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Is ebola non-contagious until symptoms appear? Why?

Is ebola non-contagious until symptoms appear? Why?



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There's been a lot of talk lately about the man who recently came down with ebola in Dallas, Texas. While I live elsewhere, I keep hearing quotes from CDC and state officials that ebola is not contagious until a person shows symptoms. This is generally used in the context of "Don't worry too much; we have the situation under control." Is this true in all cases? Why?


First, confirmation from the World Health Organisation:

The incubation period, that is, the time interval from infection with the virus to onset of symptoms is 2 to 21 days. Humans are not infectious until they develop symptoms.

But

People remain infectious as long as their blood and body fluids, including semen and breast milk, contain the virus. Men who have recovered from the disease can still transmit the virus through their semen for up to 7 weeks after recovery from illness.

They also state that deceased people may still transmit the virus via body fluids.

As to why the patients become infectious only when symptoms show, there are several related ideas. For example, from the CDC:

Ebola virus enters the patient through mucous membranes, breaks in the skin, or parenterally and infects many cell types, including monocytes, macrophages, dendritic cells, endothelial cells, fibroblasts, hepatocytes, adrenal cortical cells and epithelial cells. The incubation period may be related to the infection route (i.e., 6 days for injection versus 10 days for contact). Ebola virus migrates from the initial infection site to regional lymph nodes and subsequently to the liver, spleen and adrenal gland.

According to Dr. Ray Schilling:

Ebola virus disease has an incubation time of 8 to 10 days where the person may complain of some tiredness, but is not sick yet. This is the time when the Ebola virus multiplies. It paralyzes the immune system and distributes itself through the organ system.

From there, the symptoms and effects of Ebola are fast, according to the article "Ebola Virus Pathogenesis: Implications for Vaccines and Therapies" (Sullivan et al. 2003):

Ebola virus replicates at an unusually high rate that overwhelms the protein synthesis apparatus of infected cells and host immune defenses


Every infectous disease works this way: if you had contact with x particles (virus, bacteria, etc… ), then you have y% chance to get infected (depends on your immune system, luck, etc… ), so it has a distribution. This is called virulence, and it can be measured with ID50 (infectious dose by 50% of subjects) and LD50 (lethal dose by 50% of subjects) values. According to animal studies the LD50 is very low by ebola, so it is highly virulent, but it highly depends on the mode of transmission. So this virulency is compensated by low transmissibility: people infected with ebola, but not showing symptoms release too small amount (or nothing) of the virus to infect others. By hemorrhagic fever you bleed out of every hole of your body, and that blood contains a lot of viruses, that's when it can infect others. So this is not a"Don't worry too much; we have the situation under control."case, it works this way currently. This can probably change due to mutations.

Symptoms usually begin with a sudden influenza-like stage characterized by feeling tired, fever, pain in the muscles and joints, headache, and sore throat.1[12][13] The fever is usually greater than 38.3 °C (100.9 °F).[14]

This is often followed by: vomiting, diarrhea and abdominal pain.[13] Shortness of breath and chest pain may occur next along with swelling, headaches and confusion.[13] In about half of cases the skin may develop a maculopapular rash (a flat red area covered with small bumps).[14]

In some cases, internal and external bleeding may occur.1 This typically begins five to seven days after first symptoms.[15] All people show some decreased blood clotting.[14] Bleeding from mucous membranes or from sites of needle punctures is reported in 40-50% of cases.[16] This may result in the vomiting of blood, coughing up of blood, or blood in stool.[17] Bleeding into the skin may create petechiae, purpura, ecchymoses, or hematomas (especially around needle injection sites).[18] There may also be bleeding into the whites of the eyes. Heavy bleeding is uncommon and if it occurs is usually within the gastrointestinal tract.[14][19]

Recovery may begin between 7 and 14 days after the start of symptoms.[13] Death, if it occurs, is typically 6 to 16 days from the start of symptoms and is often due to low blood pressure from fluid loss.2 In general, the development of bleeding often indicates a worse outcome and this blood loss can result in death.[12] People are often in a coma near the end of life.[13] Those who survive often have ongoing muscle and joint pain, liver inflammation, and decreased hearing among other difficulties.[13]

The time between exposure to the virus and the development of symptoms of the disease is usually 2 to 21 days.1[10] Estimates based on mathematical models predict that around 5% of cases may take greater than 21 days to develop.[11]

  • wikipedia - Ebola virus disease

The LD50 of mouse-adapted EBO-Z virus inoculated into the peritoneal cavity was ~1 virion. Mice were resistant to large doses of the same virus inoculated subcutaneously, intradermally, or intramuscularly. Mice injected peripherally with mouse-adapted or intraperitoneally with non-adapted EBO-Z virus resisted subsequent challenge with mouse-adapted virus.

  • 1998 - A Mouse Model for Evaluation of Prophylaxis and Therapy of Ebola Hemorrhagic Fever

Although outbreaks of Ebola virus have largely been confined to endemic regions, their high fatality rate, ability to transmit person-to-person, and low lethal infectious dose make Ebola virus a dangerous threat to public health and pose a great risk for researchers working with these viruses as well as health care personnel treating patients during outbreaks. Furthermore, their potential to be developed into aerosolized biological weapons also causes grave concern for their use as a bioterrorism agent ( Bray, 2003).

  • 2008 - Protection against lethal challenge by Ebola virus-like particles produced in insect cells

Some interesting story about the topic (others were not so lucky):

In 2004, a virologist at USAMRIID was working in a BSL-4 laboratory with mice that had been infected 2 days before with a mouse-adapted variant of the Zaire species of Ebola virus (ZEBOV) (2). The virulence and infectious dose of this variant of ZEBOV are unknown in humans; wild-type virus has a case-fatality rate of up to 90% (3).

The person had been following standard procedure, holding the mice while injecting them intraperitoneally with an immune globulin preparation. While the person was injecting the fifth mouse with a hypodermic syringe that had been used on previous mice, the animal kicked the syringe, causing the needle to pierce the person's left-hand gloves, resulting in a small laceration. The virologist immediately squeezed the site to force the extravasation of blood. After decontamination of the blue suit in the chemical shower, the injured site was irrigated with 1 liter of sterile water and then scrubbed with povidone-iodine for 10 minutes.

In terms of exposure risk, the needle was presumed to be contaminated with virus-laden blood, although it was suspected that low levels of virus were present on the needle. The animals had not yet manifested signs of infection, and much contamination may have been removed mechanically when the needle pierced the gloves. The local decontamination of the site also reduced potential for infection.

USAMRIID medical, scientific, and executive staff concluded that the person with potential exposure warranted quarantine in the MCS. Contact plus airborne precautions (gown, gloves, N95 mask, eye protection) were used, with a plan to upgrade to BSL-4 precautions for signs or symptoms of illness. These extra precautions were instituted while the patient was asymptomatic for several reasons: 1) the timing of initial clinical manifestations with regard to potential for shedding virus were not known for this specific isolate in human infection; 2) there was interest in ensuring all infection control procedures were being followed appropriately in advance of clinical illness; and 3) there was interest in reducing any potential confounders, such as a caregiver transmitting a febrile respiratory infection to the patient, which might lead to unnecessary procedures or additional isolation. The person was monitored for routine vital signs; daily laboratory studies (coagulation studies, blood counts, chemistries, viral isolation, D-dimer) and regular physician assessments were performed.

Over the next several days, discussions were held with several internationally recognized filovirus experts regarding potential treatments or postexposure prophylaxis options. Local and state public health officials were also notified. The consensus opinion was that there was no safe, readily available source of immune plasma and little evidence existed to support its use. Emergency investigational new drug (IND) protocols were established for treatment with recombinant nematode protein (rNAPc2) and antisense oligomers, with the intention to consider implementation only if the patient demonstrated evidence of infection.

Ultimately, none of the 5 mice had confirmed viremia at the time of the incident. The patient did not become ill or seroconvert and was discharged after 21 days.

  • 2008 - Managing Potential Laboratory Exposure to Ebola Virus by Using a Patient Biocontainment Care Unit

Why people without symptoms aren’t going to give you Ebola

Stephen Goldstein does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.

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The Conversation UK receives funding from these organisations

Fear of Ebola has put many on high alert and there is increasing anxiety about the possibility of individuals with minimal exposure and no symptoms introducing the virus into communities – people such as Craig Spencer, the doctor who contracted Ebola while working in Guinea who then went bowling and rode the subway in New York before exhibiting symptoms.

Fear has kept people away from school and work, despite reassurances from the World Health Organisation (WHO) and the American Centers for Disease Control and Prevention (CDC) that someone with Ebola becomes contagious only once they develop symptoms.

In light of this, it is worthwhile explaining the data behind these assurances, which the WHO and CDC haven’t done, to make clear why we are so confident that people without symptoms can’t give you Ebola.


Ebola

Infected animals
When the infection occurs in humans, the virus
can spread in several ways
• Direct contact through broken skin or mucous
membranes (e.g. the eyes, nose or mouth).
• Symptoms may appear in 2-21 days after
exposure to Ebola, but the average is 8-10 days
• "Contact tracing" finds new cases quickly so they
can be isolated to stop further spread
• Once someone recovers from Ebola, they no
longer can spread the virus.
EXCEPT
EVD has
been found in the semen up to 3 months. People
who recover from Ebola are advised to abstain
from sex or use condoms for 3 months

High-Risk of Exposure
• Percutaneous or mucous
membrane exposure or
direct skin contact with
body fluids of a person with
confirmed or suspected
EVD without PPE or
• Lab processing of bodily
fluids of suspected or
confirmed EVD without
PPE/standard biosafety
precaution

Collect 4 ml blood in plastic tube and contact
CDC & DCHHS to determine the proper
category for shipment to nearest Ebola
testing lab (one now in Dallas)

10/29/2014
5
Testing
• Patients with high-risk or low-risk that
develop fevers > 101.5 F (38.6 C) with or
without any compatible symptoms should be
tested
• Include testing for malaria diagnostics (most
common cause of febrile illness from affected
countries)
• Collect 4 ml blood in plastic tube and contact
CDC & DCHHS to determine the proper
category for shipment to nearest Ebola
testing lab (one now in Dallas)
Prevention
• There is no FDA approved vaccine or medicine (antiviral
drug) available for Ebola
• NIH is undergoing clinical trials for an Ebola vaccine
• Strict Isolation with PPE
• Single patient rooms with private bathroom
• Avoid aerosol-generating procedures
• Implement environmental infection control
• Limit number of staff who interact directly with EVD patient
• Notify lab that source of specimen is EVD patient and
hand carry them to the lab- only use plastic lab tubes
• Self monitoring if suspected of exposure
(Monitor temperature
twice daily for 21 days from
last
exposure)
• Seek medical evaluation at first sign of illness


Ebola Hemorrhagic Fever (Ebola Virus Disease)

As the disease worsens in severity, symptoms can include bleeding at various sites within or outside of the body.

The latest news on Ebola virus disease

More articles on Ebola virus disease

What is Ebola hemorrhagic fever?

Ebola hemorrhagic fever is a viral disease caused by Ebola virus (a member of the Filoviridae family or filoviruses) that results in nonspecific symptoms (see symptom section of this article) early in the disease and often causes internal and external hemorrhage (bleeding) as the disease progresses. Ebola hemorrhagic fever is one of the most life-threatening viral infections the mortality rate (death rate) may be very high during outbreaks (reports of outbreaks range from about 25%-100% of people infected, depending on the Ebola strain). Because most outbreaks occur in areas where high-level intensive care supportive public health services are not available, survival rates are difficult to translate to potential outbreaks in Ebola-affected areas with more resources.

What is the history of Ebola hemorrhagic fever?

Ebola hemorrhagic fever first appeared in Zaire (currently, the Democratic Republic of the Congo or DRC or Congo) in 1976. The original outbreak was in a village named Yambuku near the Ebola River after which the disease was named. During that time, researchers identified the virus in person-to-person contact transmission. Of the 318 patients diagnosed with Ebola, 88% died. The second outbreak occurred in Nzara, South Sudan, in 1976, with 151 deaths.

Since that time, there have been multiple outbreaks of Ebola virus, and researchers have identified five strains four of the strains are responsible for the high death rates. The four Ebola strains are termed as follows: Zaire, Sudan, Tai Forest, and Bundibugyo virus, with Zaire Ebola virus being the most lethal strain. Researchers have found a fifth strain termed Reston in the Philippines. The strain infects primates, pigs, and humans and causes few if any symptoms and no deaths in humans. Most outbreaks of the more lethal strains of Ebola have occurred in sub-Saharan West Africa and mainly in small- or medium-sized towns. Health care professionals believe bats, monkeys, and other animals maintain the non-human virus life cycle in the wild humans can become infected from handling and/or eating infected animals.

Once an Ebola outbreak is recognized, African officials isolate the area until the outbreak ceases. However, in the outbreak that began in West Africa in March 2014, some of the infected people reached larger city centers before the outbreak was recognized this caused further spread. The infecting Ebola virus detected during this outbreak was the Zaire strain, the most pathogenic strain of Ebola. Health agencies are terming this outbreak as an "unprecedented epidemic." This epidemic spread quickly in the West African countries of Guinea and Sierra Leone. In addition, countries of Liberia, Nigeria, Senegal, Uganda, and Mali all reported confirmed infections with Ebola. In addition, a few infections or flare-ups of Ebola virus infection appeared in the United States, Spain, and the United Kingdom (see for example, the case of Pauline Cafferkey, a nurse who became infected) most of the people with Ebola in these countries either were imported infections from West Africa or were newly spread infections from treating patients who originally became infected in Africa. Another outbreak occurred in the DRC in May 2018 in Bikoro, a small town 80 miles from Mbandaka, with 46 reported infections and 26 deaths. Unfortunately, the large city of Mbandaka, with over 1 million people, has recorded at least three people with Ebola. The DRC hopes to isolate or stop the spread of Ebola in the two areas by vaccinating anyone who may have had some physical contact with an infected person with a new chimeric virus vaccine that in 2015 showed good results in Ebola-infected patients.

Health officials now report over 1,000 deaths due to Ebola in areas like Butembo in the Congo (DRC) and neighboring countries in an ongoing outbreak over the last 9 months. This outbreak is difficult to control because it is happening in a war zone where cooperation between countries to control the outbreak is uncoordinated and even considered unwelcome.

SLIDESHOW

Is the Ebola virus contagious?

Ebola viruses are highly contagious once early symptoms such as fever develop. The infected patient sheds infectious viruses in all body secretions (bodily fluids) direct contact with any of these secretions may cause the virus transmission to uninfected individuals. The Centers for Disease Control and Prevention (CDC) suggests that infection with Ebola that is airborne is theoretically possible but unlikely. Although Ebola is contagious, careful hygiene and barrier techniques can make the infection low risk for contagion measles is considered by some experts to be the fastest-spreading disease.

What causes Ebola hemorrhagic fever?

The cause of Ebola hemorrhagic fever is Ebola virus infection that results in coagulation abnormalities, including gastrointestinal bleeding, development of a rash, cytokine release, damage to the liver, and massive viremia (large number of viruses in the blood) that leads to damaged vascular cells that form blood vessels. As the massive viremia continues, coagulation factors are compromised and the microvascular endothelial cells are damaged or destroyed, resulting in diffuse bleeding internally and externally (bleeding from the mucosal surfaces like nasal passages and/or mouth and gums and even from the eyes [termed conjunctival bleeding]). This uncontrolled bleeding leads to blood and fluid loss and can cause hypotensive shock that causes death in many Ebola-infected patients.

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What are risk factors for Ebola hemorrhagic fever?

The risk factors for Ebola hemorrhagic fever are travel to areas with reported Ebola infections (see current CDC travel advisories for African countries). In addition, association with animals (mainly primates in the area with reported Ebola infections) is potentially a health risk factor according to the Centers for Disease Control and Prevention. Another potential source of the virus is eating or handling "bush meat." Bush meat is the meat of wild animals, including hoofed animals, primates, bats, and rodents. Evidence for any airborne transmission of this virus is lacking. During Ebola hemorrhagic fever outbreaks, health care workers and family members and friends associated with an infected person (human-to-human transfer) are at the highest risk of getting the disease. Researchers who study Ebola hemorrhagic fever viruses are also at risk of developing the disease if a laboratory accident occurs. Caring for infected patients who are near-death or disposing of bodies of individuals that have recently died of Ebola infection is a very high-risk factor because in these situations, the Ebola virus is highly concentrated in any blood or bodily secretions. Caregivers should wear appropriate full-length personal protective equipment (See the CDC site http://www.cdc.gov/vhf/ebola/healthcare-us/hospitals/infection-control.html for details).

IMAGES

What are Ebola virus disease symptoms and signs?

Unfortunately, early symptoms of Ebola virus disease are nonspecific and include

    , (severe), , , ,
  • stomach discomfort or pain in the abdomen, , and
  • joint and muscle discomfort.

As the disease progresses, patients may develop other symptoms and signs such as

  • a rash or red spots on the skin, , , , and/or coughing up blood, , ,
  • mental confusion,
  • bleeding both inside and outside the body (for example, mucosal surfaces, eyes), and and breathing.

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What types of health care professionals treat Ebola hemorrhagic fever?

Because Ebola infections can spread rapidly to others and because patients can easily infect health care workers, the CDC and other agencies recommend that only highly trained personnel treat Ebola patients. This treatment involves high-level barrier techniques to protect all health care professionals (hospital care workers, nurses, doctors, lab technicians, janitors, and hospital infectious-disease-control personnel). Unfortunately, these trained individuals and resources are often not available in the Ebola high-risk areas. Ideally, individuals diagnosed with Ebola in the U.S. should be treated in specific designated treatment centers and treatment monitored by the CDC. Types of specialists who may treat Ebola-infected patients are emergency medicine specialists, infectious disease specialists, critical care doctors and nurses, pulmonologists, hematologists, hospitalists, and hospital infection-control personnel.

What is the contagious period for the Ebola virus?

For those patients who survive infection, they may remain contagious for approximately 21-42 days after symptoms abate. However, health care professionals can remove the viruses from semen, breast milk, spinal column, and ocular fluids. It is unclear, according to the CDC, if these fluids can transmit viruses, although the CDC suggests that Ebola can be spread by semen and suggest male survivors of the disease abstain from sex or use a condom for all sexual activity.


Persistence of the virus

The virus can remain in areas of the body that are immunologically privileged sites after acute infection. These are sites where viruses and pathogens, like the Ebola virus, are shielded from the survivor&rsquos immune system, even after being cleared elsewhere in the body. These areas include the testes, interior of the eyes, placenta, and central nervous system, particularly the cerebrospinal fluid. Whether the virus is present in these body parts and for how long varies by survivor. Scientists are now studying how long the virus stays in these body fluids among Ebola survivors.

During an Ebola outbreak, the virus can spread quickly within healthcare settings (such as clinics or hospitals). Clinicians and other healthcare personnel providing care should use dedicated, preferably disposable, medical equipment. Proper cleaning and disposal of instruments such as needles and syringes are important. If instruments are not disposable, they must be sterilized before using again.

Ebola virus can survive on dry surfaces, like doorknobs and countertops for several hours in body fluids like blood, the virus can survive up to several days at room temperature. Cleaning and disinfection should be performed using a hospital-grade disinfectant.


Ebola: What Is It and What Do You Have to Worry About?

Ebola has been in the headlines a lot lately, mostly because the current outbreak is the largest one we’ve ever seen. There have also been people transported into the United States who were infected, raising concerns about an Ebola outbreak happening in the country. However, while Ebola is a terrifying disease, it is unlikely to spread in the U.S. Here we’ll explore what Ebola is, what makes it so scary, and why there won’t be an outbreak in the U.S.

The Ebola virus (Reston virus strain). (Image credit: Cynthia Goldsmith/Centers for Disease Control and Prevention)

Ebola (also called hemorrhagic fever) is a disease caused by a virus. (It specifically belongs to the RNA virus family Filoviridae, which are filamentous viruses, in the genus Ebolavirus.) It was first discovered in 1976 in the Democratic Republic of the Congo, near the Ebola River, which it is named after. Researchers have since then identified five subspecies of the Ebola virus, four of which cause the Ebola disease in humans (the fifth causes it in nonhuman primates). An outbreak usually happens when people come in contact with infected wild animals (typically fruit bats [a highly suspected reservoir], rodents, pigs, or primates), and then the virus is transmitted from person-to-person.

When a person becomes infected by the Ebola virus, it can take 2 to 21 days before they show symptoms (although it’s typically 8 to 10 days). Symptoms include fever (above 101.5°F), chills, muscle aches, and a headache initially. By the fifth day, a rash may appear on the skin. Symptoms can progress to nausea, vomiting, diarrhea, and chest and abdominal pain, and then to jaundice (yellow skin), confusion, bleeding (hemorrhaging), severe weight loss, and organ failure. Ebola usually kills 50% to 90% of infected people (although the current epidemic has about a 55% to 60% fatality rate).

What makes the Ebola virus so effective at killing a person once they’re infected? It has to do with which types of cells the virus goes after. Its main targets are the cells in the immune system. The virus is able to evade the immune system by blocking how those cells normally signal each other. At the same time, the virus also hitches a ride on the immune system’s cells so that they carry it through the body to different organs. The damage the virus inflicts on the body triggers a fever and inflammation, as the immune system attacks the body itself. Additionally, the virus infects cells that are lining the interior of blood vessels, causing those cells to be unable to adhere to each other well and leading to bleeding disorders (i.e., hemorrhaging).

The current Ebola outbreak, which was first reported in late March of this year, is unusual and concerning because it is larger than any other recorded Ebola outbreak. As of July 27, 2014, there have been 729 fatalities and 1,323 cases total. Previously, there has always been fewer than 1000 people infected by Ebola each year. What’s also different about the current outbreak is its location – prior outbreaks have been in Central Africa (near tropical rainforests), whereas this year’s is in West Africa. Specifically, the current outbreak is in Guinea, Sierra Leone, and Liberia, with a few suspected cases in Nigeria.

The current Ebola outbreak is in Guinea, Liberia, and Sierra Leone. (Image credit: Elizabeth Ervin/Centers for Disease Control and Prevention)

But, there still should not be concern for an outbreak occurring in the U.S. The Ebola virus is spread through bodily fluids (i.e., blood, sweat, saliva, urine, semen, and breast milk), but it cannot be caught through air, water, or food. This means that for a person to get infected, they’d need to directly touch bodily fluids from a person who is sick with Ebola and is showing symptoms (or died from Ebola), or they’d need to handle objects (like syringes) that were directly touched by infected bodily fluids. So, basically, a person needs close contact with somebody who’s clearly sick to get Ebola. (An exception is transmission via semen – a man’s semen is still infectious up to 7 weeks after he’s recovered from the disease.) To prevent the disease from spreading, medical workers wear masks, gloves, and goggles. Other precautions need to be taken as well, such as properly cooking meat that could be infected, properly disposing of bodies and tissues/fluids from a sick person, and washing hands when around a person who is sick.

Another reason that an outbreak in the U.S. is not of concern is that Ebola is relatively rare. Even if a person has a fever and is from an area where Ebola is present, it’s more likely they’re sick with a different infectious disease. Other similar-looking diseases include malaria, cholera, hepatitis, meningitis, typhoid fever, and other hemorrhagic fevers caused by viruses. (To confirm that a person has Ebola, a blood sample is tested for the presence of antibodies the body has made against the virus, or the RNA of the virus itself.) But even still, the Centers for Disease Control and Prevention (CDC) in West Africa is actively working to prevent sick passengers from getting on planes, and is prepared to immediately isolate any sick passengers (and disinfect other passengers and crew) who might land in the U.S. And if a person with Ebola needs treatment in the U.S., there are clear transportation guidelines and hospital guidelines for safely treating them.

Due to the relative rarity of the Ebola virus and its inability to spread via air, water, and food, it shouldn’t be too surprising that Ebola has only ever had outbreaks in Africa &mdash there have been no cases of people contracting Ebola outside of the continent.

While there is no specific treatment available for Ebola, just last week two American medical workers received an experimental drug and appear to be doing well after the treatment. The drug, called ZMapp (made by Mapp Biopharmaceutical Inc.), is an antibody made against the virus (it prevents the virus from infecting new cells) and had never been tested in humans before. Dr. Kent Brantly started feeling better just one hour after receiving the drug in Liberia, while Nancy Writebol felt improved after two doses. Both have been evacuated back to the U.S. since then. Legal and cultural barriers need to be overcome before Africans can be treated with the drug. (Other drugs, such as TKM-Ebola, are also being developed, and while there is no vaccine yet, one may be in clinical trials in September.)

So while it is easy to be concerned about Ebola due to its horrific nature and high mortality rate, it’s important to keep in mind that there are many other ways you’re much more likely to die, such as getting in a car accident, having the measles, or catching syphilis.


News from Brown

Infectious disease researcher Dr. Ian Michelow, assistant professor of pediatrics in the Alpert Medical School and at Hasbro Children’s Hospital, studied the Ebola virus and a potential therapy earlier in his career. He spoke with David Orenstein about what makes the virus so difficult to treat and about some of the recent research, including his own, that is searching for a way to beat it.

Dr. Ian Michelow
“It is unlikely that Ebola viruses can be eradicated from nature. Therefore, the goal is to develop robust vaccines . and effective therapeutics for humans who develop the disease.”

Is there something particular about the basic biology of Ebola that makes it so dangerous?

Like many other pathogens, Ebola viruses have developed and perfected strategies to evade, suppress, or manipulate the host’s immune response. To subvert humans’ armamentarium, the enveloped Ebola viruses must deposit their genetic material within a cell to survive and propagate without interference. They hijack macrophages and dendritic cells to spread infection to nearly every organ of the body, especially the liver, spleen and lymph nodes.

Ebola viruses strike rapidly to immobilize humans’ early innate immune responses. The viruses ensconce themselves in a cloak of glycans in an attempt to shield themselves from neutralizing antibodies and to direct the production of antibodies to highly variable or dispensable regions on the viral surface. Ebola viruses also produce free glycoproteins that are thought to cause production of non-neutralizing antibodies, thereby preventing effective neutralization of the virus.

In a desperate attempt to counter the viruses, human cells produce large amounts of cytokines and chemokines, but the response is highly dyregulated because the virus disrupts the immune system. The consequent “cytokine storm” leads to systemic inflammatory response syndrome and the death or dysfunction of many immune system cells. As the disease progresses, it leads to problems such as clots and extensive tissue death, hemorrhage in a third of patients, and possible multi-organ failure and death within seven to 10 days in up to 90 percent of cases caused by the most virulent strains.

The overwhelming viral onslaught in conjunction with fragile socio-economic environments and under-resourced healthcare infrastructures in Africa is conspiring to make the latest outbreak in Guinea, Liberia, Sierra Leone, and Nigeria devastating. The implicated virus is related to Zaire ebolavirus, which is the most virulent of the five known Ebola virus species.

Ebola is not necessarily new and is part of a broader family of viruses. Why is the world so challenged by it still?

The first recorded outbreak of Ebola virus disease was in 1976 in what’s now the Democratic Republic of the Congo and South Sudan. Since then outbreaks of Ebola virus disease have occurred regularly, but all involved fewer than 500 people.

Research on combating Ebola viruses has not received much attention until the last couple of decades because of their relatively restricted geographic range, lack of perceived global threat, competing demands such as HIV, absence of reliable small animal models, and lack of political motivation. After the terrorist attacks on the United States in 2001, Ebola viruses were prioritized as CDC Category A biological agents that could be weaponized. For this reason, federal funding agencies have directed considerably more support to researching Ebola viruses more recently, but the fruits have yet to be realized.

Outbreaks in humans are presumed to arise from animal reservoirs. The reservoir is not known but there is evidence to implicate fruit bats. Because humans are immunologically naïve against Ebola viruses, they are highly susceptible to becoming incidental hosts when they come into contact with infected animal products or other infected humans, which explains the intermittent and unpredictable nature of outbreaks.

It is unlikely that Ebola viruses can be eradicated from nature. Therefore, the goal is to develop robust vaccines to prevent and treat disease in humans and effective therapeutics for humans who develop the disease. There are now a number of candidates for these purposes but more time is needed to study their safety and efficacy.

What have you studied about Ebola?

My colleagues at the U.S. Army Medical Research Institute of Infectious Diseases, Massachusetts General Hospital, and I studied new potential treatments for Ebola viruses based on natural human immune proteins called mannose-binding lectin (MBL) and L-ficolin6-8. These defense proteins are synthesized by the liver and secreted into the circulation where they survey the bloodstream for invading organisms. Once they recognize certain patterns of sugars adorning the surface of pathogens, they activate the lectin pathway of complement and mount an immune response to eradicate the microbes. We synthesized MBL and hybrid molecules consisting of MBL and L-ficolin, which we mixed with authentic and synthetic Ebola viruses and showed that infections of human cells in the laboratory were reduced by more than 90 percent.

We confirmed that human complement was an essential ingredient in the antiviral attack complex. But to our surprise, when we reduced the concentrations of complement in experiments, we noticed that high levels of MBL paradoxically enhanced Ebola virus uptake into human cells. We then determined the mechanism by which that happens.

Our findings reflect the yin-yang nature of MBL. Severe MBL deficiency can predispose infants and immunodeficient humans to infections but MBL levels that are high relative to complement levels may enhance certain infections.

How does MBL appear to work?

We hypothesized that mice infected with massive lethal doses of Ebola virus could be effectively treated with high-dose recombinant human MBL before or 12 hours after the virus’s challenge. We demonstrated that almost 50 percent of mice survived regardless of timing of treatment compared with 100 percent mortality among mock-treated animals and complement deficient mice. MBL-treated mice had higher antibody-producing B-lymphocytes and neutrophils, lower proinflammatory cytokines and greater inhibition of viral replication early in the course of infection. Most importantly, surviving MBL-treated mice developed effective adaptive immunity that totally protected them against repeat infection.

Therefore, we concluded that recombinant MBL might bridge the gap between early immune paralysis and recovering adaptive immune responses that enable some mice to survive.

Do you still see this as a pathway to treating Ebola? Do other ideas show promise?

Recombinant human MBL may be useful for treating Ebola virus disease in conjunction with other agents. The World Health Organization recently declared that there is an ethical imperative to offer available experimental interventions that have shown promising results in laboratory and animal experiments to people suffering from disease.

However, there needs to be a cautious approach based on our mice and laboratory experiments. Ebola virus disease often causes a condition in which complement levels are diminished. We demonstrated that high levels of MBL relative to low complement levels could result in enhanced viral uptake in the laboratory and absence of protection in mice. Therefore, it is unknown if MBL therapy will be effective in humans with Ebola virus disease or if it could lead to serious adverse effects.

The most promising therapeutic candidate is ZMapp, a “cocktail” of humanized-mouse antibodies, which has shown promise in nonhuman primates, even when antibodies are administered more than 72 hours after infection. ZMapp was recently administered to two U.S. citizens who were evacuated from Liberia to Atlanta, and both patients improved.

Other therapeutic candidates include RNA-polymerase inhibitors and small interfering RNA nanoparticles that inhibit protein production. BCX4430, a novel synthetic adenosine analogue, inhibits infection of human cells by Ebola viruses as well as several other viruses. It is very encouraging that post-exposure administration of BCX4430 protects mice against Ebola viruses.

The vesicular stomatitis virus-based Ebola vaccines resulted in an unprecedented 50 percent protection against Ebola virus challenge in rhesus macaques when administered

30 minutes post-infection. This candidate will enter early phase human clinical trials in the next few months.


Potential biomarkers in animals could signal Ebola virus infection before symptoms appear

Scientists have identified potential biomarkers in nonhuman primates exposed to Ebola virus (EBOV) that appeared up to four days before the onset of fever, according to research published today in the journal Science Translational Medicine.

The work, a collaboration between the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) and Boston University (BU), could pave the way for developing diagnostic tools to identify EBOV infection in humans even before symptoms appear. Such tools would be invaluable in limiting the spread of disease where there are cases of known potential exposure to the virus, according to USAMRIID investigator Sandra L. Bixler, Ph.D., the paper's co-first author.

Bixler said previously developed animal models of EBOV infection have an acute disease course lasting only 7-10 days on average. This makes therapeutic intervention challenging, since the timeframe for administering treatment is very short. In addition, such models are based on high viral doses and are uniformly lethal, which does not reflect the variable and comparatively extended time to disease onset seen in humans.

"Those models make sense for testing vaccines and therapeutics," Bixler commented. "But for human infection, they don't really match what we see in the field -- especially given what we've learned from the most recent Ebola virus disease outbreak in Western Africa."

So Bixler and USAMRIID colleague Arthur J. Goff, Ph.D., decided to investigate alternative models that could still replicate human infection while extending the disease course. Instead of challenging the animals via injection, which is a standard laboratory model, they tested the intranasal route -- which would be more likely to occur in a natural outbreak where people may be exposed to infected bodily fluids.

The team designed a study using a lower dose of EBOV in 12 cynomolgus macaques. The animals, exposed by intranasal infection and closely monitored for signs of disease, fell into four categories. Three succumbed to disease in the usual timeframe of 7-10 days following infection four had a delayed onset of 10-15 days three were late-onset (20-22 days) and two survived.

"We were then faced with the challenge of teasing apart any differences between acute versus delayed disease onset, and survivors versus non-survivors," said Louis A. Altamura, Ph.D., one of the USAMRIID scientists who performed gene expression profiling to monitor the host response via changes in RNA transcripts over time. Thanks to a long-standing collaboration between USAMRIID and BU, investigators at USAMRIID's Center for Genome Sciences, along with BU scientists John H. Connor, Ph.D., and Emily Speranza, Ph.D., performed further genomic data analysis and began to look for early markers of infection.

What they found -- in all the animals except the two survivors -- were interferon-stimulating genes that appear prior to infection with Ebola virus. Importantly, the genes can be detected four days before the onset of fever, which is one of the earliest clinical signs of EBOV exposure. When Speranza compared the results to humans, using Ebola patient blood samples from the most recent outbreak, she found the same pattern.

"This demonstrates that lethal Ebola virus disease has a uniform and predictable response to infection, regardless of the time to onset," commented Gustavo Palacios, Ph.D., who directs USAMRIID's Center for Genome Sciences. "Furthermore, expression of a subset of genes could predict disease development prior to other host-based indications of infection, such as fever."

EBOV causes severe hemorrhagic fever in humans and nonhuman primates with high mortality rates and continues to emerge in new geographic locations, including Western Africa, the site of the largest recorded outbreak to date. More than 28,000 confirmed, probable and suspected cases have been reported in Guinea, Liberia and Sierra Leone, with more than 11,000 reported deaths, according to the World Health Organization (WHO). Today, WHO estimates that there are over 10,000 survivors of Ebola virus disease.

Research on Ebola virus is conducted under Biosafety Level 4, or maximum containment conditions, where investigators wear positive-pressure "space suits" and breathe filtered air as they work. USAMRIID is the only laboratory in the Department of Defense with Biosafety Level 4 capability, and its research benefits both military personnel and civilians.


Ebola hemorrhagic fever

Among humans, the virus is transmitted by direct contact with infected body fluids such as blood. The cause of the index case is unknown.

The incubation period of Ebola haemorrhagic fever varies from two days to four weeks. Symptoms are variable too, but the onset is usually sudden and characterised by high fever, prostration, myalgia (muscle pains), arthralgia (pain in the joints), abdominal pains and headache. These symptoms progress to vomiting, diarrhea, oropharyngeal lesions , conjunctivitis, organ damage (notably the kidney and liver) by co-localized necrosis, proteinuria (the presence of proteins in urine), and bleeding both internal and external, commonly through the gastrointestinal tract. Death or recovery to convalescence occurs within six to ten days.

Treatment

No specific treatment has been proven effective, and no vaccine currently exists. A vaccine is in the developmental stages. Ebola is known to exist in humans and a few monkey species can be infected. To develop the vaccine, monkeys are used but it can not be tested on humans except in outbreak environments so the vaccine must be tested extensively and meet strict government regulations. Also, in the development of a vaccine, accessibility and cost for people of poor nations and the transportation efficiency of it must be considered.

In 1999, scientist Maurice Iwu announced at the International Botanical Congress that a fruit extract of Garcinia kola, a West African tree long used by local traditional healers, stopped ebola virus replication in lab tests.

Prevention

Although there is no specific treatment for patients with Ebola, there have been entire books written about how to prevent it from spreading from the patient to health care workers or other patients. The first step in prevention is to make advanced preparations for Ebola and other viral hæmorrhagic fevers (VHFs). A VHF Coordinator should be selected to oversee preparations for VHF activities, and be responsible for the following:

  • Serving as the focal point for information and leadership when a VHF case is suspected.
  • Informing all health facility staff about VHFs and the risks associated with them.
  • Organizing training in VHF Isolation Precautions for staff that will work with VHF patients or infectious body fluids.
  • Making sure that teams are trained to prepare and transport bodies for burial (CDC 115-116).

The next step is maintaining a minimum standard of cleanliness in the hospital. This includes washing hands and sterilizing needles (CDC 9-18). Also, the medical staff must be informed about the different types of VHFs, including Ebola, and their symptoms. Symptoms that are common to many VHFs are severe weakness and fatigue, and a fever for more than 72 hours and less than three weeks. The patient also may have unexplained bleeding from the mucous membranes, skin, eyes, or gastrointestinal tract. The patient may also be going into shock (has a systolic blood pressure of less than 90 mm Hg or a rapid weak pulse). Finally, that patient may have had contact with someone in the last three weeks that had an unexplained illness with fever or bleeding or who died with an unexplained severe illness with a fever (CDC 23).

Next, the infected patient must be isolated from other, uninfected patients and from health care workers who are not directly involved in care of the infected patient. The patient should be given intravenous support, as he or she is probably dehydrated from losing fluids through vomiting and diarrhea. Finally, if the patient expires, the body should be properly disposed of, preferably through cremation, so that the dead body will not spread disease to other people (CDC 26).

Economic impact

Ebola has sharply affected tourism in the countries where it is present, especially in the Democratic Republic of the Congo 12 . Other countries that have been hard hit include Uganda, where an outbreak in 2000 stifled its waning tourism industry (Busharizi). Ebola has also made countries like Uganda, Democratic Republic of the Congo, and Sudan to lose revenue through the loss of people who would have been able to work and benefit their nation's economy. For example, many health workers' lives have been lost because they became sick in hospitals due to inadequate sanitation procedures. It is unknown how much money exactly was lost through these deaths (Busharizi).

Another loss in economic revenue has been the deaths of monkeys traded throughout the world for experimental purposes. Three out of the four Japanese airlines that transport monkeys throughout the world have quit transporting monkeys because of the risk of Ebola. Not so long ago, a monkey cost $1500 (USD) to transport, but now costs three times as much, partly because of the monkey ban 12 .

Trends

Since Ebola is so unpredictable, it is impossible to detect very many trends that it causes. Ebola first appeared out of nowhere in 1976 and disappeared until 1989 (Draper 6). It is possible to say that since this disease can be transmitted from monkeys to humans, that Ebola will probably reappear in places where there are significant monkey populations in Asia and Africa.

It is not known at this time whether there are individual trends in the Ebola virus, either. As of this date, there is no information about a person who has caught Ebola twice and lived to tell about it, so it is impossible to say whether a person is immune to it after they survive a first episode.


Where is Ebola?

There have been 33 Ebola outbreaks since 1976, but the 2014 outbreak in West Africa is by far the largest. The virus has infected thousands of people and killed more than half of them. It started in Guinea and spread to Sierra Leone, Liberia, and Nigeria. A man who traveled to the U.S. from Africa died of Ebola in October. A nurse who helped treat them came down with Ebola.


I am travelling to one of the countries in the Ebola outbreak. How can I protect myself?

The Ministry of Foreign Affairs has reviewed travel advice to the affected countries. Current travel advice is available through the webpage of the Ministry of Foreign Affairs: www.landsider.no

People travelling to an area with outbreaks should avoid:

  • contact with sick people
  • close contact with wild animals (including monkeys, antelopes, rodents and bats)
  • caves and other typical bat habitats
  • consumption of bush meat, i.e. meat from wild animals killed by hunting

It is always important to have good hand hygiene when travelling abroad. It is recommended to follow general travel advice for Africa. There is no vaccine against the disease.