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Ebola and Other Filoviruses 

Ebola and Other Filoviruses
Chapter:
Ebola and Other Filoviruses
Author(s):

Lisa M. Bebell

DOI:
10.1093/med/9780190604813.003.0002
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date: 14 December 2018

The 2014–2016 West Africa Ebola virus disease (EVD) outbreak devastated local health systems, disrupting routine childhood vaccinations as well as antenatal and maternal care. The large scale of this most recent EVD outbreak yielded greater understanding of filovirus epidemics and changed our approach to the diagnosis, management, and treatment of filovirus disease. We now have more robust clinical and outcome data supporting specific triage and management guidelines for suspected filovirus patients, especially relatively rare populations such as neonates and pregnant women. This chapter addresses disease caused by Ebola virus (EV) and Marburg virus (MV), with a focus on congenital infection.

Epidemiology and Pathogenesis

EV and MV are filoviruses and two of the most virulent and lethal human pathogens. Filoviruses are negative-stranded, lipid enveloped RNA viruses1 and are classic zoonotic diseases, with index transmission occurring from animal to human hosts1. Bats are considered the primary asymptomatic reservoir for both EV and MV2,3, although other reservoirs and hosts may exist. Nonhuman primates can become filovirus-infected, although they are dead-end hosts like humans and may also succumb to the disease. Even minimal contact with bats or infected hosts may lead to human infection2,4,5, but outside of laboratory and bush settings, filoviruses are transmitted by contact with the body fluids, clothing, or remains of an infected individual1,4. Human blood, urine, saliva, sweat, feces, vomitus, breast milk, and semen are considered infectious6,7. Filovirus inoculation occurs through skin breaks or contact with mucous membranes of the mouth, nose, and eyes. Apart from animal models, filoviruses are not thought to be transmissible by aerosols8. Any physical object contaminated by body fluids from a filovirus-infected individual can be infectious6, as evidenced by prior EVD outbreaks associated with unsafe medical procedures, including syringe reuse9. Viral RNA sequenced from EVD-infected individuals during the 2014–2016 West Africa outbreak confirmed that person-to-person transmission, rather than ongoing zoonotic or environmental exposure, was responsible for the vast majority of cases9. Transmission features are largely similar for MV, though transmission dynamics are less well studied. Subclinical or asymptomatic filovirus infection is possible, but serosurveys of EV antibodies demonstrated subclinical seroconversion in less than 2% of endemic populations9.

EV and MV are endemic to equatorial Africa and share similar presentations, pathophysiology, and fatality rate. MV was first identified in 1967 as the cause of Marburg hemorrhagic fever, since renamed Marburg virus disease (MVD). All 12 reported outbreaks of MVD occurred in sub-Saharan Africa, among travelers returned from Africa, or in European laboratories10. Of 466 known MVD cases, 80% died. Since 1976, EVD has caused more than 25 outbreaks in sub-Saharan Africa, with case fatality ranging from 30%–90%11. From 2014–2016, West Africa faced the largest recorded viral hemorrhagic fever epidemic in history, with over 28,000 suspected and confirmed Zaire EVD cases and 11,000 fatalities11. The overall case fatality rate was 37%–74%12,13,14, and the majority of patients were of reproductive age (15–44 years)12.

Historically, children were underrepresented in EVD outbreaks, a phenomenon thought to result from outbreak dynamics and behavioral practices that spare children from EV exposure15. Reliable pediatric case estimates are limited, although the World Health Organization (WHO) estimated 1,400 pediatric EVD deaths during the 2014–2016 West Africa outbreak16. During previous EVD outbreaks in Kikwit, Democratic Republic of Congo, and in West Africa in recent years, children appeared to have lower EVD incidence than other age groups17. Children were thought to have less EVD exposure due to infrequent burial attendance, being sent away when household members became ill, and nonparticipation in nursing the sick17. However, for the 2014–2016 West Africa EVD outbreak, the lower incidence of EVD in children persisted after adjusting for exposure to infected individuals17. Although EVD incidence may be lower among children, infected children die more frequently and faster than adults18, which may have contributed to age-related surveillance biases and underestimation of the true pediatric disease burden19. High pediatric EVD mortality is hypothesized to result from concomitant medical conditions and immature immune systems, supported by low levels of the chemoattractant protein RANTES and overexuberant endothelial activation15.

Infants and young children are most likely to contract EVD through direct close contact with a parent20,21. One cohort study of children under three years of age examined associations between maternal illness, survival, breastfeeding, and children’s outcomes20. Of 77 children aged two years or less who were household contacts of EVD survivors, 43% contracted EV. In addition, 63% of children of EVD-infected mothers developed EVD20. There was no increased risk associated with breastfeeding20. The risk of EVD was 54% in infants and decreased with increasing age20.

Less is known about MVD epidemiology in children. From 1998–1999, the first community outbreak of 73 MVD cases occurred in the Democratic Republic of Congo22. Here, the first confirmed pediatric MVD case was documented, an eight-month-old infant who was breastfed and cared for by her MVD-infected mother22. Identical MV base pair sequencing in maternal and infant samples suggested direct transmission of the virus from mother to infant, and both survived22. In contrast to EVD, there is no serologic evidence for asymptomatic or mild MV infection23.

Clinical Manifestations in the Infant

Disease presentation is largely the same in MVD and EVD, though MVD pathophysiology and disease course are less extensively studied. While labeled as hemorrhagic fevers, filovirus infections do not commonly cause gross bleeding and may be conceptualized as febrile gastrointestinal diseases7,24. Viral incubation ranges from 2–21 days, with the median being 9–11 days1,25. Incubation time is shortest in infants (mean 7 days)18, who also have shorter disease duration from symptom onset to hospitalization and death18. In early filovirus infection, symptoms are nonspecific and shared with other endemic infectious diseases, including typhoid, cholera, malaria, and Lassa and Rift Valley fevers1. Notably, filovirus patients may present with multiple concomitant infections, including viruses, malaria, and bacteremia from translocated gastrointestinal tract bacteria26,27.

Early filovirus symptoms include high fever, fatigue, malaise, and myalgia13. During the 2014–2016 West Africa EVD outbreak, fever was a near-universal symptom in infants, reported in 92% before clinical presentation18, although 25% of children were afebrile on admission21. Children were less likely than adults to report abdominal, chest, joint, or muscle pain, difficulty breathing or swallowing, or hiccups18. These differences may reflect difficulties that young children have in reporting symptoms rather than different symptom profiles. At one West African treatment center, common pediatric EVD symptoms included weakness (75%), fever (71%), generalized distress (64%), loss of appetite (60%), diarrhea (59%), and cough (53%)21.

Once infection is established, the predilection of filoviruses for the gastrointestinal tract leads to life-threatening dehydration from cholera-like diarrhea7,24 and recurrent emesis. Rapid intravascular volume depletion, coupled with poor absorption of nutrients, leads to electrolyte disarray and acid-base disorders7,24, which can result in hypoperfusion, shock, and multiorgan failure. Patients with severe intravascular volume depletion, metabolic abnormalities, tachypnea, anuria, delirium, coma, and shock have a poor prognosis9. In critically ill filovirus patients, tissue hypoperfusion is dramatic and marked by elevated lactate levels, regardless of the degree of dehydration24. Common laboratory findings include leukopenia, thrombocytopenia, electrolyte abnormalities, transaminase elevation, and renal and coagulation abnormalities (Table 2.1)9.

Table 2.1 Common laboratory abnormalities in filovirus disease

Blood Test

Common Abnormality

Clinical Implication

Recommended Testing Frequency

Hemoglobin/hematocrit

Late: Ebola and Other Filoviruses or Ebola and Other FilovirusesEbola and Other Filoviruses

  • Bleeding or volume expansion dehydration

Daily, unless visible bleeding or suspected hemolysis

Early: Ebola and Other Filoviruses or Ebola and Other FilovirusesEbola and Other Filoviruses

White blood cell (WBC) count

Early: Ebola and Other Filoviruses or Ebola and Other FilovirusesEbola and Other Filoviruses

  • Rapid increase in neutrophil count late in disease correlates with poor outcome

  • Rapid change in WBC count could indicate concomitant bacterial infection

Daily

Late: Ebola and Other FilovirusesEbola and Other Filoviruses

  Neutrophil (PMN) count

Late: Ebola and Other FilovirusesEbola and Other Filoviruses

  Lymphocyte count

Ebola and Other Filoviruses or Ebola and Other FilovirusesEbola and Other Filoviruses

Platelets

Early: Ebola and Other Filoviruses or Ebola and Other Filoviruses

  • Low production or consumption from disseminated intravascular coagulation (DIC)

Daily, unless visible bleeding, petechiae, ecchymoses, or suspected DIC

Late: Ebola and Other Filoviruses or Ebola and Other FilovirusesEbola and Other Filoviruses

Liver function

  • AST is usually more elevated than ALT

Daily

  Aspartate aminotransferase (AST)

Ebola and Other Filoviruses or Ebola and Other FilovirusesEbola and Other Filoviruses

  Alanine aminotransferase (ALT)

Ebola and Other Filoviruses

  Alkaline phosphatase

Ebola and Other Filoviruses or Ebola and Other FilovirusesEbola and Other Filoviruses

Coagulation measurements

  • D-dimers are often elevated on Day 1 of illness

  • PT, PTT, and INR may be normal

  • Rapid INR increase should raise suspicion for Disseminated intravascular coagulation (DIC)

Daily, unless visible bleeding, petechiae, ecchymoses, or suspected DIC

  Prothrombin time (PT)

Ebola and Other Filoviruses or Ebola and Other FilovirusesEbola and Other Filoviruses

  Partial thromboplastin time (PTT)

Ebola and Other Filoviruses or Ebola and Other FilovirusesEbola and Other Filoviruses

  International normalized ratio (INR)

Ebola and Other Filoviruses or Ebola and Other FilovirusesEbola and Other Filoviruses

  D-dimers

Ebola and Other FilovirusesEbola and Other Filoviruses or Ebola and Other FilovirusesEbola and Other FilovirusesEbola and Other Filoviruses

Among pediatric EVD patients in the 2014–2016 West Africa outbreak, case fatality was highest among children under four years of age18, which was partially explained by higher EV concentrations in young children28. One pediatric study reported 77% (26/34) mortality in children under two years; and 82% of those with high EV concentrations at admission died, as opposed to 46% with low EV concentrations21. Signs significantly associated with increased mortality risk were fever, vomiting, and diarrhea. Hiccups, bleeding, and confusion occurred only in children who died21. In fatal EVD cases, death usually occurs between days 6 and 1612,29 and results from persistent circulatory shock and multiorgan failure with marked hepatic and renal dysfunction30,31. High viral titers, elevated lactate, leukocytosis, and coagulopathy are common32,33,34,35. Among survivors, symptoms often improve by day 1036, and nearly all patients alive at day 13 ultimately survive36. EVD recovery is prolonged, marked by weakness, fatigue, arthralgia, and failure to regain weight lost during illness9. Neuropsychiatric symptoms, skin sloughing, and hair loss are common9.

Filoviruses can be acquired congenitally, and transmission by this route is almost universally fatal. Hematogenous spread of live virus through the placenta and into fetal tissue and amniotic fluid is likely, as high EV concentrations have been detected in placental tissue and amniotic fluid during acute EVD and after full maternal recovery37,38,39,40,41,42. Such cases suggest that the placenta is a viral reservoir, and transplacental filovirus spread may result from altered immune defenses during pregnancy. However, there is no evidence that pregnant women are more susceptible to filovirus infection38,43.

Although the 2014–2016 West Africa EVD outbreak was historically the largest, only 111 cases of pregnant EVD patients have been reported in the literature34,36,39,40,41,44,45,46,47,48,49, with 86% aggregate maternal mortality. Fetal outcomes have been reported for 59 confirmed or suspected EVD cases in pregnancy, resulting in 47 (80%) stillbirths or miscarriages and 12 (20%) live births, of whom all except one died within 19 days of life34,36,39,40,41,44,45,46,47,48,49. From the few case reports available, it remains unclear whether the EVD course in neonates is the same as in older children and adults50. Survival beyond 19 days of life for an infant born to an EV-infected mother was not reported in prior EVD outbreaks51. However, in 2017 Médecins Sans Frontières (Doctors Without Borders) reported on one infant born of an EV-infected mother who survived for over 1 year after receiving experimental therapy GS 573452. Beyond fetal demise and neonatal mortality, understanding EVD effects on fetuses and neonates is limited by international guidelines recommending against examination of fetal and placental tissue due to risk of viral exposure to staff performing autopsies40,53,54.

Diagnosis

A putative diagnosis of filovirus disease is based on clinical presentation with corollary travel or exposure history, and confirmed by laboratory testing. Filovirus disease should be considered in the differential diagnosis for all children with acute febrile illnesses presenting from an area with active EV or MV transmission in the preceding three weeks. Other febrile illnesses endemic to the area should also be considered. In addition, any child born to a mother with current or recent filovirus disease should be considered potentially infected. Public health authorities should be notified of a suspect filovirus case at first evaluation, and trained personnel should implement infection control precautions immediately.

Filovirus testing is virus-specific, with testing more widely available for EV than for MV, owing to the recent EVD outbreak. In the United States (U.S.), a provider considering filovirus infection should wear full personal protective equipment, collect 4 mL of whole blood in a nonheparinized, preservative-coated tube, and refrigerate or freeze the sample immediately for shipment to the Centers for Disease Control and Prevention (CDC)9. The CDC uses reverse transcription polymerase chain reaction (RT-PCR) testing to confirm the MVD or EVD diagnosis. Detailed instructions from the CDC website should be followed, including notifying CDC before sending specimens.

Outside the U.S., RT-PCR assays of either blood or oral swab samples55 can detect EV RNA1. MV testing is more limited owing to its rarity. Filoviral antigen and nucleic acid are detectable in blood from as early as day 1 through at least day 10 of symptomatic illness, and detectable viral RNA can persist for weeks in specific body tissues and fluids. While EV RNA is detectable in some patients within the first 24 h after symptom onset, a negative RT-PCR test cannot rule out EVD until more than 72 h after symptoms begin36,42. This time window likely also applies to MVD. Filoviral antibodies develop as early as day 2 for the IgM subtype and as early as day 6 for the IgG subtype1; IgM persists for 1–6 months after infection, while IgG persists for up to 10 years27.

New filovirus point-of-care diagnostics with high sensitivity and specificity are being evaluated56. The Cepheid Xpert EVD test has been tested in children as young as 1 day old, with 100% sensitivity and 96%–100% specificity, using both blood and buccal swab samples57. In future outbreaks, oral swabbing may be the preferred testing method to reduce healthcare worker filoviral exposure risk55.

Treatment

Diagnosis and triage of pediatric and pregnant patients with suspected filovirus disease are challenging but critical first steps. No viral-specific therapies are approved for either EVD or MVD. Current filovirus disease treatment recommendations are based on clinical experience treating patients during outbreak settings, and evidence-based guidelines are limited. For patients suspected of filovirus disease, early and aggressive supportive care is the mainstay of management58. Filovirus patients should be admitted to an intensive care unit (ICU) or another highly monitored isolation ward when resources allow. In general, despite clear differences in disease pathogenesis and clinical course between patients with filovirus disease and other forms of sepsis, patients can be treated according to severe sepsis guidelines59. Vital signs should guide initial therapy, with massive fluid resuscitation as the main supportive treatment58. In the setting of ongoing gastrointestinal loss, adult patients usually require at least 5–10 L of intravenous (IV) or oral fluid daily24, but pediatric repletion needs are more variable and less well established.

Care providers during the 2014–2016 West Africa EVD outbreak advocate the liberal use of oral rehydration solution (ideally flavored so as to improve intake), and early, aggressive parenteral fluid resuscitation, even among apparently well hydrated children60. Obtaining IV access may be easiest at admission, before further fluid loss makes vascular access difficult. A second IV line should be considered in “wet” patients with active vomiting or diarrhea60. Intraosseous and subcutaneous fluid resuscitation may be necessary for children unable to tolerate oral or IV rehydration60. Lactated Ringer’s solution was commonly used in the 2014–2016 West Africa EVD outbreak, supplemented with glucose, potassium, and magnesium where possible, guided by clinical status and i-STAT monitoring60. Portable bedside ultrasonography may be useful to overcome some physical examination limitations imposed by personal protective equipment, and it also may facilitate volume status evaluation and IV access60.

Medications to decrease gastrointestinal loss, including antiemetics like ondansetron (IV and by mouth) and antidiarrheals like loperamide, may be used60. Due to the risk of exacerbating toxicity when using antidiarrheals in children with bacterial diarrhea, loperamide is recommended only when test-confirmed filovirus patients when nonbloody diarrhea60. Loperamide was used successfully with no reported adverse effects in children during the 2014–2016 West Africa EVD outbreak60. Micronutrient supplementation (including oral zinc) may also decrease diarrhea severity and duration in children from concomitant infections60.

Antibacterial therapy with IV ceftriaxone or oral ciprofloxacin or amoxicillin/clavulanate is recommended for empiric treatment of Gram-negative bacterial translocation thought to occur during filovirus infection and misdiagnosed or co-occurring bacterial sepsis in settings with low diagnostic capabilites60. Empiric metronidazole may be used for severe or bloody diarrhea but it may increase abdominal pain and nausea60. Empiric artesunate-based antimalarial treatment is recommended for all patients with suspected EVD due to 31% lower mortality in patients receiving artesunates compared with other antimalarials, with a stronger effect observed among patients without malaria61. One EVD treatment center started all children on IV artesunate, followed by a complete course of artemisinin-combination therapy60.

Nutrition is a high priority in children with filovirus disease, using prepared or ready-to-use therapeutic food60 and treating malnourished children according to acute malnutrition therapeutic feeding protocols60. Vitamin K should be considered for all filovirus patients to improve synthetic hepatic function and coagulation factor consumption60. Of 27 EVD patients managed in the U.S. and Europe, 19 (70%) received at least two investigational therapies62. Although mortality in this group of EVD patients was low (19%), it is not possible to determine whether, or which, investigational therapies resulted in lower mortality62. Furthermore, there are no data on treatment of MVD aside from supportive care.

Several filovirus therapeutics are in various stages of development and testing56. Recent trials of favipiravir indicated the potential benefit of lowering EV concentrations when used as combination therapy in both pediatric and adult patients63,64. Additional targeted EVD therapies are being tested in Phase I and Phase II trials56. ZMapp, an antibody cocktail based on blood products from EVD survivors, was given to several patients in 2015, where it demonstrated some effectiveness, and it is currently being evaluated in clinical trials65. Owing to similarities between filoviruses, successful treatments for EVD may also be used to treat MVD, but this has not been tested.

For filovirus-infected pregnant women, the value of common obstetric interventions such as fetal monitoring, cesarean delivery, induction of labor, or pregnancy interruption must be considered on a case-by-case basis58. In addition to careful deliberation about obstetric intervention, appropriate anticipatory guidance should be provided to all pregnant women. To this end, urine pregnancy testing should be part of routine triage to appropriately counsel pregnant women about expectations and options. Pregnant filovirus patients are at high risk of spontaneous, preterm labor, and healthcare providers should be prepared for delivery at any time. Pregnancy outcomes can include spontaneous abortion, stillbirth, or delivery of a live infant, and appropriate precautions should be taken for each case. Regardless of the pregnancy outcome, all products of delivery should be considered potentially infectious and handled accordingly. Neonatal survival in EVD is poor, and high fetal loss rates underscore the need to focus treatment efforts on the pregnant mother43; these recommendations likely also apply to MVD.

Prevention

Currently, no vaccines are licensed to protect against filovirus infection, though there are several candidate EV vaccines in Phase II and III clinical trials56 after Phase I studies demonstrated their safety in humans66,67. The preliminary results of one ring-cluster, randomized EV vaccine trial showed promise in preventing infection among exposed contacts68. Of note, vaccine safety and efficacy have not yet been studied in special populations such as children and pregnant women.

The mainstay of filovirus prevention is avoiding contact with infected animal vectors, contaminated objects, and body fluids of human filovirus cases. EV has been cultured from breast milk 15 days after symptom onset and EV RNA detected 26 days after symptom onset69,70. This evidence suggests that EV may be transmitted through breast milk, although frequent intimate contact between mothers and their children leaves open other modes of transmission as possibilities. A recent study of EVD survivors in Sierra Leone demonstrated no excess risk of EV transmission to infants during breastfeeding20. Despite this fact, it is recommended that mothers with suspected or confirmed EVD avoid close contact with their infants if safe alternatives to breastfeeding exist71. This includes cessation of breastfeeding and resuming only when laboratory testing demonstrated breast milk is EV-free71. The same caveats likely apply to MVD, although no studies of breast milk or breastfeeding in MVD exist to support evidence-based guidelines.

Extreme care should be taken when caring for filovirus patients and handling waste exposed to the virus. It is recommended that only providers trained in the use of personal protective equipment care for potentially infected patients, and that they be monitored by other trained staff to avoid breaches in protocol72. Soap-and-water handwashing and alcohol hand gel can disrupt the lipid membrane of filoviruses and interrupt transmission, although hand hygiene is no substitute for the correct use of personal protective equipment. Supplies used for infected patients should be disposable whenever possible, and the use of sharps should be minimized.

Of note, amniotic fluid, the placenta, and other products of conception are highly infectious, and virus persists in these tissues even after the mother has recovered39. Handling human remains should be minimized, and autopsies should be avoided altogether72. Government and local authorities should be notified of suspected filovirus deaths and disposal needs, and contaminated items and human remains should be disposed of with infection control guidance53.

Once recovered from filovirus disease, a patient is likely immune to future infection by the same viral strain and is considered noninfectious to the general public. Currently, it is not known whether persistent filovirus in semen and vaginal fluid affects future birth outcomes. WHO recommends close monitoring of survivors who later become pregnant, but it does not recommend enhanced precautions at delivery73.

Future Directions

Systematic prospective observational studies are essential to clarify the pathogenesis and pathophysiology of filovirus disease in children and pregnant women and inform the development of evidence-based management algorithms. Until studies can provide guidance on optimal treatment, improving access to basic supportive care during future outbreaks is essential. Developing point-of-care filovirus testing is necessary to differentiate EVD and MVD from filovirus mimics and to limit nosocomial filovirus transmission. Improving treatment unit staffing ratios, considering staffing units with immune filovirus survivors, developing lighter-weight personal protective equipment, and implementing environmental cooling measures in treatment centers may all provide better supportive care to filovirus patients.

Further research is needed on the effect of caregiver accompaniment for children with filovirus disease, as well as on the effect of filovirus infection on survivors’ future fertility and obstetric outcomes. Studying pediatric survivors of the 2014–2016 West Africa EVD outbreak will also provide much-needed data on long-term outcomes and residual effects of filovirus disease. Finally, vaccines to prevent infection in endemic settings or to provide prophylaxis for exposed individuals against disease development would be revolutionary. Differences in pediatric immune and inflammatory responses may necessitate unique approaches to pediatric vaccination and treatment9. Despite promising results of vaccines reaching Phase III trials68,74, there are minimal safety or immunogenicity data in children—a crucial knowledge gap that must be addressed in future trials.

Conclusions

Congenital and pediatric EVD and MVD are severe or lethal infections. Historically, children have been underrepresented in filovirus disease outbreaks, and evidence-based treatment strategies are lacking as well. Existing data suggest that case fatalities are highest among children under four years, partially explained by higher virus concentrations in young children. Prevention and aggressive resuscitation, nutrition and supportive care are the mainstays of management until filovirus-specific therapies can be developed. Studying pediatric survivors of the 2014-2016 West Africa EVD outbreak will provide much-needed data on long-term outcomes and residual effects of filovirus disease while awaiting effective filovirus-specific vaccines and therapies.

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