Operations, Patient Care

A First Responder’s Guide to Ebola

Issue 5 and Volume 40.

“Filoviridae is the only known virus family about which we have such profound ignorance.”

— C.J. Peters & J.W. LeDuc, National Center for Infectious Diseases, CDC

Learning Objectives

  • Identify the signs and symptoms of Ebola.
  • Learn the pathogenesis of Ebola.
  • Understand how Ebola is transmitted and how to protect yourself when caring for an infected patient.

KEY Terms

Cytokine: Proteins important in cell signaling in immune response.
Dendritic cells: Immune cells that encourage T-cell response.
Macrophages: White blood cells that engulf foreign cells and assist in inflammation and immune processes.
Tissue factor: A protein that assists with the clotting cascade.
Tumor necrosis factor: A type of cytokine that encourages cell death.

 

Although we can still claim a great deal of ignorance when it comes to the virus family to which Ebola belongs, we’ve accumulated more knowledge during the current outbreak than throughout all of the previous 40 years. Ebola virus disease (EVD) is a zoonosis caused by a virus from the family referred to as filoviridae. It gets its name from its characteristic shape, which resembles that of a filament. Members of this family cause what is frequently referred to as a viral hemorrhagic fever. It’s known that new virus particles bud off of host cells, but otherwise not much is known about how filoviruses replicate. Two types of filovirus have been identified: Marburg and Ebola. Cuevavirus is potentially a third form of filovirus.1

Ebola was first recognized in 1976 near the Ebola River Valley in Zaire, but has appeared irregularly. There were no identified human infections between 1979 and 1994; outbreaks have been increasing in frequency since 2000. Ebola has five species: Reston (which hasn’t been known to cause illness in humans), Bundigbugyo (which has been responsible for approximately 185 cases in two outbreaks), Taï Forest/Ivory Coast (which has been responsible for a single patient following infection after an autopsy performed on an infected chimp), Sudan and Zaire. Ebola Zaire is often simply referred to as “Ebola” because it’s the strain seen most often and is the deadliest. The mortality rate for Ebola Zaire varies between outbreaks and ranges between 60–90%.2 The current outbreak, which is the largest in history with more patients than all other known outbreaks combined (the authors estimate 2,345 total known Ebola patients prior to this outbreak, excluding outbreaks limited to laboratory infections), carries a current mortality rate of greater than 70% in Africa and 25% in the United States, for those diagnosed in the U.S.

The natural reservoir of the virus is uncertain, though the fruit bat is known to play an important role in the maintenance of the virus in the environment. Following the initial human infection, the virus is spread between humans. The current outbreak is believed to have started with a 2-year-old child in Guinea who died December 2013.3 The Centers for Disease Control and Prevention (CDC) and international responders believed the outbreak was under control before it was recognized as being out of control in May 2014.4

Ambulances outside the Tubmanburg General Hospital in Bomi County, Liberia, standing idle, each missing a front passenger side tire. With no functional ambulances, the county health officers are unable to transfer patients to the Ebola treatment unit in Monrovia, the country’s capital city. Photo courtesy CDC/Sally Ezra

 

Transmission

Ebola is known to be transmitted between humans through the bodily fluids of a person who’s sick. To be contagious, the patient must demonstrate at least one sign of illness, although the experience of clinicians in Monrovia, Liberia, suggests that a patient exhibiting only fever appears to be very unlikely to transmit the disease.5 Although this hasn’t been proven scientifically, it seems to be a commonly accepted conclusion based on experience. This also appears to be the experience with the Texas nurse who was infected and traveled by aircraft with a fever. Nobody who was in contact with her became infected.

Fluids in which the virus has been detected include sweat, blood, saliva, semen, urine, feces, vomit, vaginal fluids and tears. The virus is also transmissible after death, with many patients in West Africa having contracted the virus during funeral rituals. The reason it’s transmissible after death is that the virus buds from dermal cells where it persists for days following death, so that touching an infected dead body is very risky. The route by which a person becomes infected is also important; for example, infections acquired through needlesticks and injections with contaminated needles are normally fatal and appear to have a shorter incubation period.6 Additionally, the risk of infection increases threefold with any aerosol-generating procedures, including artificial ventilation.7

Ebola poses a significant threat to healthcare workers (HCWs). Some HCWs who appear to be taking all the right precautions become infected with Ebola. Sheik Khan, MD, who kept a mirror in his office in order to check for breaches, always meticulously donned and doffed his personal protective equipment (PPE) with an observer, died of Ebola. Others in the U.S. became ill without any identified breaches in protocol. On the other hand, dozens of HCWs who cared for a dying Ebola patient in Texas, and the many HCWs involved in treating patients in previous outbreaks (often those who are inadequately trained and wearing inadequate PPE) didn’t become ill. The reasons for these variances are unknown.8

What’s known about personal risk factors beyond those of distance, duration, type of exposure, severity of illness in the infected patient at the time of exposure, and time before treatment concern the likelihood of death versus survival when infection occurs. Pregnant women who become infected with Ebola almost always die, and there has been no known case of a viable pregnancy.9 For this reason a woman who’s pregnant should never care for an Ebola patient. Comorbidities also appear to greatly contribute to mortality, as does age.

Pathogenesis

The pathogenesis of EVD isn’t completely understood. The current model of EVD infection is based on the virus being transmitted via droplet or body fluids and making entry into the host body through lesions in the skin or mucus membranes. However, it’s important to note that few diseases spread through a single mode (airborne, droplet or aerosol), and transmission of disease is a complex and dynamic process. The virus, not only present on the skin and in body fluids, has also been known to be present on mucus membranes in the nose, oropharynx, conjunctiva and the rectum.2,10–12 The incubation period is recognized as 2–21 days and is thought to be related to the portal of entry. In the case of direct inoculation such as through needlestick, the incubation period is much shorter and the course of the disease is often more aggressive, normally leading to death.6,13 In the current outbreak, the incubation period most frequently seen has been seven days.4

Early targets of the Ebola virus are macrophages and dendritic cells. This initial attack creates systemic inflammation and cytokine release. Macrophage infection triggers tumor necrosis factor, which causes the release of tissue factor, further increasing inflammation and leading to coagulation disorders such as disseminated intravascular coagulation (DIC).6,14 The increased production of cytokines creates an affiliated inflammatory response. Over-release of cytokines, called “cytokine storm,” has in itself the capacity to be fatal and is believed to be responsible for the high fatality of the 1918 Spanish flu, and is at times seen in sepsis.15 Conversely, viral infection of dendritic cells doesn’t further cytokine production. In fact, the dendritic cells hardly respond to the viral invasion. Instead, they develop problems reaching maturity, diminishing their ability to support T cells.6,15

In some patients, shock begins to appear as early as three days, with edema and DIC presenting on day four. Increased endothelial permeability caused by cytokine release along with DIC can quickly lead to shock, and sometimes death.6 Considering the average patient doesn’t attempt to obtain treatment until five days after symptom onset (this has been true for healthcare workers as well), the patient may likely appear very ill when he calls EMS or arrives at a hospital.

Other cells that are recognized as being targeted by the Ebola virus are monocytes, fibroblasts, epithelial cells, endothelial cells, hepatocytes and adrenal cortical cells. After the virus enters the macrophages, it’s transported to the lymph nodes and moves from there to the liver, spleen and adrenal glands. The virus replicates so rapidly that it overwhelms the host’s adaptive and inflammatory immune response. This leads to necrosis of the liver, spleen, kidney and lymph nodes, with necrosis of the renal tubules and related anuria associated with very high mortality.16

In short summary, the primary pathways through which the virus does its damage is by the dysregulation of the immune system and disruption of coagulation pathways. Most patients exhibit some form of coagulopathy, often seen in the conjunctiva, or as unexplained bruising; it may present as disseminated intravascular coagulation in some cases.6

It’s through these two mechanisms that the virus causes the occasional hemorrhagic symptoms the disease is most known for. However, it’s important to note that significant hemorrhagic symptoms occur in fewer than 50% of patients. Clinicians in Monrovia, Liberia, reported that approximately 5% exhibited such symptoms.5 The clinical picture of a person bleeding from every orifice is simply not reality.

Members of the Centers for Disease Control and Prevention and Médecins Sans Frontières, or Doctors Without Borders, don personal protective equipment before entering the Ebola treatment unit, known as ELWA 3. Photo courtesy CDC/Sally Ezra

 

Assessment

The assessment for Ebola in the prehospital environment is based on system guidance. There are so many emerging diseases in the world, deadly and otherwise, that present as influenza-like illnesses (ILIs), that it’s impossible to identify a set of presenting signs or symptoms that would be pathognomonic for Ebola early in the disease. Like other ILIs, Ebola initially presents with fever, myalgias, loss of appetite and gastrointestinal (GI) symptoms. Many patients complain of generally feeling “off” for days preceding typical Ebola symptom onset; not enough studies exist to demonstrate whether this should be considered symptom onset or if it’s prodromal and not at all indicative of infectiousness.9

It’s simply unreasonable to expect the ED staff to test for Ebola or any other dangerous disease that would be out of the norm every time someone presented with an ILI. Therefore, it’s important to have another screening parameter; currently that parameter is the question as to whether or not the patient has been exposed to Ebola or has been to a country where Ebola is present. This is prudent, especially in consideration of the fact that other emerging diseases such as Middle East respiratory syndrome coronavirus also present with similar initial symptoms. Taking it a step further, EMS should ask about other family members who may be ill about their recent travel history. Note that GI symptoms are extremely common and nearly all Ebola patients exhibit some level of GI complaint, including abdominal pain.

The viral load of Ebola is initially contained outside of the bloodstream, so that the most reliable lab testing method is negative until at least the onset of symptoms, with negative results being unreliable until 72 hours after symptom onset. Further, there’s the possibility that with mutation of the virus17 or with testing errors false negatives may occur, though it’s unknown how frequently this may happen. To minimize the chances of false negatives, most labs will perform two separate tests looking for two different markers. Due to the risk of false negatives early into symptom onset, patients who otherwise meet suspected Ebola criteria, with no other diagnosis, should be treated as though they have Ebola.

To put things in perspective, it may take less than one plaque-forming unit (the number of virions necessary to form a plaque, or pieces of virus capable of infecting a cell) to cause infection.18 This creates concern over the possibility of infection through needlestick from a patient who is not yet symptomatic. Even though they aren’t yet demonstrating signs and symptoms of the disease, viremia is developing at the start of infection, and is going down after symptoms have resolved, which means there may be a theoretical risk of virus being present on sharps.

Table 1: How the 2014 outbreak will end

Management

There are several things to think about when considering the treatment of an Ebola patient in the back of an ambulance in the traditional EMS setting:

  1. The tightly enclosed space in the back of the ambulance puts the EMS provider in the “high-risk zone” as identified by the CDC should there be a breach in PPE;
  2. Wearing PPE to the level required for Ebola encounters impairs the ability to safely handle sharps and impairs safe movement in a moving ambulance;
  3. A risk/benefit analysis suggests little gain can be had by many interventions during a short ambulance transport when compared to the great harm that can be done to the caregivers in that same period of time; and
  4. Wearing PPE of the type required while working with a patient who has a disease that carries such a high mortality rate while feeling enclosed by the PPE (claustrophobia), and potentially feeling overheated, can lead to panic attacks. Therefore, it’s best to have EMS members do what they can without the use of sharps or unnecessary touching of the patient, while limiting interventions to only those that are absolutely necessary.
  5. The spraying of cleaner to disinfect the back of the ambulance creates the concern that it may aerosolize virus.9

However, this article isn’t written only for EMS workers in traditional settings. Many EMS workers have volunteered or have otherwise worked in West Africa, or will do so. It’s important to know experience has demonstrated that antidiarrheals, antiemetics and anxiolytics (when available) all may greatly contribute to reducing mortality. The overall goals in treatment of the Ebola patient are supportive in nature, avoiding electrolyte imbalances and treating other issues as they arise. The hope in this treatment is that the patient may survive long enough for his immune system to recognize the virus and build a response against it.

Excellent and early supportive care brings the best likelihood of survival from Ebola infection. Oral rehydration salts or other aggressive rehydration should be given to all patients from the time Ebola is suspected, even if the patient is normotensive and not exhibiting vomiting or diarrhea.

Hypovolemic shock appears to lead to metabolic acidosis in patients. This should be treated appropriately, and preferably avoided by attempting to maintain adequate hydration in the patient. Antidiarrheals and antiemetics should be administered to patients frequently. Zofran (ondansetron) has shown effectiveness in the Ebola patient, as has Ativan (lorazepam), with the added benefits of being an anxiolytic and relieving insomnia.

Aerosolizing procedures, such as artificial ventilation, CPAP, intubation, and nebulized treatments, should be avoided as much as possible and should never be performed in the back of an ambulance due to the likelihood of transmission increasing threefold.7 High-flow oxygen isn’t thought to be an aerosolizing procedure as the virus tends to be maintained in the lower airway until at least the terminal stage of the infection.19

Patient Outcomes

Unfortunately, until either an effective Ebola treatment is discovered or the virus mutates into something less pathogenic, the majority of Ebola patients will likely die. However, aggressive high-quality supportive care from early symptom onset greatly lessens patient mortality, as is seen in the U.S., where singular patients are receiving extremely high-quality care.

A patient is considered “convalescing” when symptoms associated with active infection have resolved and when the patient has tested negative in lab testing twice at least 48 hours apart; this effectively means the patient doesn’t have any active virus in the blood, and the patient can at this point be safely touched or share food. However, some sites in the body are considered protected–they aren’t as affected by the immune system and, while never demonstrated, the risk of transmission from these areas may exist.20 These include vaginal fluids, semen, breast milk and possibly the cerebrospinal fluid and eyes.10,21 Viral antigens have been found in semen as long as 101 days after symptom onset, well after the patient would be considered convalescing.9 Because of these risks, survivors should abstain from sex or use condoms, and women should not breastfeed, for at least three months.

During convalescence a patient may experience a variety of problems from the nagging to the serious. Early on, a patient may develop dysrhythmias or pericarditis, which can lead to death. Arthritis and severe weakness are common. The patient should be considered immunosuppressed until fully recovered and should avoid other illness. Survivors are considered immune to the strain of Ebola they were infected by, though inadequate studies exist to show that this immunity is permanent.

More than half of Ebola patients will die from their illness. This presents a challenge to HCWs, as the dead represent the greatest risk of infection. In terminal cases viral load increases until death. At death, the body is extremely infectious, and may be considered infectious until at least four days to over a week after death.9,22  

Both authors have recently attended the Centers for Disease Control and Prevention’s in-residence course Preparing Healthcare Workers to Work in Ebola Treatment Units in West Africa and plan to go to Sierra Leone this summer.

References

1. Negredo A, Palacios G, Vázquez-Morón S. Discovery of an Ebola-like filovirus in Europe. PLoS Pathog. Oct. 20, 2011. [ePub ahead of print].

2. Peters CJ, LeDuc JW. An introduction to Ebola: The virus and the disease. J Infect Dis. 1999;179(Suppl 1):ix–xvi.

3. Weyer J, Blumber LH, Paweska JT. Ebola virus disease in West Africa–An unprecedented outbreak. S Afr Med J. 2014;104(8):555–556.

4. What U.S. hospitals need to know to prepare for Ebola virus disease. (Sept. 24, 2014.) Centers for Disease Control and Prevention. Retrieved March 28, 2015, from http://emergency.cdc.gov/coca/transcripts/2014/call-transcript-080514.asp.

5. Chertow DS, Kleine C, Edwards JK, et al. Ebola virus disease in West Africa–Clinical manifestations and management. N Engl J Med. 2014;371(22):2054–2057.

6. Hoenen T, Groseth A, Falzarano D, et al. Ebola virus: Unravelling pathogenesis to combat a deadly disease. Trends Mol Med. 2006;12(5):206–215.

7. MacIntyre CR, Chughtai AA, Seale H, et al. Respiratory protection for healthcare workers treating Ebola Virus Disease (EVD): Are facemasks sufficient to meet occupational health and safety obligations? Int J Nurs Stud. 2014;51(11):1421–1426.

8. Richards GA. Sept. 29, 2014. Personal communication.

9. Preparing Healthcare Workers to Work in Ebola Treatment Units (ETUs) in West Africa. November 2014. Information obtained in the in-residence course conducted by the CDC.

10. Rodriguez LL, De Roo A, Guimard Y, et al. Persistence and genetic stabilitiy of Ebola virus during the outbreak in Kikwit, Democratic Republic of the Congo, 1995. J Infect Dis. 1999;179(Suppl 1):S170–S176.

11. Bausch DG, Towner JS, Dowell SF, et al. Assessment of the risk of Ebola virus transmission from bodily fluids and fomites. J Infect Dis. 2007;196(Suppl 2):S142–S147.

12. Review of human-to-human transmission of Ebola Virus. (Oct. 29, 2014.) Centers for Disease Control and Prevention. Retrieved March 28, 2015, from www.cdc.gov/ebola/transmission/ human-transmission.html.

13. Ebola Virus Disease Information for Clinicians in U.S. Healthcare Settings. (March 16, 2015.) Centers for Disease Control and Prevention. Retrieved March 28, 2015, from http://www.cdc.gov/vhf/ebola/healthcare-us/preparing/clinicians.html.

14. Bray M, Mahanty S. Ebola hemorrhagic fever and septic shock. J Infect Dis. 2003;188(11):1613–1617.

15. Schulte W, Bernhagen J, Bucala, R. Cytokines in sepsis: Potent immunoregulators and potential therapeutic targets–An updated view. Mediators Inflamm. June 18, 2013. [ePub ahead of print].

16. Approaches to Clinical Management for Patients with Ebola Treated in U.S. Hospitals. (Oct. 23, 2014.) Centers for Disease Control and Prevention. Retrieved March 28, 2015, from http://emergency.cdc.gov/coca/transcripts/2014/call-transcript-102014.asp.

17. Gire SK, Goba A, Andersen KG. et al. Genomic surveillance elucidates Ebola virus origin and transmission during the 2014 outbreak. Science. 2014;345(6202):1369–1372.

18. Bavari S. Oct. 31, 2014. Personal communication.

19. Richards GA. Nov. 5, 2014. Personal communication.

20. Uyeki TM. Oct. 10, 2014. Personal communication.

21. Groseth A, Feldman H, Strong JE. The ecology of the Ebola virus. Trends Microbiol. 2007;15(9):408–416.

22. Bermejo M, Rodríguez-Teijeiro JD, Illera G. Ebola outbreak killed 5000 gorillas. Science. 2006;314(5805):1564.

23. Althause, C. L. Estimating the reproduction number of Ebola Virus (EBOV) during the 2014 outbreaks in West Africa. PLoS Curr. 2014;6(1):1–9.