Monthly Topics in Clinical Biosecurity Series
By Eric Toner, M.D., May 2, 2005
Angola is currently suffering the largest outbreak of Marburg Hemorrhagic Fever (MHF) to date. Originating in the northern province of Uige in October 2004, the outbreak was not diagnosed as MHF until March 2005. By that time cases had appeared in approximately 50% of the country’s provinces (see www.who.int for current data). As of this writing, the fatality rate of known cases exceeds 90%; however, given the difficulties of conducting epidemiological surveillance in such a poor country, many milder cases are likely going unrecognized.
MHF was first discovered in Marburg, Germany in 1967 during an outbreak involving laboratory workers in Marburg, Frankfurt, and Belgrade who were handling African green monkeys imported from Uganda. There were 25 primary cases and 6 secondary cases, with a 23% case fatality rate. Over the next 30 years there were 3 small outbreaks, each of which involved a single foreign visitor to central Africa with very limited secondary transmission. The only other large outbreak occurred in 1998, in and around gold mines in Durba, Democratic Republic of Congo, which involved 141 cases over 2 years with an 83% case fatality rate. This epidemic was the result of several distinct introductions of the virus with slightly different strains. In sum, prior to the current outbreak, there had been 178 known cases of MHF; the present epidemic is affecting approximately twice as many victims as all previous outbreaks combined.
MHF is caused by the genus Marburgvirus of the Filovirus family, which also includes the genus Ebolavirus. These are single stranded negative RNA viruses with only 7 genes. The prefix filo- comes from the filamentous appearance of these viruses on electron microscopy. For purposes of biopreparedness policy and planning, the Filoviruses are often grouped together with a number of viruses from other viral families, each of which causes illness characterized by fever and bleeding. Collectively referred to as Viral Hemorrhagic Fevers (VHF), these diseases are included in the list of Category A bioweapons and, with the exception of Denguevirus, they have been proven infectious when delivered in aerosol form. Although Marburgvirus infection has been found in several primates and in bats, the natural host reservoir of the virus is not known.
The illness caused by Marburg virus is usually quite severe. In its early stages, it is indistinguishable from other diseases endemic to central Africa, such as malaria. After an incubation period of about a week, patients develop high fever, vomiting, diarrhea, and often a nonspecific rash. Jaundice and pancreatitis are common, as is an altered mental status or even coma; pharyngitis and a nonproductive cough are less common. In mild cases, patients may have conjunctival hemorrhages and bruising before the illness resolves; however, in lethal cases, full blown disseminated intravascular coagulation (DIC) develops with diffuse bleeding. Septic shock with cardiovascular collapse and multi-organ failure is typical. Death usually occurs within 7 to 10 days of onset of symptoms.
Once the virus enters the body though breaks in the skin or mucous membranes, it infects dendritic cells and macrophages which then carry it to lymph nodes. From there, replicating virus is released into the blood stream, resulting in hematogenous spread to a wide variety of organs, causing widespread tissue necrosis. Infected macrophages express tissue factor on their surfaces, which initiates DIC and the release of cytokines and chemokines, resulting in septic shock. At the same time, both innate and adaptive immune responses are suppressed.
Filovirus infection should be suspected in patients with the clinical presentation described above who have an epidemiological link to an area where Marburg or Ebola has been recognized or who are part of an unusual cluster of such cases even in the absence of any known outbreak. Typical laboratory findings include leukopenia and lymphopenia with evidence of DIC and elevated transaminases. Confirmation of the diagnosis in a clinically useful timeframe requires RT-PCR or ELISA, which is typically only available through state laboratories and usually requires prior consultation with experts in the health department. Clinical specimens must be considered highly infectious and handled with extreme caution, and the laboratory must be forewarned that VHF is being considered.
No treatment has been shown to be clinically effective in humans; however, in laboratory animals, early experimental outcomes suggest that a recombinant tissue factor-activated factor VII complex not only decreased the coagulopathy, but also lowered viral loads and improved survival (Lancet 2003; 362:1953-58). There are no studies of this treatment in humans. Furthermore, no vaccine exists, and passive immunization with hyperimmunglobulin has not been shown to be beneficial. A recent study reported that inhibitors of enzymes called cathepsins prevent replication of Ebolavirus in vitro. Cathepsin inhibitors are being developed as cancer chemotherapy drugs, but are not currently available (Science 2005 0: 11106561)
The disease is most typically transmitted through close contact with bodily fluids of infected individuals. The virus remains active in the corpses of victims as well as on surfaces for several days. It is thought that many of victims of the current outbreak in Angola were infected through participation in funeral rituals that involve close contact with the dead. There is no evidence of transmission by asymptomatic individuals.
While there is no documented respiratory transmission of naturally occurring Marburg, on at least one occasion, Ebola seems to have been transmitted by a small droplet aerosol. In the laboratory, aerosolized Marburgvirus is infectious to primates. Given this knowledge, and the possibility that infectious droplets may be produced during medical procedures or when bleeding patients vomit, sneeze or cough, the CDC recommends the use of airborne precautions for patients suspected of having VHF.
Standard infection control measures (gloves, masks, gowns) are effective for controlling transmission of the virus. While isolation of victims, contact tracing and quarantine of contacts have been effective in past outbreaks, cultural and socioeconomic factors have hampered control of the current outbreak. There are few roads, supplies, or means of communications in the remote parts of Angola. Hospitals in the affected parts of the country lack even basic means of infection control, and often often operate with no electricity or clean water. Further complicating a very difficult situation, the people of Uige speak a different language than people in other parts of the country, are distrustful of strangers after 30 years of war, have little experience with modern medicine, and when they get sick, they go to traditional healers, some of whom use nonsterile injections as part of their treatments.
Given modern air travel, it is conceivable that the incubating disease could be exported to any place in the world with great speed. If a case of Marburg were exported to a country with modern hospitals and infection control practices, it is unlikely that the disease would spread very far. Routine universal precautions practiced in countries with modern healthcare systems will prevent most or all transmission of the virus, limiting spread to close family members and unprotected healthcare workers who are in contact with the first cases. It is reasonable to believe that a cluster of such cases would provoke consideration of VHF as a diagnosis, followed by initiation of appropriate diagnostic testing, treatment, and isolation (contact plus airborne precautions). Persons who have been exposed to a patient with Marburg must be observed closely for 3 weeks; at the first sign of fever, they should be isolated until Marburg can be ruled out.
Naturally occurring VHFs like Marburg or Ebola, are a public health threat to underdeveloped counties, but do not present a serious public health threat to the U.S. or other developed countries; nonetheless, the current outbreak in Angola illustrates the lethality of this virus. Given the lack of vaccine or specific treatments and the resources needed to care for its victims, aerolized/weaponized Marburg could present a serious challenge to any healthcare system.
Pathogenesis of filovirus haemorrhagic fevers, Mahanty and Bray, The Lancet Infectious Diseases; Vol. 4, Aug 2004
Hemorrhagic Fever Viruses as Biological Weapons, Borio, et al, JAMA. 2002;287:2391-2405.