Cover Story

Children struggle with limited options during Ebola outbreaks

About 1 week after an outbreak of Ebola was declared over in the Democratic Republic of Congo, or DRC, officials announced another outbreak of the hemorrhagic viral illness. This marked the country’s 10th outbreak since the emergence of the virus near the Ebola River in 1976.

As of Sept. 25, a total of 151 cases have been reported in the country in the latest outbreak, according to WHO — 17 in children aged 14 years and younger. WHO spokesman Tarik Jasarevic acknowledged that this outbreak, which is occurring in the eastern province of North Kivu, initially affected a slightly younger population, but the case distribution is now closer to that seen during previous outbreaks. Additionally, more women have been affected.

Anne W. Rimoin, PhD, MPH, from the University of California, Los Angeles Fielding School of Public Health, on her way to Mbandaka, the Democratic Republic of the Congo, in May 2018 to assess Ebola vaccine performance.

Source: UCLA-DRC Health Research and Training Program

“Approximately 58% of cases with a known cause are female, and the median age of confirmed and probable cases is 32.5 years,” Jasarevic told Infectious Diseases in Children. “Given that women of this age are often caretakers, mothers and their families could be particularly vulnerable.”

According to Anne W. Rimoin, PhD, MPH, associate professor of epidemiology at the University of California, Los Angeles Fielding School of Public Health and director of the UCLA-DRC Research Program in Kinshasa, armed conflict between the DRC military and Rwandan Hutu rebel forces in North Kivu has made diagnosing the disease a serious challenge, and health officials have had difficulty accurately gauging the size of the outbreak. Some areas, she said, “are just off limits.”

Although some experimental treatments and prevention methods, including the monoclonal antibody “cocktail” ZMapp (Mapp Biopharmaceutical) and vaccines like V920 (live-attenuated Ebola vaccine, Merck), are available in the DRC, WHO currently does not allow these products to be used in children aged younger than 6 years or in pregnant women.

Merck officials said that because the vaccine is investigational, data available regarding V920’s use in these populations are limited. Oly Ilunga Kalenga, MD, the minister of health in the DRC, told Infectious Diseases in Children that the only strategy currently available for the prevention of Ebola virus in pregnant women and children is “insisting on prevention, especially hygiene practices, avoiding contact with sick individuals and tracing contacts who [may be infected].”

Infectious Diseases in Children spoke with pediatric infectious disease specialists, epidemiologists and those on the ground in the DRC to understand how Ebola virus affects the pediatric population and how it may impact their future.

Symptoms and outcomes

Once a person is infected with Ebola virus, it may take 2 to 21 days for signs and symptoms to appear. According to the CDC, these may include fever, severe headaches, muscle pain, weakness, fatigue, diarrhea, vomiting, abdominal pain and unexplained bleeding or bruising. Anita McElroy, MD, PhD, a physician scientist at the University of Pittsburgh, said in an interview that although children have the same signs and symptoms as adults, it can be difficult to differentiate the infection from other conditions.

“The one thing that is really different between kids and adults is that kids get fevers and all of those nonspecific symptoms all the time,” McElroy said. “It is a normal part of childhood for kids to develop different typical viral illnesses. When you are talking about areas like West Africa or sub-Saharan Africa, physicians also have to consider typhoid and malarial infections. These are much more common than Ebola, and the challenge is that more children are going to be evaluated because they get fevers more often than adults.”

Study findings published in the European Journal of Pediatrics demonstrated that in a previous outbreak in Guinea, nearly 83% of pediatric patients diagnosed with Ebola were aged younger than 5 years. Most of these children had fever (91%), and the most commonly reported reasons for admitting pediatric patients to the hospital were fatigue (87%) and gastrointestinal signs and symptoms (70%). Only about a quarter of patients had signs of bleeding.

A review published in 2017 highlighted the dangers of Ebola among the youngest pediatric patients — neonates. According to the researchers, congenital Ebola infection is a risk when pregnant women are infected with the virus, and mortality rates are high among pregnant women (86%). However, mortality rates are highest among infants born to these mothers, with only one infant documented to have survived longer than 1 month after birth.

The infant, a female named Nubia, was born to a mother who received favipiravir. According to researchers, Nubia tested positive for Ebola infection at birth and was treated with ZMapp, an experimental antiviral drug called remdesivir (GS-5734), and a buffy coat transfusion from an Ebola survivor. PCR testing revealed that the child was negative for Ebola on day 20, and she was discharged in good health after approximately 1 month in the hospital.

Anita McElroy

The survival of this infant raises several questions about how the virus can be treated and prevented with pharmaceutical interventions. However, gaps in research exist regarding the transmission of this disease, as well as the characteristics that differentiate those who survive from those who do not.

“If we knew this information,” McElroy said, “we could develop targeted therapies toward the people who really need the intervention — those who are likely to die — and really impact outcomes.”

Epidemiology

According to Rimoin, when an Ebola outbreak begins, the first case is usually infected through contact with an animal host.

“While there appear to be a range of animals that may be able to transmit Ebola virus, it seems like the most probable suspects are either fruit bats or nonhuman primates,” she told Infectious Diseases in Children. “Several previous outbreaks in the DRC have been linked to a spillover event, such as someone finding a dead primate in the forest and bringing it back to a village to feed a family. There have been other outbreaks where we are just not sure how it happened because the index case may be dead or may have had exposure to many animal species that may be capable of infection and transmission of the virus.”

The genus Ebolavirus includes six species: Tai Forest ebolavirus, Sudan ebolavirus, Zaire ebolavirus, Bundibugyo ebolavirus, Reston ebolavirus and the newly discovered Bombali ebolavirus. The Zaire strain has the highest mortality rates and is the cause of the current DRC outbreak, according to health officials.

Although the effects of Ebola can be devastating to young children, Annabelle de St. Maurice, MD, MPH, assistant professor in the division of pediatric infectious diseases at UCLA, told Infectious Diseases in Children that in past Ebola outbreaks, children have comprised a minority of the cases. She speculated that this might be because many cases of Ebola are contracted when people are caring for family members who have become ill, a task in which children are not typically included.

However, de St. Maurice mentioned that it may be more difficult to prevent the spread of Ebola virus in children because it is difficult to rationalize infection prevention recommendations with children. Additionally, children may seek out comfort from family members, may not adhere to hand hygiene efforts and frequently interact with their environment.

An additional risk factor for children is breastfeeding. Ilunga Kalenga said that when women have been potentially exposed to the virus and are listed as contacts of people with active illness, they are asked to find alternative ways of feeding their infants, a recommendation that is supported by the CDC.

“The ministry of health and partners can provide these mothers with powdered milk and baby bottles for their children,” he said.

Currently, pregnant women and young children aged younger than 6 years residing in Ebola-affected areas have limited options for the prevention and treatment of the infection. However, trials have begun for several pharmacologic interventions.

Treatment and prevention

The 2014-2016 outbreak of Ebola in West Africa, which included more than 28,000 cases and 11,000 deaths, pushed health officials and industry to find new ways to contain outbreaks. Several clinical trials and manufacturing scale-ups have begun for vaccines, therapeutics and diagnostic tests.

In 2014, an Ebola outbreak took place in Boende, DRC. Rimoin and colleagues conducted research in this field lab related to the outbreak.

Source: UCLA-DRC Health Research and Training Program

During the DRC’s ninth outbreak, WHO approved the use of five different investigational products to treat Ebola under compassionate use. These included the monoclonal antibody cocktails ZMapp and REGN-EB3; the monoclonal antibody mAB 114; and the antivirals GS-5734 and favipiravir. The organization said clinicians working in Ebola treatment centers could decide which drugs to use, provided they had the consent of their patients and followed study protocols.

“So far, 38 patients have received mAb 114, remdesivir or ZMapp,” Ilunga Kalenga said. Of these patients, 19 have been cured and discharged from Ebola treatment centers, 12 died, and seven were still hospitalized at the time of publication.

Other vaccines are being developed by manufacturers in the Partnership for Research on Ebola Vaccination for use in children. These vaccines are currently being examined in clinical trials throughout West Africa.

In the absence of a vaccine, the CDC has said that treating the symptoms of Ebola can significantly improve a patient’s likelihood of survival. This may include replacing electrolytes and body fluids intravenously, providing oxygen and using medications to reduce fever and pain, stabilize blood pressure and limit diarrhea and vomiting.

Pregnant women and young children are protected largely through public health efforts, including contact tracing and standard infection prevention methods. McElroy stressed the importance of these measures.

“All those classic epidemiologic methods that have been used for decades to control these outbreaks have been absolutely critical and will remain so,” she said. “Just because we have a vaccine or drug does not mean that all these efforts are not the first and most important things we should do.”

Research and preparedness

In the aftermath of previous Ebola outbreaks, researchers have discovered more about how the virus spreads and is contracted. One research program, led by Rimoin, has examined the immune responses of people in the DRC for the past 16 years.

“Since this is the DRC’s 10th Ebola outbreak, we suspect that these populations have had much greater exposure to Ebola over time,” she said. “We have had several studies document high levels of antibody to Ebola in populations that have never known they had exposure to the virus, which suggests that there could be nonpathogenic strains, strains that do not produce acute symptoms or exposure to Ebola virus in smaller, noninfectious quantities.”

Researchers are still attempting to better understand how these exposures may affect children and adult survivors of the disease. Studies have demonstrated that the RNA of Ebola virus can persist in semen for up to 2 years, and one study published in The New England Journal of Medicine described how the virus was found in the eye of an American physician 14 weeks after he acquired the disease in 2014. This physician also developed serious ocular complications.

A recent study led by Rimoin’s team published in Clinical Infectious Diseases showed that Ebola survivors had lower cognitive scores and more symptoms of depression and anxiety compared with close contacts more than 20 years after a 1995 outbreak in Kikwit, DRC.

De St. Maurice and colleagues are also investigating the long-term outcomes of Ebola. According to her research, children who survive the infection have high rates of long-term health problems.

“It has been reported that survivors in general, not specifically children, can have problems with arthritis, uveitis and psychological problems as well,” de St. Maurice said. “In pediatrics, this is something that we really need to pay attention to because children may have a hard time reporting symptoms due to language barriers and other factors. I think that as physicians are caring for survivors, they really need to be aware of some of these long-term consequences.”

Annabelle de St. Maurice

Past outbreaks have also shown that not only are individuals affected by Ebola, but entire communities and their infrastructures can be destabilized. Health care initiatives for other diseases, such as malaria, were put on the backburner in previous outbreaks. During the 2014-2016 West African outbreak, fewer people sought care for malaria, and fewer antimalarial drugs were administered, according to researchers. An additional study during this outbreak found a 41% reduction in antenatal care visits. One reason for this may be a fear of contracting Ebola in a health care setting.

“We know that people may avoid medical care because of the fear that they may be diagnosed with Ebola,” Rimoin said. “People may be afraid of the health facilities because, often, Ebola outbreaks can propagate in health facilities. Certainly, when you start to see health care workers becoming infected, it can impact the provision of care not only for Ebola patients, but for all things. The provision of health services and public health efforts are often put on the backburner during an outbreak because the focus is trying to contain the outbreak and extinguish it before it becomes a greater threat to the community.”

However, a study published in Clinical Infectious Diseases showed that the risk of nosocomial Ebola virus transmission during an outbreak in Sierra Leone was only 0.5%.

Regarding the risk that the current DRC outbreak will spread outside the country and into the United States, de St. Maurice believes the chances are low, but it never hurts to be prepared for the possibility.

“I think there is always concern regarding international travel, Ebola and cases developing in the U.S.,” de St. Maurice said. “However, I think that the largest concern is preparedness. Here at UCLA, we are doing drills and we have a robust emerging infections program. I think that a lot of places have done a really good job of creating programs and creating awareness about Ebola.”

Ilunga Kalenga said that once the outbreak is over, the infrastructure built by the DRC’s Ministry of Health will remain available and will be used for other public health issues like cholera. Teams will be initiated to disinfect community health centers where confirmed cases were treated. This process will include destroying all equipment and completely refurbishing health centers.

McElroy remains hopeful, noting that the most recent outbreaks in the DRC can provide crucial information about vaccines and other treatments.

“These novel vaccines were not available until the end of the West African outbreak,” McElroy said. “Because of this, these past two outbreaks in the DRC are game changers for Ebola. We never had vaccination strategies in the past, and they have the potential to have an immense impact.” – by Katherine Bortz

Disclosures: Jasarevic, IIunga Kalenga, McElroy, Rimoin and de St. Maurice report no relevant financial disclosures.

About 1 week after an outbreak of Ebola was declared over in the Democratic Republic of Congo, or DRC, officials announced another outbreak of the hemorrhagic viral illness. This marked the country’s 10th outbreak since the emergence of the virus near the Ebola River in 1976.

As of Sept. 25, a total of 151 cases have been reported in the country in the latest outbreak, according to WHO — 17 in children aged 14 years and younger. WHO spokesman Tarik Jasarevic acknowledged that this outbreak, which is occurring in the eastern province of North Kivu, initially affected a slightly younger population, but the case distribution is now closer to that seen during previous outbreaks. Additionally, more women have been affected.

Anne W. Rimoin, PhD, MPH, from the University of California, Los Angeles Fielding School of Public Health, on her way to Mbandaka, the Democratic Republic of the Congo, in May 2018 to assess Ebola vaccine performance.

Source: UCLA-DRC Health Research and Training Program

“Approximately 58% of cases with a known cause are female, and the median age of confirmed and probable cases is 32.5 years,” Jasarevic told Infectious Diseases in Children. “Given that women of this age are often caretakers, mothers and their families could be particularly vulnerable.”

According to Anne W. Rimoin, PhD, MPH, associate professor of epidemiology at the University of California, Los Angeles Fielding School of Public Health and director of the UCLA-DRC Research Program in Kinshasa, armed conflict between the DRC military and Rwandan Hutu rebel forces in North Kivu has made diagnosing the disease a serious challenge, and health officials have had difficulty accurately gauging the size of the outbreak. Some areas, she said, “are just off limits.”

Although some experimental treatments and prevention methods, including the monoclonal antibody “cocktail” ZMapp (Mapp Biopharmaceutical) and vaccines like V920 (live-attenuated Ebola vaccine, Merck), are available in the DRC, WHO currently does not allow these products to be used in children aged younger than 6 years or in pregnant women.

Merck officials said that because the vaccine is investigational, data available regarding V920’s use in these populations are limited. Oly Ilunga Kalenga, MD, the minister of health in the DRC, told Infectious Diseases in Children that the only strategy currently available for the prevention of Ebola virus in pregnant women and children is “insisting on prevention, especially hygiene practices, avoiding contact with sick individuals and tracing contacts who [may be infected].”

PAGE BREAK

Infectious Diseases in Children spoke with pediatric infectious disease specialists, epidemiologists and those on the ground in the DRC to understand how Ebola virus affects the pediatric population and how it may impact their future.

Symptoms and outcomes

Once a person is infected with Ebola virus, it may take 2 to 21 days for signs and symptoms to appear. According to the CDC, these may include fever, severe headaches, muscle pain, weakness, fatigue, diarrhea, vomiting, abdominal pain and unexplained bleeding or bruising. Anita McElroy, MD, PhD, a physician scientist at the University of Pittsburgh, said in an interview that although children have the same signs and symptoms as adults, it can be difficult to differentiate the infection from other conditions.

“The one thing that is really different between kids and adults is that kids get fevers and all of those nonspecific symptoms all the time,” McElroy said. “It is a normal part of childhood for kids to develop different typical viral illnesses. When you are talking about areas like West Africa or sub-Saharan Africa, physicians also have to consider typhoid and malarial infections. These are much more common than Ebola, and the challenge is that more children are going to be evaluated because they get fevers more often than adults.”

Study findings published in the European Journal of Pediatrics demonstrated that in a previous outbreak in Guinea, nearly 83% of pediatric patients diagnosed with Ebola were aged younger than 5 years. Most of these children had fever (91%), and the most commonly reported reasons for admitting pediatric patients to the hospital were fatigue (87%) and gastrointestinal signs and symptoms (70%). Only about a quarter of patients had signs of bleeding.

A review published in 2017 highlighted the dangers of Ebola among the youngest pediatric patients — neonates. According to the researchers, congenital Ebola infection is a risk when pregnant women are infected with the virus, and mortality rates are high among pregnant women (86%). However, mortality rates are highest among infants born to these mothers, with only one infant documented to have survived longer than 1 month after birth.

The infant, a female named Nubia, was born to a mother who received favipiravir. According to researchers, Nubia tested positive for Ebola infection at birth and was treated with ZMapp, an experimental antiviral drug called remdesivir (GS-5734), and a buffy coat transfusion from an Ebola survivor. PCR testing revealed that the child was negative for Ebola on day 20, and she was discharged in good health after approximately 1 month in the hospital.

PAGE BREAK
Anita McElroy

The survival of this infant raises several questions about how the virus can be treated and prevented with pharmaceutical interventions. However, gaps in research exist regarding the transmission of this disease, as well as the characteristics that differentiate those who survive from those who do not.

“If we knew this information,” McElroy said, “we could develop targeted therapies toward the people who really need the intervention — those who are likely to die — and really impact outcomes.”

Epidemiology

According to Rimoin, when an Ebola outbreak begins, the first case is usually infected through contact with an animal host.

“While there appear to be a range of animals that may be able to transmit Ebola virus, it seems like the most probable suspects are either fruit bats or nonhuman primates,” she told Infectious Diseases in Children. “Several previous outbreaks in the DRC have been linked to a spillover event, such as someone finding a dead primate in the forest and bringing it back to a village to feed a family. There have been other outbreaks where we are just not sure how it happened because the index case may be dead or may have had exposure to many animal species that may be capable of infection and transmission of the virus.”

The genus Ebolavirus includes six species: Tai Forest ebolavirus, Sudan ebolavirus, Zaire ebolavirus, Bundibugyo ebolavirus, Reston ebolavirus and the newly discovered Bombali ebolavirus. The Zaire strain has the highest mortality rates and is the cause of the current DRC outbreak, according to health officials.

Although the effects of Ebola can be devastating to young children, Annabelle de St. Maurice, MD, MPH, assistant professor in the division of pediatric infectious diseases at UCLA, told Infectious Diseases in Children that in past Ebola outbreaks, children have comprised a minority of the cases. She speculated that this might be because many cases of Ebola are contracted when people are caring for family members who have become ill, a task in which children are not typically included.

However, de St. Maurice mentioned that it may be more difficult to prevent the spread of Ebola virus in children because it is difficult to rationalize infection prevention recommendations with children. Additionally, children may seek out comfort from family members, may not adhere to hand hygiene efforts and frequently interact with their environment.

An additional risk factor for children is breastfeeding. Ilunga Kalenga said that when women have been potentially exposed to the virus and are listed as contacts of people with active illness, they are asked to find alternative ways of feeding their infants, a recommendation that is supported by the CDC.

PAGE BREAK

“The ministry of health and partners can provide these mothers with powdered milk and baby bottles for their children,” he said.

Currently, pregnant women and young children aged younger than 6 years residing in Ebola-affected areas have limited options for the prevention and treatment of the infection. However, trials have begun for several pharmacologic interventions.

Treatment and prevention

The 2014-2016 outbreak of Ebola in West Africa, which included more than 28,000 cases and 11,000 deaths, pushed health officials and industry to find new ways to contain outbreaks. Several clinical trials and manufacturing scale-ups have begun for vaccines, therapeutics and diagnostic tests.

In 2014, an Ebola outbreak took place in Boende, DRC. Rimoin and colleagues conducted research in this field lab related to the outbreak.

Source: UCLA-DRC Health Research and Training Program

During the DRC’s ninth outbreak, WHO approved the use of five different investigational products to treat Ebola under compassionate use. These included the monoclonal antibody cocktails ZMapp and REGN-EB3; the monoclonal antibody mAB 114; and the antivirals GS-5734 and favipiravir. The organization said clinicians working in Ebola treatment centers could decide which drugs to use, provided they had the consent of their patients and followed study protocols.

“So far, 38 patients have received mAb 114, remdesivir or ZMapp,” Ilunga Kalenga said. Of these patients, 19 have been cured and discharged from Ebola treatment centers, 12 died, and seven were still hospitalized at the time of publication.

Other vaccines are being developed by manufacturers in the Partnership for Research on Ebola Vaccination for use in children. These vaccines are currently being examined in clinical trials throughout West Africa.

In the absence of a vaccine, the CDC has said that treating the symptoms of Ebola can significantly improve a patient’s likelihood of survival. This may include replacing electrolytes and body fluids intravenously, providing oxygen and using medications to reduce fever and pain, stabilize blood pressure and limit diarrhea and vomiting.

Pregnant women and young children are protected largely through public health efforts, including contact tracing and standard infection prevention methods. McElroy stressed the importance of these measures.

“All those classic epidemiologic methods that have been used for decades to control these outbreaks have been absolutely critical and will remain so,” she said. “Just because we have a vaccine or drug does not mean that all these efforts are not the first and most important things we should do.”

Research and preparedness

In the aftermath of previous Ebola outbreaks, researchers have discovered more about how the virus spreads and is contracted. One research program, led by Rimoin, has examined the immune responses of people in the DRC for the past 16 years.

PAGE BREAK

“Since this is the DRC’s 10th Ebola outbreak, we suspect that these populations have had much greater exposure to Ebola over time,” she said. “We have had several studies document high levels of antibody to Ebola in populations that have never known they had exposure to the virus, which suggests that there could be nonpathogenic strains, strains that do not produce acute symptoms or exposure to Ebola virus in smaller, noninfectious quantities.”

Researchers are still attempting to better understand how these exposures may affect children and adult survivors of the disease. Studies have demonstrated that the RNA of Ebola virus can persist in semen for up to 2 years, and one study published in The New England Journal of Medicine described how the virus was found in the eye of an American physician 14 weeks after he acquired the disease in 2014. This physician also developed serious ocular complications.

A recent study led by Rimoin’s team published in Clinical Infectious Diseases showed that Ebola survivors had lower cognitive scores and more symptoms of depression and anxiety compared with close contacts more than 20 years after a 1995 outbreak in Kikwit, DRC.

De St. Maurice and colleagues are also investigating the long-term outcomes of Ebola. According to her research, children who survive the infection have high rates of long-term health problems.

“It has been reported that survivors in general, not specifically children, can have problems with arthritis, uveitis and psychological problems as well,” de St. Maurice said. “In pediatrics, this is something that we really need to pay attention to because children may have a hard time reporting symptoms due to language barriers and other factors. I think that as physicians are caring for survivors, they really need to be aware of some of these long-term consequences.”

Annabelle de St. Maurice

Past outbreaks have also shown that not only are individuals affected by Ebola, but entire communities and their infrastructures can be destabilized. Health care initiatives for other diseases, such as malaria, were put on the backburner in previous outbreaks. During the 2014-2016 West African outbreak, fewer people sought care for malaria, and fewer antimalarial drugs were administered, according to researchers. An additional study during this outbreak found a 41% reduction in antenatal care visits. One reason for this may be a fear of contracting Ebola in a health care setting.

“We know that people may avoid medical care because of the fear that they may be diagnosed with Ebola,” Rimoin said. “People may be afraid of the health facilities because, often, Ebola outbreaks can propagate in health facilities. Certainly, when you start to see health care workers becoming infected, it can impact the provision of care not only for Ebola patients, but for all things. The provision of health services and public health efforts are often put on the backburner during an outbreak because the focus is trying to contain the outbreak and extinguish it before it becomes a greater threat to the community.”

PAGE BREAK

However, a study published in Clinical Infectious Diseases showed that the risk of nosocomial Ebola virus transmission during an outbreak in Sierra Leone was only 0.5%.

Regarding the risk that the current DRC outbreak will spread outside the country and into the United States, de St. Maurice believes the chances are low, but it never hurts to be prepared for the possibility.

“I think there is always concern regarding international travel, Ebola and cases developing in the U.S.,” de St. Maurice said. “However, I think that the largest concern is preparedness. Here at UCLA, we are doing drills and we have a robust emerging infections program. I think that a lot of places have done a really good job of creating programs and creating awareness about Ebola.”

Ilunga Kalenga said that once the outbreak is over, the infrastructure built by the DRC’s Ministry of Health will remain available and will be used for other public health issues like cholera. Teams will be initiated to disinfect community health centers where confirmed cases were treated. This process will include destroying all equipment and completely refurbishing health centers.

McElroy remains hopeful, noting that the most recent outbreaks in the DRC can provide crucial information about vaccines and other treatments.

“These novel vaccines were not available until the end of the West African outbreak,” McElroy said. “Because of this, these past two outbreaks in the DRC are game changers for Ebola. We never had vaccination strategies in the past, and they have the potential to have an immense impact.” – by Katherine Bortz

Disclosures: Jasarevic, IIunga Kalenga, McElroy, Rimoin and de St. Maurice report no relevant financial disclosures.

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