Maryn Mckenna pointed out in her 2010 blog Lassa fever: Coming to an airport near you, with our increasingly mobile population, opportunities for exotic tropical diseases like VHF to hop on an airplane and arrive in any major city in the world are increasing.

 

While the zoonotic reservoir for the Ebola virus has yet to be firmly established, bats are considered to be the most likely candidate. 

 

In 2012 NIAID produced the following short (3 minute) video on Ebola, and the research ongoing in the Congo to determine its source, which also makes a good primer on the disease.

 

There are currently five known strains of the disease, of which four are highly pathogenic in humans. 

 

Ebola Zaire, with a mortality rate approaching 90%, is considered to be the deadliest strain, followed by Ebola Sudan (50%-70% fatal). Taï Forest virus (formerly Côte d’Ivoire ebolavirus) and Bundibugyo ebolavirus (BEBOV) are less well studied, but appear to have lower mortality rates.

 

With no vaccine, and no effective treatment, the primary public health focus during an outbreak is breaking the chain of transmission.  The following comes from the CDC’s Ebola webpage.

 

Prevention

The prevention of Ebola HF presents many challenges. Because it is still unknown how exactly people are infected with Ebola HF, there are few established primary prevention measures.

When cases of the disease do appear, there is increased risk of transmission within health care settings. Therefore, health care workers must be able to recognize a case of Ebola HF and be ready to employ practical viral hemorrhagic fever isolation precautions or barrier nursing techniques. They should also have the capability to request diagnostic tests or prepare samples for shipping and testing elsewhere.

MSF (Médecins Sans Frontières) health staff in protective clothing constructing perimeter for isolation ward.

Barrier nursing techniques include:

• wearing of protective clothing (such as masks, gloves, gowns, and goggles)
• the use of infection-control measures (such as complete equipment sterilization and routine use of disinfectant)
• isolation of Ebola HF patients from contact with unprotected persons.

The aim of all of these techniques is to avoid contact with the blood or secretions of an infected patient. If a patient with Ebola HF dies, it is equally important that direct contact with the body of the deceased patient be prevented.

CDC, in conjunction with the World Health Organization, has developed a set of guidelines to help prevent and control the spread of Ebola HF. Entitled Infection Control for Viral Hemorrhagic Fevers In the African Health Care Setting  [PDF - 2MB], the manual describes how to:

• recognize cases of viral hemorrhagic fever (such as Ebola HF)
• prevent further transmission in health care setting by using locally available materials and minimal financial resources.

 

A listing of known outbreaks over the past 38 years can be found at:

 

Chronology of Ebola Hemorrhagic Fever Outbreaks

 

The odd virus out - Ebola Reston - which can infect and kill non-human primates, has not been shown to produce disease in man (it has been shown to produce serious illness in pigs, however). Ebola Reston is also the only Ebola virus known to be endemic outside of Africa.

 

Ebola Reston was first discovered in crab-eating macaques, imported from the Philippines, at a research laboratory in Reston, Virginia (USA) (hence the name) in 1989. This discovery was recounted in the book, The Hot Zone, by Richard Preston.

 

Since pigs and humans share many commonalities in their physiology (if that induces discomfiture in you, think how the pig feels) any disease that jumps to (and causes illness) in swine is of concern to scientists. 

 

While humans can be infected by the this non-lethal strain (3 researchers in Reston developed high antibody titers to the virus), it has not been shown to cause human illness. In 2009, the World Health Organization reported the following on Ebola Reston infections in humans and pigs in the Philippines.

 

Ebola Reston in pigs and humans in the Philippines

3 February 2009 - On 23 January 2009, the Government of the Philippines announced that a person thought to have come in contact with sick pigs had tested positive for Ebola Reston Virus (ERV) antibodies (IgG). On 30 January 2009 the Government announced that a further four individuals had been found positive for ERV antibodies: two farm workers in Bulacan and one farm worker in Pangasinan - the two farms currently under quarantine in northern Luzon because of ERV infection was found in pigs - and one butcher from a slaughterhouse in Pangasinan. The person announced on 23 January to have tested positive for ERV antibodies is reported to be a backyard pig farmer from Valenzuela City - a neighbourhood within Metro Manila.

(Continue . . .)

 

The good news is, none of the human cases developed signs of illness.

 

The caveat is, that viruses can, and do, mutate over time. And we have no idea what changes would be needed to turn Ebola Reston into a pathogenic virus for humans.

 

For more on the hunt for emerging viruses from the jungles and forests of Africa, you may wish to revisit these blogs:

 

WSJ: Nathan Wolfe & Viral Chatter 

Bushmeat,`Wild Flavor’ & EIDs

Disease Transmission At The Human-Animal Interface

H7N9 Transmission and Replication In The Guinea Pig Model

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While MERS-CoV has captured most of our attention these past few weeks, we continue to keep a wary eye on the H7N9 avian flu virus in China, which last spring suddenly sprang to the top of our `worry list’.   So far, the number of cases reported this fall have been small, but concerns remain that it could return with a vengeance over the winter and spring (see Chinese CDC: Be Alert For H7N9).

 

Over the summer we’ve seen a parade of studies that have painted this emerging virus as being better suited to mammalian hosts, and possessing greater pandemic potential, than any other avian flu studied to date.  A few examples include:

 

Nature: Limited Airborne Transmission Of H7N9 Between Ferrets

BMJ: `Probable Person-to-Person Transmission’ Of H7N9

Lancet: Tropism Of H7N9 In the Human Respiratory Tract

Science: H7N9 Transmissibility Study In Ferrets

 

Although we normally hear about flu research being conducted on ferrets – due to their human-like response (sneezing, coughing) to influenza infections - in recent years a number of researchers have looked at guinea pigs as alternative mammalian model for influenza studies (see PNAS The guinea pig as a transmission model for human influenza viruses by Peter Palese et al. 2006).

 

Bouvier and  Lowen,  in Animal Models for Influenza Virus Pathogenesis and Transmission, describe the advantages of the guinea pig model below:

 

The strengths of the guinea pig model lie in the natural susceptibility of these animals to human influenza virus isolates, the efficiency with which human strains transmit among guinea pigs and the relative ease of obtaining, housing and working with these animals. The main drawback of the guinea pig model for influenza research is the lack of disease signs exhibited by infected animals.

 

Earlier this year (see CIDRAP NEWS report Study: Lab-made H5N1-H1N1 viruses spread in guinea pigs) we learned that Chinese scientists had recently used guinea pigs to study reassortant viruses, explaining:

 

. . .   guinea pigs are comparable with ferrets as models of human flu transmission. Although guinea pigs have both avian and mammalian types of airway receptors, flu viruses that bind only to avian receptors (alpha2,3-linked sialic acids) don't spread by respiratory droplets in the animals, they report.

 

Which brings us to a study, published this week in the Journal of Virology, that looks at how well the newly emerging H7N9 avian flu virus replicates and transmits in guinea pigs.

 

And the answer . . .  pretty darn well.

 

Novel H7N9 influenza virus shows low infectious dose, high growth and efficient contact transmission in the guinea pig model

Jon D. Gabbard, Daniel Dlugolenski, Debby Van Riel, Nicolle Marshall, Summer E. Galloway, Elizabeth W. Howerth, Patricia J. Campbell, Cheryl Jones, Scott Johnson, Lauren Byrd-Leotis, David A. Steinhauer, Thijs Kuiken, S. Mark Tompkins, Ralph Tripp, Anice C. Lowen and John Steel

ABSTRACT

The zoonotic outbreak of H7N9 subtype avian influenza virus that occurred in eastern China in the spring of 2013 resulted in 135 confirmed human cases, 44 of which were lethal. Sequencing of the viral genome revealed a number of molecular signatures associated with virulence or transmission in mammals.

 

Here we report that, in the guinea pig model, a human isolate of novel H7N9 influenza virus, A/Anhui/1/2013 (An/13), is highly dissimilar to an H7N1 avian isolate and instead behaves similarly to a human seasonal strain in several respects. An/13 was found to have a low 50% infectious dose, grow to high titers in the upper respiratory tract, and transmit efficiently among co-caged guinea pigs.

 

The pH of fusion of the HA and the binding of virus to fixed guinea pig tissues were also examined. The An/13 HA displayed a relatively elevated pH of fusion characteristic of many avian strains, and An/13 resembled avian viruses in terms of attachment to tissues. One important difference was seen between An/13 and both the H3N2 human and H7N1 avian viruses: when inoculated intranasally at high dose, only the An/13 virus led to productive infection of the lower respiratory tract of guinea pigs.

 

In sum, An/13 was found to retain fusion and attachment properties of an avian influenza virus but displayed robust growth and contact transmission in the guinea pig model atypical of avian strains and indicative of mammalian adaptation.

 

The bottom line here is the H7N9 virus behaves more like a humanized flu virus than an avian flu virus in the guinea pig model.  And the AN/13 H7N9 virus actually out performed the H3N2 human virus in some respects, traveling more readily from the upper respiratory system to the lower respiratory tract.

 

This study adds to the growing body of evidence showing that the H7N9 virus is better adapted to mammals than other avian flu strains that we’ve observed.  Adaptations, some researchers believe, the virus most likely acquired while inhabiting an (as yet, unidentified) intermediate mammalian host.

 

Whether this ability means H7N9 will turn into a serious global public health threat, is something we will just have to wait to see.  But its ability to infect mammals, `right out of the box’, is impressive. 

 

One of the big unanswered questions regarding this avian virus is:  how, and from what reservoir(s), it is spreading?

 

Poultry and wild birds are immediately suspect, but out of hundreds of thousands of birds tested, only a handful have proven positive (see Poultry Samples Around Dongguan H7N9 Case Test Negative).

 

Last May, the Lancet published Origin and diversity of novel avian influenza A H7N9 viruses causing human infection: phylogenetic, structural, and coalescent analyses by Liu D et al.,  which looked at the virus’s genomic sequences, and found:

 

The novel avian influenza A H7N9 virus might have evolved from at least four origins. Diversity among isolates implies that the H7N9 virus has evolved into at least two different lineages. Unknown intermediate hosts involved might be implicated, extensive global surveillance is needed, and domestic-poultry-to-person transmission should be closely watched in the future.

 

In recent years we’ve discovered a good many mammalian species are capable of hosting various influenza strains, in addition to humans, swine, and equines. The (formerly) pandemic H1N1 2009 flu virus was documented in  turkeys, skunks, ferrets, cats, elephant seals and dogs. While in That Touch Of Mink Flu I wrote about 11 farms in Holstebro, Denmark that were reported to be infected with a variant of the human H3N2 virus.

 

Less commonly reported - camels, whales and seals have all been shown to be susceptible to influenza viruses (cite Evolution and ecology of influenza A viruses R.G. Webster et al.)  In  2012, an avian flu strain was identified in New England seals (see mBio: A Mammalian Adapted H3N8 In Seals).

 

And last year (see EID Journal: Guinea Pigs As Reservoirs For Influenza by Leyva-Grado VH, Mubareka S, Krammer F, Cárdenas WB, Palese P.), we looked at a serological study that found that Peruvian and Ecuadorian guinea pigs – raised as livestock – are commonly infected by influenza A and B viruses. 

 

Despite finding high seroprevalence results, the authors cautioned:

 

We did not determine whether guinea pigs are an incidental host for influenza virus infection or, if instead, the virus has been adapted to these animals or if guinea pigs are a natural reservoir for some influenza viruses.

 

And lastly, in 2010  I wrote a blog entitled Mixing Vessels For Influenza  which explored research done by two wildlife disease experts from the San Diego Zoo - Mark Schrenzel and Bruce Rideout – who identified the North American Striped Skunk - along with a handful of other small carnivores - as potential hosts for influenza reassortment.

 
None of this brings us any closer to knowing what species – other than avian – might be serving as an intermediate host for H7N9.

 

But it does illustrate that there are a wide range of possibilities that ought to be explored and tested.

EID Journal: Guinea Pigs As Reservoirs For Influenza

 

 

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From the CDC’s EID Journal we’ve a new study that looks at influenza infections in farm-raised guinea pigs in Ecuador, that provides several surprising results.

 

Ferrets and mice are often used in influenza research, but neither is truly ideal.

 

So in recent years a number of researchers have looked at guinea pigs as possible model mammalian host for influenza virus studies (see PNAS The guinea pig as a transmission model for human influenza viruses by Peter Palese et al. 2006).

 

The success in using guinea pigs in lab studies has led some scientists to wonder just how guinea pigs might fit into the hosting and spread of flu viruses outside of the laboratory.

 

Which brings us to a dispatch (again from Peter Palese et al.) that was published yesterday in the EID journal called:

 

Dispatch

Influenza Virus Infection in Guinea Pigs Raised as Livestock, Ecuador

Victor H. Leyva-Grado, Samira Mubareka, Florian Krammer, Washington B. Cárdenas, and Peter Palese

Abstract

To determine whether guinea pigs are infected with influenza virus in nature, we conducted a serologic study in domestic guinea pigs in Ecuador. Detection of antibodies against influenza A and B raises the question about the role of guinea pigs in the ecology and epidemiology of influenza virus in the region.

 

 

Guinea pigs are raised and used as food in parts of South America (Peruvians reportedly consume more than 65 million of them each year, and they may also be found on the menu in Bolivia, Ecuador, and Columbia).

 

While the consumption of guinea pigs may seem an unusual culinary choice to many of us, it is so entrenched in the Andean culture that in 1753 - when Marcos Zapata painted his version of `The Last Supper’ for Peru (which now hangs in The Cathedral Of Cusco ) - he depicted Christ and the Apostles dining on a platter of cuy, or guinea pig.

Photo Source – Wikipedia.

 

But I digress . . .

 

Most of these animals are raised on small farms, and often in close contact with other livestock as well as humans.

 

Given these conditions, and their propensity for hosting and spreading influenza in laboratory studies, a seroprevalence study was undertaken to see how widespread influenza infection among guinea pigs might be outside of the laboratory.

 

This study examined blood samples from 40 guinea pigs taken from 3 locations across Ecuador, and subsequently found evidence of previous Influenza A infections in a unusually large number of them.

 

The surprises (of which there were several) included:

 

• The high percentage of positive influenza A samples (50% H1, 45% H3)
• The detection of several (n=14)animals carrying antibodies to an H5 virus
• And perhaps the biggest surprise of all – finding evidence of influenza B infections (previously only thought to infect humans) in 27 of the 40 samples tested.

 

 

An earlier seroprevalence study of influenza A among humans in Ecuador showed a seroprevalence of H1 (5.1%) and H3 (5.5%) -  about 1/10th that found in these guinea pigs.

 

The authors suggest that the way these animals are raised (caged together and in close quarters) may facilitate the spread of influenza. 

 

The discovery of H5 antibodies is intriguing, but since this study only tested only for seroreactivity to parts of the H5 virus, further study will be required to identify and quantify the prevalence of avian influenza viruses in this population.

 

And the last finding - that of Influenza B in roughly 2/3rds of the samples – support the idea that this type of influenza can be readily transmitted from humans to other hosts.

 

The authors write:

 

Further studies are needed to isolate and characterize the type B influenza virus present in the population of guinea pigs to determine if there has been an adaptation to the new host or if the guinea pig is only a transient reservoir for the human virus.

 

The authors conclude this dispatch by stating:

 

We did not determine whether guinea pigs are an incidental host for influenza virus infection or, if instead, the virus has been adapted to these animals or if guinea pigs are a natural reservoir for some influenza viruses. To this end, virus isolation and characterization would be necessary to determine the virus strains circulating in this population. In the laboratory, guinea pigs are infected and efficiently transmit influenza viruses to naive hosts without showing any overt clinical signs of disease (1). Therefore, further studies are needed to address the specific role of guinea pigs raised as livestock in the ecology and epidemiology of influenza viruses in the region.

 

 

For more details on the methods used, the full text is available online at this link.

 

While this research might seem a bit obscure to all but the most ardent infectious disease geeks, it serves to show just how little we still know about influenza viruses and their host range,  and that there are still plenty of surprises waiting out there yet to be uncovered.