Libby Burch

March 9, 2012

Lassa, Ebola, & Marburg Viruses

Objectives:

During the course of this presentation, we will focus on three viral diseases: Lassa Virus, Ebola Virus, and Marburg Virus. You will gain a greater understanding of how these diseases apply to a humanitarian crisis situation or a resource poor setting, and explore some strategies for diagnosis, treatment, and outbreak avoidance and control that are appropriate for these circumstances. Each of these diseases will be described in turn, and you will learn the biological basis of these viruses, their modes of transmission, symptoms, global prevalence, and associated epidemiology. By the end of this presentation, you will recognize the risk factors inherent to these viral diseases in humanitarian crises, and have an understanding of the strategies necessary to combat these diseases.

Disease Background: Viral Hemorrhagic Fevers (VHFs)

  • Viral Hemorrhagic fevers are a diverse group of viral diseases that are characterized by widespread systemic symptoms that in their most severe manifestations can cause vessel and organ damage and bleeding (hence the name “hemorrhagic”). (WHO/CDC 1996).
  • Symptoms are often extremely similar and hard to distinguish and include fever, headache, malaise, nausea, vomiting blood and hemorrhage from mucus membranes such as the nose, gingiva (gums), rectum, and conjunctiva (CDC 2006; WHO; SFDPH 2005). Death occurs due to blood loss through widespread hemorrhage or associated organ failure (Cohen 2004). Incubation periods vary from disease to disease and from outbreak to outbreak, but fall within the range 2 to 20 days post-exposure (GIDEON Informatics: Lassa, Marburg, Ebola).
  • Although found elsewhere, VHF diseases are most commonly found in Africa and cause sporadic outbreaks and epidemics in endemic areas. This presentation will cover Ebola hemorrhagic fever, Lassa virus, and Marburg virus, but Rift Valley fever, Yellow Fever, Dengue hemorrhagic fever, and Crimean-Congo hemorrhagic fever are also VHF diseases (SFDPH 2005).
  • For the three diseases focused on today, human-to-human transmission is high after initial infection from the animal reservoir. Transmission occurs readily via direct contact with infected urine, blood, sweat, saliva, secretions, vaginal fluids, and semen (Lamunu 2004). For these reasons, any contaminated objects or samples of virus from these diseases are classified as Biohazard Safety Level 4 (the highest designation) by the United States CDC (CDC).
  • Risk of transmission of VHFs in hospitals, health care settings, and in areas of crowding is extremely high. All bodily fluids from an infected person are possible modes of transmission; health care workers must take utmost care to practice barrier nursing and other outbreak control strategies (SFDPH 2005).
  • International virologist Nathan Wolfe describes pathogen evolution in stages leading up to exclusively infecting humans, with no need for an animal reservoir. A disease like rabies is classified as Stage 2 because although human-to-human transmission is possible, no cases occur because rabies is so easily identified and transmission to another human is relatively difficult. Lassa, Ebola, and Marburg outbreaks are Stage 3 diseases because they are highly infectious, but have such high mortality rates that the outbreaks invariably are contained and burn themselves out. HIV is a classic example of a Stage 5 pathogen that originated in an animal, but now exclusively infects humans (Wolfe et al. 2007).

Distribution in Africa

  • All three VHFs that we will focus on today are endemic to central, west, or eastern Africa (CDC).
  • Lassa virus is found commonly in Nigeria, Sierra Leone, Guinea, Liberia, the Central African Republic, and adjacent regions (McCormick 1987; CDC). Outbreaks are projected to expand in distribution as logging routes and inter-regional travel become more widespread (Wolfe 2011).
  • Ebola Virus occurs in humid rain forests of central and western Africa, such as in Zaire, Republic of the Congo, Gabon, Sudan, and Uganda. (GIDEON Informatics: Ebola).
  • Marburg is found in drier areas of Africa, such as regions in Kenya, Uganda, Democratic Republic of the Congo, and Angola (GIDEON Informatics: Marburg).
  • As you can see by the disease distributions [Pictured: Maps of Lassa, Ebola, Marburg viruses. Photos courtesy of Travel Approved and Mehedi et al. 2011], extensive overlap of endemic regions means diagnosis cannot be based on location. Furthermore, as you will hear about later, new cases in new areas are being identified as better diagnostics are designed and human mobility continues to increase (Geisbert 2011).

Lassa Virus: Biological Background

  • Lassa Virus (or Lassa fever) is transmitted to humans by a species of wild rodent called the multimammate rat (Mastomys natalensis) and is therefore a zoonotic disease (GIDEON Informatics: Lassa; Ogby et al. 2007).
  • The actual virus is classified as an arenavirus, which is characterized by its spherical, sand-like appearance (Emonet et al. 2011).
  • Current estimates state that the annual caseload is between 300,000 and 500,000 cases, with about 5,000 deaths yearly across West Africa (Ogbu et al 2007).
  • The overall mortality rate is about 1%, but increases to 15-20% in hospitalized patients. Death rates are highest for pregnant women and fetuses have a 95% mortality rate (CDC Lassa).
  • Symptoms are varied, but include fever, muscle aches, nausea, vomiting, abdominal pain, hemorrhagic symptoms in severe cases, and deafness in one or both ears (Carey et al. 1972; CDC Lassa 2004).

Lassa Virus: A Zoonotic Disease

  • Multimammate rats (Mastomys natalensis), or bush rats, are wild rodents that are extremely common in most of sub-Saharan Africa (Werner 2004). Infected rats show no averse symptoms, and shed the virus in their urine in concentrations upwards of 1000-10,000 infectious viral particles per milliliter of urine and feces throughout their lifetimes (GIDEON Informatics: Lassa; Kernéis et al. 2009).
  • Transmission to humans can occur when aerosolized particles of rat urine or feces are inhaled or with direct contact with rodent excreta with open wounds or mucous membranes. Eating rodent meat is also a risk factor, as preparation of the infected rodent can make viral transmission more likely, and undercooked meat will be infective in ingested (Kernéis et al. 2009).
  • Again, with all of these diseases, after initial human infection from a rodent reservoir, human-to-human transmission is high and results in the characteristic sporadic outbreak pattern (Ogbu et al. 2011).

Lassa Virus: Risk Factors

  • Contact with infected or possibly infected bush rat populations increases risk of rodent-to-human transmission. Rat infiltration in homes and around food stores increases the likelihood of rodent excreta being inhaled or ingested. This is especially true in dry regions where dust and excreta are more easily kicked up into the air (GIDEON Informatics: Lassa).
  • However, the most at-risk population is associated with human-to-human transmission: the health workers and family members that care for the infected person. With high viral loads in symptomatic (and possibly hemorrhaging) hospitalized or bedridden patients, the risk of infection for people in contact with bodily fluids and contaminated materials is elevated. This is one reason why nosocomial (hospital or clinically acquired) infections are so common and outbreaks often start in hospitals (CDC).

Ebola Virus: Biological Background

  • Ebola virus (or Ebola hemorrhagic fever) is a rare but extremely severe hemorrhagic fever that has a mortality rate of 50-90% (GIDEON Informatics: Ebola).
  • Ebola virus belongs to the viral family filoviridae, and is caused by 5 species of filovirus, four of which have been seen to cause disease in humans. Filoviruses are characterized by causing severe viral hemorrhagic fevers, infecting pigs, bats, or primates in nature, and by their characteristic filamentous appearance when viewed at high magnification. [Pictured: A strand-like viron of Ebola virus, with characteristic looping at one end, as seen with a electron microscope. Photo courtesy of the CDC Public Health Image Library].
  • Although an animal reservoir must exist, it is currently unknown. Initial infection is speculated to occur with contact with an infected animal and then spread throughout human populations. Human-to-human transmission is just like with Lassa (through blood, urine, secretions, contaminated objects like syringes). The fifth species of Ebola virus, the one that has not been seen in humans (only in primates), was observed to spread through airborne particles (CDC fact sheet). This could have implications for containment should this species be found in humans in the future.
  • Ebola is typically found in regions of humid rainforest in central and western Africa (GIDEON Informatics: Ebola).

Ebola Virus: A mysterious reservoir

  • Researchers have been searching for an animal reservoir but have not conclusively identified one yet. Gorillas, chimpanzees, and other non-human primates have been seen to be infected with Ebola virus, but it is inconclusive whether this is just an intermediate reservoir and the primates are getting infected via another animal. Bats have been implicated as a possibility, but no definitive species have been found and the mechanism of transmission is still unknown. (CDC: Ebola).

Ebola Virus: Risk factors

  • Interaction with non-human primates increases the likelihood of animal-to-human transmission. This is especially true for bush hunters that hunt primates and prepare the meat for consumption, and therefore have extended contact with the blood and bodily fluids of the animal (Wolfe 2011).
  • Again, health care workers and family members that are caring for sick patients are also at elevated risk.

Marburg Virus: Biological Background

  • Marburg virus is a highly severe hemorrhagic fever with a typical mortality of 23- 30%, but that can increase to upwards of 80% in extreme outbreaks (CDC; Towner 2006). Marburg is clinically indistinguishable from Ebola virus.
  • Like Ebola hemorrhagic fever, Marburg is a filovirus. [pictured: Marburg viron, showing the characteristic ‘6’ and ‘U’ shaped filaments. Photo courtesy of the CDC Public Health Image Library].
  • Marburg is found mostly areas of dry climate in central and eastern Africa (Peterson 2004).
  • Although a definitive animal reservoir is still being researched, recent studies show that Marburg virus has been found in a species of bat common to Africa (Towner 2007) and strongly implicate that this bat (Rousettus aegyptiacus) might be the animal reservoir that initially transmits the virus to primates and humans (Manganga 2011).

Marburg Virus: Risk Factors

  • Human activities in caves, especially mining projects, has been associated with outbreaks in the past, and supports the recent research that bats could be the animal reservoir (Swanepoel 2007).
  • [Pictured: Egyptian Fruit Bats (Rousettus aegyptiacus), the possible zoonotic reservoir of Marburg,in a human home. Photo courtesy of Dietmar Nill and naturepl.com.]
  • As with all three of these diseases, contact with infected humans (or primates, in the case of Ebola and Marburg) is extremely risky and requires proper barrier nursing techniques and extreme care when handling infectious material (CDC).
  • Marburg outbreaks are typically sporadic but spread quickly throughout communities if not contained (CDC; Towner 2006).

Diagnosis & Treatment

  • All three diseases are diagnosed with laboratory tests due to their non-specific symptoms. Again, they are characterized by fever, malaise, diarrhea, headache, sore throat, vomiting, and hemorrhage.
  • Characteristic diagnostics for Lassa virus include inflammation of the throat with while tonsilar patches (GIDEON Informatics: Lassa).
  • Laboratory diagnostic tests consist of immunoglobulin (IgG) antibody serology, positive PCR from serum or autopsy tissues, or isolation of the virus itself in biosafety level 4 laboratories (Harper 2010).
  • There is only a specific treatment for Lassa Virus, which consists of intravenous Ribavirin for 10 days. The mechanisms of Ribivarin therapy are unknown, but are highly effective (GIDEON Informatics).
  • Treatment for Ebola and Marburg (and Lassa after Ribivarin) consists of strict isolation while implementing supportive care. This entails intravenous fluids to maintain electrolytes, oxygen and breathing devices, or medications that could control fever or maintain blood pressure (CDC Fact Sheets).

Ebola Outbreak: A case study

  • The most recent large outbreak of Ebola occurred in Uganda between October 2000 and January 2001. During these four and a half months, a total of 425 cases and 224 deaths were recorded and attributed to Ebola hemorrhagic fever. This results in a mortality rate for this outbreak of 53% (Lamunu et al. 2004; Cohen 2007).
  • The outbreak was first reported to the Ministry of Health on October 8, 2000 by a non-governmental hospital in the Gulu district of Uganda, at which point there were three deaths and eight critically ill patients with symptoms characteristic of viral hemorrhagic fever. Upon investigation by the Minitsry of Health team, most of the patients had a history of attending a funeral just days before fever symptoms appeared.
  • A limited isolation unit was set up in the hospital on October 10, and barrier nursing techniques were introduced and medical workers were provided with masks, gloves, plastic aprons, gum boots, and head ware.
  • Outreach to the public was started a week after initial reports, and consisted of widespread educational posters, documentary films, and, radio programs were distributed. Cultural practices such as handshaking, large gatherings (funerals and dances) and traditional healing techniques were halted throughout effected districts.
  • Burial of infected corpses was delegated to trained burial teams of volunteers and military personnel. [Pictured: Proper burial technique by trained teams, wearing extensive barrier clothing. Photo courtesy of CDC Public Health Image Library.]
  • Extensive cooperation between the health workers, military, community leaders, teams from the CDC, and the public helped minimize spread and contain the outbreak.
  • The outbreak was declared to be over at the end of February 2001, after two incubation periods after the last case sero-converted and had passed without further infection. (Lamunu et al. 2004).
  • [Pictured: The epidemic curve and timeline of the Uganda 2000 Ebola outbreak. Graphic courtesy of Scott Harper and the CDC].

Containment and Control in a typical non-crises outbreak

  • Steps in an outbreak situation are focused on containment and control of the epidemic. This includes several steps (Harper 2010; CDC/WHO):
  • (1) Logistics and Coordination: Supplies for barrier nursing, body disposal, medical supplies, transportation of personnel. Coordination between international response teams is necessary to plan resupply needs and make sure adequate professionals are informed and participating. [Pictured: barrier nursing strategies]
  • (2) Social Mobilization: All levels of the effected areas, including community leaders, civilians, and the military must be constantly communicating. Outreach education to the public must occur early and be widespread, and collaboration with the media is ideal. [Pictured: A poster used for public education about the spread of Ebola virus]
  • (3) Laboratory Diagnosis: Diagnosis of the species of virus should occur for as many patients as possible through antibody detection, immunoglobulin detection, PCR correlation, and serology tests.
  • (4) Epidemiology and Surveillance: Cases and contacts must be maintained (ideally in a database) such that daily checkups can be made by surveillance teams. Coordination with burial teams and community outreach teams should be reported to the Ministry of Health to better assess what needs to be added to the strategies.

Humanitarian Crises: A risk-enhanced situation

  • Humanitarian crises situations add a whole new set of dimensions to the already complicated field of outbreak control. With internally displaced persons due to conflict, natural disaster, or other factors, population densities increase while standards of living plummet.
  • Access to sterile or even clean medical supplies are lacking, and personnel trained in all aspects of infectious disease outbreaks are probably rare.
  • Logistical coordination of medical teams and surveillance of the outbreak is complicated by refugee camps, widespread disorganization, and a myriad of other factors.
  • Diagnosis is difficult because symptoms are common to many diseases associated with resource poor settings (malaria, dengue, other fevers), and laboratory diagnostic tests are unavailable or limited. Therefore, outbreaks can go unmonitored and uncontained for longer period of time before officials take notice.
  • Furthermore, in food-limited situations, bush meat may become the best option. This can increase the likelihood that animal-to-human transmission occurs if primates, bats, or rodents are hunted, slaughtered, and eaten.

Key Strategies in Humanitarian Crises

  • Isolation: infected or suspected cases should be isolated from others as soon as possible. This is especially important in crowded living situations where spread of disease is extremely fast.
  • Identification without laboratory resources can be hard, especially if there is only on case. Look for headache, high fever, unexplained bleeding, and treat accordingly. Fortunately most of these patients will have other fever-causing diseases that are less infectious, such as dysentery, malaria, or typhoid fever. Should multiple similar cases arise and treatment for other suspected diseases fails, immediately notify other health care providers and start isolation precautions.
  • Isolation precautions in a crisis setting may be difficult: even setting aside a corner of a large room for suspected cases can help reduce nosocomial outbreaks. In settings where separate rooms are not possible, put screens or tarps between patients to reduce transmission via spills or splashes. Assign one set of medical equipment (blood pressure cuff, stethoscope, thermometer) for the isolation ward or area. Disinfect after each use with alcohol.
  • Reduce transmission: This can be both preventative and post-infection. Infected corpses should be buried properly and as soon as possible, ideally away from the refugee camp or other volatile area. Infective agents and contaminated bedding, clothing, or bandages should be burned. Injections and other invasive procedures should be minimized to limit the opportunity for contamination or accidental infection of health care workers. Use disposable needles and scalpels only once, and dispose of them in a puncture-resistant burnable container. A good replacement for a standard sharps container is a plastic water, oil, or bleach bottle.
  • If disposable syringes are not available, disinfect reusable syringes and needles with full strength bleach several times and let air dry.
  • Low-tech disinfection is effective with soap and water and bleach. Sterilization without an autoclave or steam sterilizer consists of boiling items in water for 20 minutes. This is effective to kill VHF viruses.
  • Barrier nursing supplies may be limited. Ideally a thin and thick pair of gloves should be worn at all times, but in short supply substitute plastic bags and regular kitchen gloves for latex medical gloves and thick rubber gloves. HEPA-filters or biosafety masks are ideal, but surgical masks, and cotton masks are good substitutes and can be reused if not contaminated.
  • More detailed instructions for each of these strategies can be found on the CDC website where they have a public document called Infection Control for Viral Hemorrhagic Fevers in the African Health Care Setting.

Future Directions