Posts Tagged ‘ebola’


Dr. Jean-Jacques Muyembe first encountered Ebola in 1976, before it had been identified. Since then, from his post at the Congo National Institute for Biomedical Research, he has led the global search for a cure.

by EYDER PERALTA

Dr. Jean-Jacques Muyembe says his story starts in 1973. He had just gotten his Ph.D. at the Rega Institute in Belgium. He could have stayed in Europe, but he decided to return to Congo, or what was then known as Zaire, which had only recently attained independence from Belgium.

If he had stayed in Belgium, he says, he would have been doing routine lab work. But in Congo, he would be responsible for the “health of my people.”

“But when I arrived here the conditions of work were not good,” he says. “I had no lab; I had no mice for the experimentation, so it was very difficult to work here.”

Being a microbiologist without mice or a lab was useless, so he took a job as a field epidemiologist. In 1976, he was called to an outbreak of a mysterious disease in central Congo.

Lots of people had died of something that presented like yellow fever, typhoid or malaria. Muyembe arrived to a nearly empty hospital. He says people thought the infection was coming from the hospital, and he found only a mother and her baby.

“I thought that it was malaria or something like this,” he says. “But in the night the baby died, so the hospital was completely empty.”

By morning, as the people of Yambuku heard Muyembe had been sent by the central government in Kinshasa, they started lining up at the hospital hoping he had medicine for them.

“I started to make physical exam,” he says. “But at that time we had no gloves in the whole hospital.”

And, of course, he had to draw blood, but when he removed the syringes, the puncture would gush blood.

“It was the first time for me to see this phenomenon,” he says. “And also my fingers were soiled with blood.”

Muyembe says he washed his hands, but it was really luck that kept him from contracting an infection. He knew immediately this was something he’d never seen before. Some of the Belgian nuns in the village had been vaccinated against yellow fever and typhoid, but this disease was different. It was killing people fast. When he took liver samples with a long needle, the same thing would happen — blood would continue to gush.

He persuaded one of the nuns who had the disease to fly with him to Kinshasa. He took blood samples before she died and sent them to Belgium, where they had an electron microscope to try to identify the culprit. Scientists there and in the United States saw this was a new virus that caused hemorrhagic fever.

They named it Ebola, after a river near the village.

The discovery, says Muyembe, was thanks to a “consortium of research.”

But Google “Who discovered Ebola?” and you get a bunch of names — all of them white Western males. Dr. Jean Jacques Muyembe has been written out of history.

“Yes, but it is …” he pauses. He takes a breath and laughs, looking for the right way to respond.

“Yes. It is not correct,” he says. “It is not correct.”

The man who gets the bulk of the credit for discovering Ebola is Dr. Peter Piot. At the time, he was a young microbiologist at the Institute for Tropical Medicine in Belgium. He was the one to receive the blood samples sent by Muyembe.

He describes his experience in No Time to Lose, a book about his professional life, including his vast work on HIV.

But Ebola was his big break. In the book, he describes how vials of blood had arrived in melting ice, some of them broken.

He describes how the World Health Organization ordered them to give up the samples, to send them to England and eventually the Centers for Disease Control and Prevention in the United States, which was one of the only labs equipped to handle a deadly virus like Ebola.

He describes how angry that made him and Dr. Stefaan Pattyn, the man running the lab at the time, who died in 2008.

“[Pattyn] claimed that we needed a few more days to ready it for transport,” Piot wrote. “So we kept a few tubes of VERO cells, as well as some of the newborn mice, which were dying. Perhaps it was a stubborn rebellion against the whole Belgian history of constantly being forced to grovel to a greater power. That material was just too valuable, too glorious to let it go.”

Almost simultaneously, scientists at the CDC and Piot looked at the samples under an electron microscope and saw a snakelike filament — huge in comparison to other viruses and very similar to the Marburg virus. The CDC, which kept the world’s reference lab for hemorrhagic viruses, confirmed this was something new. This was Ebola.

The Congo National Institute for Biomedical Research sits in the middle of Kinshasa.

There are ragged couches along the corridors and goats feeding in the courtyard. But this is where the bulk of the science is being done on the second largest Ebola outbreak in history.

Tucked in corners around the building, there are high-tech labs. Scientists in full biohazard suits run Ebola samples through sophisticated machines that spit out DNA sequences. On the bulletin boards outside the offices, scientists have pinned papers published in international journals about the science done right here.

Workers are constantly dragging in boxes of brand-new scientific gear. On this day, almost all of them are stamped with the American flag.

It’s no secret there is resentment among scientists here about what many believe is a marginalization of their work by the West.

Joel Lamika, who runs an Ebola smartphone app at the institute, says many foreign governments want to stamp their flags on the work Congolese have done.

“They want to claim like it’s theirs,” he says. “But it is theft.”

Lamika says perhaps one good thing that has come out of this latest Ebola outbreak is that it is giving the world a chance to rewrite history.

Muyembe, he says, is a national hero. His picture is on a huge banner in front of this institute. During previous Ebola outbreaks, and especially the huge one in West Africa that killed more than 11,000 people, the the scientific community used Muyembe as an example of someone who had gotten it right. Under his leadership, Congo had managed to quickly quell nine previous outbreaks.

Maybe this outbreak, he says, will give the world an opportunity to know who Muyembe is.

“It’s time for the world to learn that Ebola was discovered by a Congolese,” he said. “By Dr. Jean-Jacques Muyembe.”

Today, Peter Piot is the director of the prestigious London School of Hygiene and Tropical Medicine. He’s friends with Muyembe and expresses nothing but admiration for not only his scientific prowess, but the way he has managed public health emergencies.

But in his book, he mentions Muyembe only in passing, as a bright scientist constantly pressuring Piot for more resources.

When asked if he feels responsible for writing Muyembe out of history, Piot pauses.

“I think that’s a fair comment,” he says. “But my book was not an attempt to write the history of Ebola, but more my personal experience.”

Piot says at the time of that first Ebola outbreak, African scientists were simply excluded. White scientists — with a colonial mentality — parachuted in, took samples, wrote papers that were published in the West and took all of the credit.

But things are changing, he says. Muyembe, for example, is finally starting to get his due. He was recently given a patent for pioneering the first treatment for Ebola and he has received several international awards, including the Royal Society Africa Prize and, just this year, the Hideyo Noguchi Africa Prize.

“That reflects, I think, the [change in] power relations in global health and science in general,” he said.

During this outbreak, Muyembe has also made a decision many thought unthinkable even a few years ago. He decided that all of the blood samples collected during this Ebola epidemic will stay in Congo. Anyone who wants to study this outbreak will have to come to his institute.

American scientists, who have led the way in studying Ebola, have privately expressed frustrations. But Piot says the decision was obviously made because of how African scientists have been treated. Western scientists, he says, should get over it.

“We have to wake up to two things,” he says. “One, the world has changed. And two, it’s a matter of fairness.”

Muyembe keeps his office ice cold, and when he talks, he nervously drums a pen against his notebook. He’s terribly serious about his work, but he also offers an easy smile as he remembers his work.

The thing that makes him glow is talking about the treatment he developed.

“It is the most important achievement of my life,” he says.

In 1995, during another outbreak, he wondered whether antibodies developed by Ebola survivors could be siphoned from their blood and used to treat new cases. So he injected Ebola patients with the blood of survivors, taking inspiration from a practice used before sophisticated advances in vaccine-making.

“We did eight patients and seven survived,” he says.

The medical establishment wrote him off. He didn’t have a control group, they told him. But Muyembe knew that in this village, Ebola was killing 81% of people. Just this year, however, that science became the foundation of what is now proven to be the first effective treatment against Ebola, saving about 70% of patients.

“But if this idea was accepted by scientists, we [could have] saved a lot of people, a lot of lives,” he says.

You can tell Muyembe is hurt by all this. Ever since he returned to Congo, he has fought for recognition for his country. His whole life, he has dreamed that big science could come out of his home country.

Just as he announced that samples would not leave Congo, he also got a commitment from Japan to build a state-of-the-art research facility right here. Soon, the goats in the courtyard will be gone, replaced by a facility just as good as those in Belgium or in the United States.

At 77, Muyembe says he doesn’t regret coming back to Congo. And, unlike when he returned in 1973, now he has equipment.

“Now I have mice here,” he says, laughing. “I have mice. I have subculture. Now, everything is here.”

His biggest legacy, he says, won’t be that he helped to discover Ebola or a cure for it. It’ll be that if another young Congolese scientist finds himself with an interesting blood sample, he’ll be able to investigate it right here in Congo.

https://www.npr.org/sections/goatsandsoda/2019/11/04/774863495/this-congolese-doctor-discovered-ebola-but-never-got-credit-for-it-until-now?utm_source=Nature+Briefing&utm_campaign=c9c91341f8-briefing-dy-am-20191105&utm_medium=email&utm_term=0_c9dfd39373-c9c91341f8-44039353


Tissue samples from survivors of the Yambuku Ebola outbreak are transported to a field lab.

by Erika Check Hayden

Survivors of the world’s first known Ebola outbreak have immunity to the virus 40 years after they were infected, scientists have found.

“It’s interesting to see that after such a long time, people still have this kind of reactivity against the virus,” says virologist Stephan Becker of the Philipps University of Marburg in Germany. The findings were published online on 14 December in the Journal of Infectious Diseases1.

Becker says that the discovery was “not completely unexpected”, because previous studies had found that survivors had immune responses to Ebola virus as long as 11 years after they were infected2.

But until last year, no one had ever studied immunity in the survivors of the first recorded Ebola outbreak, which occurred in 1976 near the town of Yambuku, in what is now the Democratic Republic of the Congo (DRC).

“Nobody even knew if these people were still alive,” says Anne Rimoin, an epidemiologist at the University of California, Los Angeles (UCLA), and the lead author of the latest study.

Lessons from the past

After the disastrous 2014–16 West African Ebola outbreak that killed 11,310 people, Rimoin decided that it was crucial to find the Yambuku survivors. Many of the tens of thousands of people who survived the more recent outbreak have ongoing health problems, such as eye and joint issues. Rimoin thought that doctors might gain a better understanding of what lies ahead for these people by looking at the Yambuku survivors.

“The aperture for studying these people is closing, and they are our best opportunity to study the decades-long aftermath of Ebola,” Rimoin says.

Her team worked with Sukato Mandzomba, one of the Yambuku survivors, to recruit participants to the study. The group used handwritten maps kept by infectious-disease doctors who worked on the outbreak, which killed 280 people, to find more survivors. Ultimately, 14 people enrolled in the study.

Immune memory

Rimoin and her colleagues set up a mobile lab in Yambuku, and invited the 14 survivors to come to the town from the nearby villages where they lived. Rimoin’s team then collected blood from the survivors, stored the samples in portable freezers and drove them to labs in the capital, Kinshasa, or shipped them to the United States.

There, researchers found that cells from all 14 survivors could make defensive proteins called antibodies in response to portions of the Ebola virus. This means that the survivors’ immune systems recognize the Ebola virus, probably because they have encountered it before.

Immune cells from four of the survivors could prevent Ebola viruses from infecting other cells in the lab, indicating that these people are still protected from new Ebola infections 40 years after they became ill with the virus. It’s this type of immunity that researchers seek to mimic when they make vaccines against viruses, including Ebola; Rimoin says that the latest study could aid these attempts.

Rimoin also wants to continue working with the Yambuku survivors to understand how their infections decades ago affected their lives and their long-term health. The Ebola outbreak devastated the villages around Yambuku. Whole families were wiped out, survivors returned to find their homes and belongings destroyed, and children were moved to orphanages, says Nicole Hoff, country director for the UCLA–DRC Health Research and Training Program in Kinshasa, who has worked with survivors in Yambuku.

One survivor walked 30 kilometres to Yambuku with his adult son to participate in the study, Hoff says. When the man and his wife caught Ebola in 1976, their son was placed in an orphanage 100 kilometres away. The survivor’s wife died of Ebola, but the son escaped from the orphanage and ran home to help his father with his farm.

Hoff says that these men and other survivors were glad that the researchers were interested in their histories.“They can tell you everything that happened to them,” she says. “Their stories are so vivid, despite the fact that all of this happened 40 years ago.”

https://www.nature.com/articles/d41586-017-08664-w

by Jennifer Brown

The recent Ebola outbreak in West Africa has claimed more than 11,300 lives—a stark reminder of the lack of effective options for treating or preventing the disease.

Progress has been made on developing vaccines, but there is still a need for antiviral therapies to protect health care workers and local populations in the event of future outbreaks.

Now, a new study suggests that gamma interferon, an FDA-approved drug, may have potential as an antiviral therapy to prevent Ebola infection when given either before or after exposure to the virus.

The findings, published in the journal PLOS Pathogens, show that gamma interferon, given up to 24 hours after exposure, inhibits Ebola infection in mice and completely protects the animals from death.

Ebola infection appears to be a stepwise process. First, the virus targets and infects macrophages or dendritic cells, two types of immune system cells found in the liver, spleen, and lymph nodes. Ebola then replicates in those cells. Following this initial infection, which happens at day 3 or 4 in non-human primates, Ebola virus is released into the blood and infects a plethora of other different cell populations.

“It goes from an early stage with a very targeted infection of only these few cell types, to everything being infected,” says Wendy Maury, professor of microbiology at the University of Iowa.

“We think what’s happening with gamma interferon is that it’s targeting macrophages and blocking the infection of those initial cell targets so you don’t get the second round of infection.”

The University of Iowa does not have a specializing BioSafety Level 4 (BSL4) lab that is required for experiment using Ebola virus, so the researchers made their initial findings using a surrogate virus, which targets and infects the same cells as Ebola, but does not cause the disease.

This Ebola lookalike—a sheep in wolf’s clothing—consists of a less dangerous vesicular stomatitis virus (VSV) that expresses Ebola glycoproteins on its surface.

All of the results found using the surrogate virus were then repeated using mouse-adapted Ebola virus in the BSL4 lab of Maury’s longtime collaborator Robert Davey at Texas Biomedical Institute in San Antonio, Texas.

Gamma interferon inhibits the virus’s ability to infect human and mouse macrophages, in part by blocking virus replication in the cells. Pre-treating mice with interferon gamma 24 hours before exposure protects the animals from infection and death. The researchers were surprised to find that treatment up to 24 hours after what would have been a lethal exposure also completely protected the animals from death, and they could no longer detect any Ebola virus in the mouse’s cells.

The findings suggest that interferon gamma may be useful both as a prophylaxis and post-exposure treatment against Ebola. The team still has to determine how late gamma interferon can be given to the mice and still prevent infection. However, the results suggest a window of time after exposure when gamma interferon may be an effective antiviral therapy.

“My guess is that if you delay the gamma interferon too much, you miss this window of opportunity to block the infection in macrophage cells and the gamma interferon can no longer provide protection,” Maury says.

Maury and colleagues investigated how gamma interferon might be helping the cells fight off the Ebola virus. They identified that the expression of more than 160 genes in human macrophages is stimulated by gamma interferon. Introduction of some of these genes into cells was sufficient to prevent Ebola infection.

“This mechanistic information might suggest more precise drug targets rather than the broad effects, including adverse side-effects, that are produced by gamma-interferon,” she says.

Gamma interferon is already approved by the FDA to treat chronic granulomatous disease (an immune disease) and severe malignant osteopetrosis.

In addition to moving the studies into larger animal models, Maury next plans to study the ability of gamma interferon to inhibit Ebola infection in conjunction with other developing antivirals.

“Right now, there are no FDA-approved antiviral therapies for Ebola, but there are some being developed that target virus entry,” she says. “We know that gamma interferon blocks replication but not entry into cells. So combining an entry inhibitor with gamma interferon may allow us to reduce amount of gamma interferon needed and target two different steps in the virus’s life cycle, which has been shown in HIV to be critically important for controlling the virus.”

http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1005263

http://now.uiowa.edu/2015/12/fda-approved-drug-protects-mice-ebola

American doctor Ian Crozier was treated for Ebola in Atlanta last year and declared free of the virus in his blood. But he had no way of knowing it still lurked in his eye.

About two months after being released from the hospital, he experienced a piercing pain in his left eye, he told The New York Times. The pressure in his eye elevated while his vision decreased.

After repeated tests, doctors discovered the virus was still living in his eye.

“It felt almost personal that the virus could be in my eye without me knowing it,” he told the paper.

His case has left doctors stunned and highlighted the need for eye checkups for Ebola survivors.

Crozier, 44, was hospitalized at Emory University Hospital for more than a month in September after contracting the disease in Sierra Leone, where he worked at a hospital.

At the time, the hospital said he was the sickest of all the four Ebola patients treated there.

Crozier was discharged in October, and about two months later, he developed eye problems and returned to Emory. Doctors stuck a needle in his eye and removed some fluid, which tested positive for the virus.

“Following recovery from Ebola virus disease, patients should be followed for the development of eye symptoms including pain, redness, light sensitivity and blurred vision, which may be signs of uveitis,” said Steven Yeh, associate professor of ophthalmology at Emory University School of Medicine.

Uveitis is an inflammation of the eye’s middle layer. Ebola is also known to live in semen months after it’s gone from the blood.

No risk of spreading the virus

Despite the presence of the virus in the eye, samples from tears and the outer eye membrane tested negative, which means the patient was not at risk of spreading the disease during casual contact, Emory said in a statement Thursday.

It did not name the patient, but The New York Times did. The New England Journal of Medicine also released a study on the case.

Though the patient was not at risk of spreading the virus, all health care providers treating survivors, including eye doctors, must follow Ebola safety protocols, said Jay Varkey, assistant professor at Emory University School of Medicine.

Ebola patient for a second time

When the virus was found in Crozier’s eye, the eye started losing its original blue hue, he told the paper.

Bewildered, doctors tried different forms of treatment as he relived his Ebola nightmare.

They gave him a steroid shot above his eyeball and had him take an experimental antiviral pill that required special approval from the Food and Drug Administration, the Times reported.

His eye gradually returned to normal, but it’s unclear whether it was as a result of the steroid shot, pill or his body’s immune system.

While Ebola survivors in West Africa have reported eye problems, it’s unclear how prevalent the condition is and how often it happens.

“These findings have implications for the thousands of Ebola virus disease survivors in West Africa and also for health care providers who have been evacuated to their home countries for ongoing care,” Varkey said. “Surveillance for the development of eye disease in the post-Ebola period is needed.”

http://www.cnn.com/2015/05/08/health/ebola-eye-american-doctor/index.html

A family of viruses that Ebola belongs to may have existed over 20 million years ago, according to a new study published in the journal PeerJ.

Researchers from the University of Buffalo found that Filoviruses did not begin appearing 10,000 years ago as previously thought, but in fact have been around for much longer. The Ebola virus belongs to the family of filoviruses, also known as the Filoviridae family. “Filoviruses are far more ancient than previously thought,” said Derek Taylor, lead author of the study and a professor of biological sciences at the University of Buffalo, in the press release. “These things have been interacting with mammals for a long time, several million years.”

Despite the fact that scientists around the world are frantically searching for a cure and better treatment for Ebola, there’s still much to learn about the deadly virus. The authors of the study argue that better understanding Ebola’s evolutionary roots could “affect design of vaccines and programs that identify emerging pathogens.”

The study focused not on Ebola specifically, but the ancestors and family of Ebola to better understand where it may have come from. Both the Ebola virus and Marburg virus — also a hemorrhagic fever virus that belongs to the Filoviridae family — were found to be tied to ancient evolutionary lines, and they shared a common ancestor 16 to 23 million years ago. The authors discovered this by examining viral fossil genes, which are bits of genetic material that animals acquire from viruses during infection. They found Filovirus-like genes in rodents, particularly hamsters and voles, which means that the filovirus family is likely as old as these rodents’ common ancestor. The genetic material in these fossils were more closely related to Ebola than Marburg, meaning the two lines had already begun to diverge during the Miocene Epoch, a time period that occurred five to 23 million years ago. During this time, there were also warmer climates, as well as the first appearances of kelp forests and grasslands on Earth.

“These rodents have billions of base pairs in their genomes, so the odds of a viral gene inserting itself at the same position in different species at different times are very small,” Taylor said. “It’s likely that the insertion was present in the common ancestor of these rodents.”

The Filoviridae family is defined by viruses that form virions, or filamentous infectious viral particles. The Ebola virus and Marburg virus are the most well-known among this group, and they are both severe viruses that cause hemorrhagic fevers in both animals and humans (essentially, they’re deadly diseases that lead to fever and bleeding).

Taylor believes that the study may help in the fight against Ebola by widening our knowledge about its history, and identifying what species are most likely to be hosts of the virus. “When they first started looking for reservoirs for Ebola, they were crashing through the rainforest, looking at everything — mammals, insects, other organisms,” Taylor said. “The more we know about the evolution of filovirus-host interactions, the more we can learn about who the players might be in the system.”

Source: Taylor D, Ballinger M, Zhan J, Hanzly L, Bruenn J. Evidence that ebolaviruses and cuevaviruses have been diverging from marburgviruses since the Miocene. PeerJ. 2014.

http://www.medicaldaily.com/ebolas-family-tree-disease-may-have-existed-23-million-years-much-longer-previously-307958

Lisa M Brosseau, ScD, and Rachael Jones, PhD

The authors are national experts on respiratory protection and infectious disease transmission. In May they published a similar commentary on MERS-CoV. Dr Brosseau is a Professor and Dr Jones an Assistant Professor in the School of Public Health, Division of Environmental and Occupational Health Sciences, at the University of Illinois at Chicago.

Healthcare workers play a very important role in the successful containment of outbreaks of infectious diseases like Ebola. The correct type and level of personal protective equipment (PPE) ensures that healthcare workers remain healthy throughout an outbreak—and with the current rapidly expanding Ebola outbreak in West Africa, it’s imperative to favor more conservative measures.

The precautionary principle—that any action designed to reduce risk should not await scientific certainty—compels the use of respiratory protection for a pathogen like Ebola virus that has:

•No proven pre- or post-exposure treatment modalities
•A high case-fatality rate
•Unclear modes of transmission

We believe there is scientific and epidemiologic evidence that Ebola virus has the potential to be transmitted via infectious aerosol particles both near and at a distance from infected patients, which means that healthcare workers should be wearing respirators, not facemasks (1).

The minimum level of protection in high-risk settings should be a respirator with an assigned protection factor greater than 10. A powered air-purifying respirator (PAPR) with a hood or helmet offers many advantages over an N95 filtering facepiece or similar respirator, being more protective, comfortable, and cost-effective in the long run.

We strongly urge the US Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) to seek funds for the purchase and transport of PAPRs to all healthcare workers currently fighting the battle against Ebola throughout Africa—and beyond.

There has been a lot of on-line and published controversy about whether Ebola virus can be transmitted via aerosols. Most scientific and medical personnel, along with public health organizations, have been unequivocal in their statements that Ebola can be transmitted only by direct contact with virus-laden fluids (2,3) and that the only modes of transmission we should be concerned with are those termed “droplet” and “contact.”

These statements are based on two lines of reasoning. The first is that no one located at a distance from an infected individual has contracted the disease, or the converse, every person infected has had (or must have had) “direct” contact with the body fluids of an infected person.

This reflects an incorrect and outmoded understanding of infectious aerosols, which has been institutionalized in policies, language, culture, and approaches to infection control. We will address this below. Briefly, however, the important points are that virus-laden bodily fluids may be aerosolized and inhaled while a person is in proximity to an infectious person and that a wide range of particle sizes can be inhaled and deposited throughout the respiratory tract.

The second line of reasoning is that respirators or other control measures for infectious aerosols cannot be recommended in developing countries because the resources, time, and/or understanding for such measures are lacking (4).

Although there are some important barriers to the use of respirators, especially PAPRs, in developing countries, healthcare workers everywhere deserve and should be afforded the same best-practice types of protection, regardless of costs and resources. Every healthcare worker is a precious commodity whose well-being ensures everyone is protected.

If we are willing to offer infected US healthcare workers expensive treatments and experimental drugs free of charge when most of the world has no access to them, we wonder why we are unwilling to find the resources to provide appropriate levels of comparatively less expensive respiratory protection to every healthcare worker around the world.

How are infectious diseases transmitted via aerosols?

Medical and infection control professionals have relied for years on a paradigm for aerosol transmission of infectious diseases based on very outmoded research and an overly simplistic interpretation of the data. In the 1940s and 50s, William F. Wells and other “aerobiologists” employed now significantly out-of-date sampling methods (eg, settling plates) and very blunt analytic approaches (eg, cell culturing) to understand the movement of bacterial aerosols in healthcare and other settings. Their work, though groundbreaking at the time, provides a very incomplete picture.

Early aerobiologists were not able to measure small particles near an infectious person and thus assumed such particles existed only far from the source. They concluded that organisms capable of aerosol transmission (termed “airborne”) can only do so at around 3 feet or more from the source. Because they thought that only larger particles would be present near the source, they believed people would be exposed only via large “droplets” on their face, eyes, or nose.

Modern research, using more sensitive instruments and analytic methods, has shown that aerosols emitted from the respiratory tract contain a wide distribution of particle sizes—including many that are small enough to be inhaled (5,6). Thus, both small and large particles will be present near an infectious person.

The chance of large droplets reaching the facial mucous membranes is quite small, as the nasal openings are small and shielded by their external and internal structure. Although close contact may permit large-droplet exposure, it also maximizes the possibility of aerosol inhalation.

As noted by early aerobiologists, liquid in a spray aerosol, such as that generated during coughing or sneezing, will quickly evaporate (7), which increases the concentration of small particles in the aerosol. Because evaporation occurs in milliseconds, many of these particles are likely to be found near the infectious person.

The current paradigm also assumes that only “small” particles (less than 5 micrometers [mcm]) can be inhaled and deposited in the respiratory tract. This is not true. Particles as large as 100 mcm (and perhaps even larger) can be inhaled into the mouth and nose. Larger particles are deposited in the nasal passages, pharynx, and upper regions of the lungs, while smaller particles are more likely to deposit in the lower, alveolar regions. And for many pathogens, infection is possible regardless of the particle size or deposition site.

It’s time to abandon the old paradigm of three mutually exclusive transmission routes for a new one that considers the full range of particle sizes both near and far from a source. In addition, we need to factor in other important features of infectivity, such as the ability of a pathogen to remain viable in air at room temperature and humidity and the likelihood that systemic disease can result from deposition of infectious particles in the respiratory system or their transfer to the gastrointestinal tract.

We recommend using “aerosol transmissible” rather than the outmoded terms “droplet” or “airborne” to describe pathogens that can transmit disease via infectious particles suspended in air.

Is Ebola an aerosol-transmissible disease?

We recently published a commentary on the CIDRAP site discussing whether Middle East respiratory syndrome (MERS) could be an aerosol-transmissible disease, especially in healthcare settings. We drew comparisons with a similar and more well-studied disease, severe acute respiratory syndrome (SARS).

For Ebola and other filoviruses, however, there is much less information and research on disease transmission and survival, especially in healthcare settings.

Being at first skeptical that Ebola virus could be an aerosol-transmissible disease, we are now persuaded by a review of experimental and epidemiologic data that this might be an important feature of disease transmission, particularly in healthcare settings.

What do we know about Ebola transmission?

No one knows for certain how Ebola virus is transmitted from one person to the next. The virus has been found in the saliva, stool, breast milk, semen, and blood of infected persons (8,9). Studies of transmission in Ebola virus outbreaks have identified activities like caring for an infected person, sharing a bed, funeral activities, and contact with blood or other body fluids to be key risk factors for transmission (10-12).

On the basis of epidemiologic evidence, it has been presumed that Ebola viruses are transmitted by contaminated hands in contact with the mouth or eyes or broken skin or by splashes or sprays of body fluids into these areas. Ebola viruses appear to be capable of initiating infection in a variety of human cell types (13,14), but the primary portal or portals of entry into susceptible hosts have not been identified.

Some pathogens are limited in the cell type and location they infect. Influenza, for example, is generally restricted to respiratory epithelial cells, which explains why flu is primarily a respiratory infection and is most likely aerosol transmissible. HIV infects T-helper cells in the lymphoid tissues and is primarily a bloodborne pathogen with low probability for transmission via aerosols.

Ebola virus, on the other hand, is a broader-acting and more non-specific pathogen that can impede the proper functioning of macrophages and dendritic cells—immune response cells located throughout the epithelium (15,16). Epithelial tissues are found throughout the body, including in the respiratory tract. Ebola prevents these cells from carrying out their antiviral functions but does not interfere with the initial inflammatory response, which attracts additional cells to the infection site. The latter contribute to further dissemination of the virus and similar adverse consequences far beyond the initial infection site.

The potential for transmission via inhalation of aerosols, therefore, cannot be ruled out by the observed risk factors or our knowledge of the infection process. Many body fluids, such as vomit, diarrhea, blood, and saliva, are capable of creating inhalable aerosol particles in the immediate vicinity of an infected person. Cough was identified among some cases in a 1995 outbreak in Kikwit, Democratic Republic of the Congo (11), and coughs are known to emit viruses in respirable particles (17). The act of vomiting produces an aerosol and has been implicated in airborne transmission of gastrointestinal viruses (18,19). Regarding diarrhea, even when contained by toilets, toilet flushing emits a pathogen-laden aerosol that disperses in the air (20-22).

Experimental work has shown that Marburg and Ebola viruses can be isolated from sera and tissue culture medium at room temperature for up to 46 days, but at room temperature no virus was recovered from glass, metal, or plastic surfaces (23). Aerosolized (1-3 mcm) Marburg, Ebola, and Reston viruses, at 50% to 55% relative humidity and 72°F, had biological decay rates of 3.04%, 3.06%. and 1.55% per minute, respectively. These rates indicate that 99% loss in aerosol infectivity would occur in 93, 104, and 162 minutes, respectively (23).

In still air, 3-mcm particles can take up to an hour to settle. With air currents, these and smaller particles can be transported considerable distances before they are deposited on a surface.

There is also some experimental evidence that Ebola and other filoviruses can be transmitted by the aerosol route. Jaax et al (24) reported the unexpected death of two rhesus monkeys housed approximately 3 meters from monkeys infected with Ebola virus, concluding that respiratory or eye exposure to aerosols was the only possible explanation.

Zaire Ebola viruses have also been transmitted in the absence of direct contact among pigs (25) and from pigs to non-human primates (26), which experienced lung involvement in infection. Persons with no known direct contact with Ebola virus disease patients or their bodily fluids have become infected (12).

Direct injection and exposure via a skin break or mucous membranes are the most efficient ways for Ebola to transmit. It may be that inhalation is a less efficient route of transmission for Ebola and other filoviruses, as lung involvement has not been reported in all non-human primate studies of Ebola aerosol infectivity (27). However, the respiratory and gastrointestinal systems are not complete barriers to Ebola virus. Experimental studies have demonstrated that it is possible to infect non-human primates and other mammals with filovirus aerosols (25-27).

Altogether, these epidemiologic and experimental data offer enough evidence to suggest that Ebola and other filoviruses may be opportunistic with respect to aerosol transmission(28). That is, other routes of entry may be more important and probable, but, given the right conditions, it is possible that transmission could also occur via aerosols.

Guidance from the CDC and WHO recommends the use of facemasks for healthcare workers providing routine care to patients with Ebola virus disease and respirators when aerosol-generating procedures are performed. (Interestingly, the 1998 WHO and CDC infection-control guidance for viral hemorrhagic fevers in Africa, still available on the CDC Web site, recommends the use of respirators.)

Facemasks, however, do not offer protection against inhalation of small infectious aerosols, because they lack adequate filters and do not fit tightly against the face (1). Therefore, a higher level of protection is necessary.

Which respirator to wear?

As described in our earlier CIDRAP commentary, we can use a Canadian control-banding approach to select the most appropriate respirator for exposures to Ebola in healthcare settings (29). (See this document for a detailed description of the Canadian control banding approach and the data used to select respirators in our examples below.)

The control banding method involves the following steps:

1.Identify the organism’s risk group (1 to 4). Risk group reflects the toxicity of an organism, including the degree and type of disease and whether treatments are available. Ebola is in risk group 4, the most toxic organisms, because it can cause serious human or animal disease, is easily transmitted, directly or indirectly, and currently has no effective treatments or preventive measures.

2.Identify the generation rate. The rate of aerosol generation reflects the number of particles created per time (eg, particles per second). Some processes, such as coughing, create more aerosols than others, like normal breathing. Some processes, like intubation and toilet flushing, can rapidly generate very large quantities of aerosols. The control banding approach assigns a qualitative rank ranging from low (1) to high (4) (eg, normal breathing without coughing has a rank of 1).

3.Identify the level of control. Removing contaminated air and replacing it with clean air, as accomplished with a ventilation system, is effective for lowering the overall concentration of infectious aerosol particles in a space, although it may not be effective at lowering concentration in the immediate vicinity of a source. The number of air changes per hour (ACH) reflects the rate of air removal and replacement. This is a useful variable, because it is relatively easy to measure and, for hospitals, reflects building code requirements for different types of rooms. Again, a qualitative ranking is used to reflect low (1) versus high (4) ACH. Even if the true ventilation rate is not known, the examples can be used to select an appropriate air exchange rate.

4.Identify the respirator assigned protection factor. Respirators are designated by their “class,” each of which has an assigned protection factor (APF) that reflects the degree of protection. The APF represents the outside, environmental concentration divided by the inside, facepiece concentration. An APF of 10 means that the outside concentration of a particular contaminant will be 10 times greater than that inside the respirator. If the concentration outside the respirator is very high, an assigned protection factor of 10 may not prevent the wearer from inhaling an infective dose of a highly toxic organism.

Practical examples

Two examples follow. These assume that infectious aerosols are generated only during vomiting, diarrhea, coughing, sneezing, or similar high-energy emissions such as some medical procedures. It is possible that Ebola virus may be shed as an aerosol in other manners not considered.

Caring for a patient in the early stages of disease (no bleeding, vomiting, diarrhea, coughing, sneezing, etc). In this case, the generation rate is 1. For any level of control (less than 3 to more than 12 ACH), the control banding wheel indicates a respirator protection level of 1 (APF of 10), which corresponds to an air purifying (negative pressure) half-facepiece respirator such as an N95 filtering facepiece respirator. This type of respirator requires fit testing.

Caring for a patient in the later stages of disease (bleeding, vomiting, diarrhea, etc). If we assume the highest generation rate (4) and a standard patient room (control level = 2, 3-6 ACH), a respirator with an APF of at least 50 is needed. In the United States, this would be equivalent to either a full-facepiece air-purifying (negative-pressure) respirator or a half-facepiece PAPR (positive pressure), but standards differ in other countries. Fit testing is required for these types of respirators.

The control level (room ventilation) can have a big effect on respirator selection. For the same patient housed in a negative-pressure airborne infection isolation room (6-12 ACH), a respirator with an assigned protection factor of 25 is required. This would correspond in the United States to a PAPR with a loose-fitting facepiece or with a helmet or hood. This type of respirator does not need fit testing.

Implications for protecting health workers in Africa

Healthcare workers have experienced very high rates of morbidity and mortality in the past and current Ebola virus outbreaks. A facemask, or surgical mask, offers no or very minimal protection from infectious aerosol particles. As our examples illustrate, for a risk group 4 organism like Ebola, the minimum level of protection should be an N95 filtering facepiece respirator.

This type of respirator, however, would only be appropriate only when the likelihood of aerosol exposure is very low. For healthcare workers caring for many patients in an epidemic situation, this type of respirator may not provide an adequate level of protection.

For a risk group 4 organism, any activity that has the potential for aerosolizing liquid body fluids, such as medical or disinfection procedures, should be avoided, if possible. Our risk assessment indicates that a PAPR with a full facepiece (APF = 50) or a hood or helmet (APF = 25) would be a better choice for patient care during epidemic conditions.

We recognize that PAPRs present some logistical and infection-control problems. Batteries require frequent charging (which requires a reliable source of electricity), and the entire ensemble requires careful handling and disinfection between uses. A PAPR is also more expensive to buy and maintain than other types of respirators.

On the other hand, a PAPR with a loose-fitting facepiece (hood or helmet) does not require fit testing. Wearing this type of respirator minimizes the need for other types of PPE, such as head coverings and goggles. And, most important, it is much more comfortable to wear than a negative-pressure respirator like an N95, especially in hot environments.

A recent report from a Medecins Sans Frontieres healthcare worker in Sierra Leone30 notes that healthcare workers cannot tolerate the required PPE for more than 40 minutes. Exiting the workplace every 40 minutes requires removal and disinfection or disposal (burning) of all PPE. A PAPR would allow much longer work periods, use less PPE, require fewer doffing episodes, generate less infectious waste, and be more protective. In the long run, we suspect this type of protection could also be less expensive.

Adequate protection is essential

To summarize, for the following reasons we believe that Ebola could be an opportunistic aerosol-transmissible disease requiring adequate respiratory protection:
•Patients and procedures generate aerosols, and Ebola virus remains viable in aerosols for up to 90 minutes.
•All sizes of aerosol particles are easily inhaled both near to and far from the patient.
•Crowding, limited air exchange, and close interactions with patients all contribute to the probability that healthcare workers will be exposed to high concentrations of very toxic infectious aerosols.
•Ebola targets immune response cells found in all epithelial tissues, including in the respiratory and gastrointestinal system.
•Experimental data support aerosols as a mode of disease transmission in non-human primates.

Risk level and working conditions suggest that a PAPR will be more protective, cost-effective, and comfortable than an N95 filtering facepiece respirator.

Acknowledgements

We thank Kathleen Harriman, PhD, MPH, RN, Chief, Vaccine Preventable Diseases Epidemiology Section, Immunization Branch, California Department of Public Health, and Nicole Vars McCullough, PhD, CIH, Manager, Global Technical Services, Personal Safety Division, 3M Company, for their input and review.

References
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2.CDC. Ebola hemorrhagic fever: transmission. 2014 Aug 13

3.ECDC. Outbreak of Ebola virus disease in West Africa: third update, 1 August 2014. Stockholm: ECDC 2014 Aug 1

4.Martin-Moreno JM, Llinas G, Hernandez JM. Is respiratory protection appropriate in the Ebola response? Lancet 2014 Sep 6;384(9946):856

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6.Chao CYH, Wan MP, Morawska L, et al. Characterization of expiration air jets and droplet size distributions immediately at the mouth opening. J Aerosol Sci 2009 Feb;40(2):122-33

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8.Bauchsch DG, Towner JS, Dowell SF, et al. Assessment of the risk of Ebola virus transmission from bodily fluids and fomites. J Infect Dis 2007;196:S142-7

9.Formenty P, Leroy EM, Epelboin A, et al. Detection of Ebola virus in oral fluid specimens during outbreaks of Ebola virus hemorrhagic fever in the Republic of Congo. Clin Infect Dis 2006 Jun;42(11):1521-6

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15.Bray M, Geisbert TW. Ebola virus: the role of macrophages and dendritic cells in the pathogenesis of Ebola hemorrhagic fever. Int J Biochem Cell Biol 2005 Aug;37(8):1560-6

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19.Chadwick PR, Walker M, Rees AE. Airborne transmission of a small round structured virus. Lancet 1994 Jan 15;343(8890):171

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http://www.cidrap.umn.edu/news-perspective/2014/09/commentary-health-workers-need-optimal-respiratory-protection-ebola

Thanks to Kebmodee for bringing this to the attention of the It’s Interesting community.

The biotech company NewLink Genetics in Ames, Iowa is closing in on human trials for an Ebola vaccine.

“From the laboratory to moving these first human trials has moved faster than I’ve ever seen anything move before in my professional career,” said Charles Link, CEO of NewLink Genetics.

Link said they are just a few days away from human testing. During Phase 1 of testing, healthy volunteers will be given the vaccine. Researchers will test to see how safe the vaccine is and what dosage is necessary for an immune reaction.

“With a dangerous virus, you don’t ever use the dangerous virus. You basically use a little snippet of it,” said Link.

Link said that snippet is a surface protein you get from Ebola and assures us there is no Ebola is in the vaccine.

“If you get an immune reaction to the surface protein an then it sees the real Ebola, it will attack it,” said Link.

Once those tests are complete, the company will move into Phase 2 where tests focus on how effective and useful the vaccine is. Those tests will be done in West Africa.

Link said he’s hoping it’ll take less than a year, but there’s no real way of telling when the vaccine will be ready for distribution until test results start coming in.

“We want to shorten the process as much as humanely possible within the bounds of safety and the ethics that’s required to conduct these sorts of studies in healthy volunteers,” said Link.

The Phase 1 of the tests will be conducted at the National Institute of Allergy and Infectious Disease and the Walter Reed Army Medical Center.
Ames Company Close to Ebola Vaccine Trials

http://www.cbs2iowa.com/news/features/top-stories/stories/ames-company-close-ebola-vaccine-trials-30679.shtml