Ebola Virus Disease: Epidemiology, Clinical Presentation, and Diagnostic and Therapeutic Modalities (Pharmacology CME)

Table of Contents

 

1. Abstract
2. Case Presentations
3. Introduction
4. Critical Appraisal of the Literature
5. Transmission
6. Pathogenesis
7. Differential Diagnosis
   1. Lassa Fever
   2. Malaria
   3. Cholera
   4. Typhoid Fever
   5. Influenza
   6. Gastroenteritis
   7. Other Diseases
8. Prehospital Care
9. Emergency Department Evaluation
10. Diagnostic Studies
11. Management
    1. Supportive Care
12. Pregnant Patients
13. Controversies And Cutting Edge
14. Disposition
15. Postepidemic Perspective
16. Summary
17. Key Points
18. Risk Management Pitfalls For Ebola Virus Disease In Children
19. Time- And Cost-Effective Strategies
20. Case Conclusions
21. Clinical Pathway For Evaluation Of Patients With Possible Ebola Virus Disease
22. Tables
    1. Table 1. World Health Organization Case Definition Of Ebola Virus Disease During An Outbreak
    2. Table 2. Differential Diagnosis Of Ebola Virus Disease
    3. Table 3. Epidemiologic Risk Categories For Ebola Virus Disease
    4. Table 4. Laboratory Abnormalities In Ebola Virus Disease
    5. Table 5. Experimental Therapeutics For Ebola Virus Disease
23. References

Abstract

Ebola virus disease (EVD) is a severe multisystem disease. Prehospital personnel, hospitals, and clinicians must be prepared to provide care for patients with EVD, with special attention to rigorous infection control in order to limit the spread of infection. Children with EVD are an especially challenging population, as the initial symptoms are nonspecific and difficult to differentiate from several common infections. For children presenting with a syndrome consistent with EVD, it is extremely important that healthcare workers identify epidemiologic risk factors, such as recent travel to an affected country or exposure to a patient with suspected or known EVD. Given the high morbidity and mortality of this disease, clinical efforts should focus on early diagnosis, appropriate infection control, and supportive care.

Case Presentations

A 4-year-old girl presents to the ED with a 4-day history of tactile fever, headache, malaise, joint pain, difficulty breathing, large-volume diarrhea, and nonbloody, nonbilious emesis. She lives at home with her parents and 8-year-old sister. She emigrated from Liberia 2 weeks ago. On examination, she is pale, ill-appearing, and lethargic. Her vital signs are: temperature, 40.4ºC (104.7ºF); respiratory rate, 40 breaths/min; heart rate, 185 beats/ min; blood pressure, 72/43 mm Hg; and oxygen saturation, 86% on room air. Dried blood is noted in her right nare. Her lung sounds are normal, but tachypnea with moderate retractions are present. She is tachycardic with a normal rhythm and a capillary refill of 4 seconds. Her abdomen is soft and mildly tender diffusely, but no distention or rebound is present. Her extremities are cool to the touch and mottled, but no rash is noted. She moans in response to the examination.

A 10-year-old girl presents with a 2-day history of cough, runny nose, fever to 38.6ºC (101.5ºF), body aches, abdominal pain, headache, and nonbloody, nonbilious emesis. She has not had diarrhea. Three other family members are ill with similar symptoms. Her aunt, who is staying with her, recently traveled to West Africa and returned 20 days ago. The girl’s vital signs are: temperature 38.6ºC (101.5ºF); respiratory rate, 34 breaths/min; heart rate, 127 beats/min; blood pressure, 98/69 mm Hg; and oxygen saturation, 93% on room air. She is moderately ill-appearing but alert and answering questions appropriately. Her mucous membranes are dry. She is tachycardic with normal rhythm. Her abdomen is soft and mildly tender diffusely, but no distention or rebound is present. Her lungs have bibasilar crackles, greater on the right than the left. Tachypnea is noted with mild intercostal retractions. Her capillary refill and skin examination are normal.

What is the first step in the prescreening of these patients? What precautions should healthcare workers take? What are the initial steps in assessment and resuscitation? What signs and symptoms point to multisystem involvement? What historical and physical examination clues would point to a diagnosis of Ebola virus disease? What other diagnoses should the clinician consider? What diagnostic testing should be undertaken? Which patient(s) requires quarantine? What management techniques should be initiated in the care of these patients?

Introduction

On March 23, 2014, the World Health Organization (WHO) announced that an Ebola virus outbreak that started in the Republic of Guinea in December 2013 had spread to numerous West African countries.^1,2 The Ebola epidemic of 2014 was the longest, largest, and most pervasive outbreak to date.³ In previous Ebola virus disease (EVD) outbreaks, children represented a small proportion of infected cases and were underrepresented in EVD studies.^4,5 However, the index case for this epidemic was traced back to an 18-month-old child in Guinea.⁶ Early data from the 2014 EVD epidemic indicate that approximately 20% of all cases were in children aged < 16 years, with case fatality rates as high as 90% in children < 1 year old.⁷

EVD is an acute disease that results in high morbidity and mortality. The Ebola virus, along with the Marburg virus, belongs to the Filoviridae family.⁸ There are 5 distinct species of Ebola virus, each of which is named for the region where it was originally identified.⁹ The species are Sudan ebolavirus, Zaire ebolavirus, Taï Forest ebolavirus, Bundibugyo ebolavirus, and Reston ebolavirus.⁸ The filoviruses are enveloped, negative-sense single-stranded RNA viruses with a filamentous structure. The virus particles typically have a diameter of 80 nm and can be as long as 14,000 nm.¹⁰

The Ebola outbreak of 2014 had significant impact on African countries and led to a global public health emergency. The likelihood of contracting EVD in the United States is extremely low unless a person has direct contact with the blood or body fluids (eg, urine, saliva, vomit, sweat, semen, or diarrhea) of a symptomatic person with EVD.³ Case definitions for EVD have been established by the WHO. (See Table 1.) Clinicians are uniquely tasked to distinguish between EVD and common pediatric illnesses, as children with EVD may present with nonspecific signs and symptoms.

Abbreviation: EVD, Ebola virus disease.

Adapted from: World Health Organization. Case definition recommendations for Ebola or Marburg virus diseases. 

This issue of Pediatric Emergency Medicine Practice focuses on the recognition, evaluation, and management of children with EVD by offering a review of the recent advances in these areas. It provides updated information and guidelines on management for clinicians who may be the first point of contact for patients. This information will allow clinicians to maintain a high index of suspicion while differentiating between common ailments and EVD. Adequate prehospital care will serve to reduce transmission to others, decrease unnecessary healthcare worker exposure, and reduce morbidity and mortality with early recognition and management.

Critical Appraisal Of The Literature

A literature review was performed in the PubMed and Ovid MEDLINE^® databases using the search terms: Ebola, Ebola virus, hemorrhagic fever, Ebola virus disease, and Ebola vaccines with limits to humans. Given the limited literature available on pediatric patients with EVD, studies involving adults were included. The search resulted in 108 articles, predominantly from the adult literature. Literature searches were also conducted using Google scholar, MDConsult, and Medscape eMedicine using the key terms: Ebola, Ebola virus, hemorrhagic fever, and Ebola virus disease. Referenced sources from these articles were also reviewed.

Unfortunately, there is scant high-grade evidence regarding EVD in children, with only 14 articles noted on MEDLINE^®. A search of the Cochrane Database of Systematic Reviews resulted in 6 publications relating to Ebola virus. One publication was a technological assessment investigating the cause of current epidemics not limited to Ebola. The only review involving EVD in pediatric patients examined routes of achieving parenteral access in patients with EVD. The other 4 articles were trials looking at genomics, vaccines, and novel therapies in nonhumans. No randomized controlled trials examining the management of EVD exist, making class I evidence for management recommendations not feasible.

The WHO and the Centers for Disease Control and Prevention (CDC) both maintain robust database information on EVD and provide extensive guidelines for healthcare workers. Additional guidelines are available from the Public Health Agency of Canada (http://www.canadiancriticalcare.org/_assets/Ebola Clinical Care Guidelines_ENG.pdf)¹¹ and the Infectious Diseases Society of America (IDSA) (http://www.idsociety.org/2014_ebola/). The IDSA primarily focuses on the adult population, but information may be extrapolated to pediatrics.¹² While the American Academy of Pediatrics (AAP) website Healthy Children (www.healthychildren.org) has a patient education sheet, a further search of the AAP (http://www.aap.org/) and the Canadian Pediatric Society (http://www.cps.ca/) sites revealed no guidelines or clinical algorithms. The European Commission Public Health Task Force published guidelines in 2004, known as the Bichat Guidelines, which outline the clinical management of hemorrhagic fever viruses, especially in the context of bioterrorism.¹³ A recent article written by a group of critical care clinicians serves as an excellent guide for the care of children with EVD in resource-rich areas.¹⁴ Most of the literature involving humans consists of case reports and case series, with the majority being retrospective in nature and not pediatric-focused. A large body of data on the pathogenesis of Ebola virus is from laboratory experiments employ-ing nonhuman primates, mice, and guinea pigs.^15,16

Following the EVD epidemic that started in Guinea, Africa in late 2013, there has been a significant increase in the literature regarding the recognition, evaluation, and management of patients with EVD. This epidemic also resulted in a greater understanding of the pathology of EVD and methods to improve survival.⁶ The CDC has released numerous statements since the start of the West African outbreak, including a clinical evaluation algorithm (See the Clinical Pathway For Evaluation Of Patients With Possible Ebola Virus Disease). Currently, additional algorithms are available regarding reduction of exposure to the virus and prevention of transmission, but gaps regarding practical application remain.¹⁷ It is difficult to establish large randomized studies given how rapidly patients with EVD deteriorate, the ethics associated with treatment, the scarce number of “treatments” available, and the high morbidity/mortality rate. New scientific research seeks to develop novel vaccines and treatments to eradicate Ebola.

Risk Management Pitfalls For Ebola Virus Disease In Children

1. “We don’t need to screen for Ebola since there have been only a few cases in the United States.”
   EVD should be considered in anyone with a fever who has traveled to or lived in an area where EVD is present or anyone who has been in contact with someone exposed to EVD. Not screening appropriately for Ebola exposure and risk factors increases the risk of transmission.
2. “I do not need to place a suspected EVD case in isolation or on contact and droplet precautions.”
   Ebola virus is extremely contagious. Delaying initiation of infection control measures could result in multiple people being exposed to EVD. Infection control is considered a critical part of management and should consist of PPE covering of all skin and mucous membranes, airborne precautions, and placement of the patient in a single-patient room with a private bathroom with the door closed.
3. “It takes too much time to put on PPE, I’ll just skip it this time.”
   One of the most effective measures for reducing the risk of transmission is the appropriate use of PPE. Unprotected exposure to blood or body fluids of patients with EVD through contact with skin, mucous membranes of the eyes, nose, or mouth increases the risk of transmission. Due to the high risk of transmission to healthcare workers and the severity of EVD, it is imperative that healthcare workers take the time to appropriately don and doff PPE.
4. “Since almost all of the cases of Ebola are in Africa, I do not need to train my staff on proper infection control measures or triage protocols.”
   Adequate training of staff is vital. Untrained staff would not be prepared to limit unnecessary exposure to Ebola. Proper training is also important to protect against injuries with contaminated needles or other sharp objects. Also, possible aerosol-generating procedures should be avoided, especially in the prehospital setting.
5. “I think that patient has Ebola, but it should be okay for all of the residents to be involved in his care, especially since Ebola is rare and they may not see this again.”
   Contact with patients with EVD should be limited to essential personnel. To protect laboratory personnel, only essential laboratory specimens should be sent. All workers who might be at risk for exposure should be adequately informed and prepared beforehand.
6. “This child has been to an Ebola-endemic area, but his symptoms are more consistent with malaria.”
   While malaria is more common, early recognition of the signs and symptoms of EVD on presentation may reduce morbidity and mortality. Both malaria and EVD should be worked up and ruled out since many of the signs and symptoms overlap. During an EVD epidemic (such as the 2014 outbreak in Africa) clinicians need to maintain a high index of suspicion regarding EVD, but not lose sight of other diseases in the differential, such as malaria or influenza.
7. “Our hospital is not equipped to handle a patient with Ebola, but I’m worried this child might have Ebola. What should I do?”
   When working in a front-line facility, it is important to ensure proper isolation of a patient in the child’s own room (with a bathroom, if possible) with the door closed. The local health department should be contacted immediately to assist with diagnosis and coordination with the CDC.
8. “He should be fine since he doesn’t look so bad. I think he can go home.”
   Patients with EVD can deteriorate quickly. EVD has a high rate of morbidity and a high case-fatality rate. Patients with suspected EVD should be admitted to the hospital for further care and observation. This allows supportive treatment to be initiated quickly.
9. “NSAIDs can’t hurt; her fever is pretty high and she looks uncomfortable.”
   In patients who look uncomfortable, antipyretics are appropriate. However, NSAIDs and aspirin should be avoided. Ebola virus causes dysfunction of platelets and coagulation pathways and those specific medications may exacerbate the problem. Acetaminophen is the preferred medication.
10. “Wow, this kid has Ebola. I don’t know how to treat that. I’ll just wait for the CDC to tell me what to do.”
    Ebola virus is known to cause endothelial damage and increased vascular permeability. The cornerstone of treatment is simple resuscitative efforts, such as those used in sepsis or shock. It is important that aggressive supportive care, such as fluid resuscitation, be initiated, especially in children who show signs of dehydration or who present with vomiting and diarrhea.

Tables

Abbreviation: EVD, Ebola virus disease.

Adapted from: World Health Organization. Case definition recommendations for Ebola or Marburg virus diseases. 

References

Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.

To help the reader judge the strength of each reference, pertinent information about the study, such as the type of study and the number of patients in the study is included in bold type following the references, where available. The most informative references cited in this paper, as determined by the authors, are noted by an asterisk (*) next to the number of the reference.

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