Proportion of Deaths and Clinical Features in Bundibugyo Ebola Virus Infection, Uganda

The first known Ebola hemorrhagic fever (EHF) outbreak caused by Bundibugyo Ebola virus occurred in Bundibugyo District, Uganda, in 2007. Fifty-six cases of EHF were laboratory confirmed. Although signs and symptoms were largely nonspecific and similar to those of EHF outbreaks caused by Zaire and Sudan Ebola viruses, proportion of deaths among those infected was lower (≈40%).

The fi rst known Ebola hemorrhagic fever (EHF) outbreak caused by Bundibugyo Ebola virus occurred in Bundibugyo District, Uganda, in 2007. Fifty-six cases of EHF were laboratory confi rmed. Although signs and symptoms were largely nonspecifi c and similar to those of EHF outbreaks caused by Zaire and Sudan Ebola viruses, proportion of deaths among those infected was lower (≈40%). E bola hemorrhagic fever (EHF) is a severe disease caused by several species of Ebolavirus (EBOV), in the family Filoviridae. Before 2007, four species of EBOV had been identifi ed; 2 of these, Zaire ebolavirus and Sudan ebolavirus, have caused large human outbreaks in Africa, with proportion of deaths ≈80%-90% and 50%, respectively (1)(2)(3)(4)(5). Large outbreaks are associated with person-to-person transmission after the virus is introduced into humans from a zoonotic reservoir. Data suggest that this reservoir may be fruit bats (6,7). During outbreaks of EHF, the virus is commonly transmitted through direct contact with infected persons or their bodily fl uids (8)(9)(10)(11). The onset of EHF is associated with nonspecifi c signs and symptoms, including fever, myalgias, headache, abdominal pain, nausea, vomiting, and diarrhea; at later stages of disease, overt hemorrhage has been reported in ≈45% of cases (12).
Bundibugyo District is located in western Uganda, which borders the Democratic Republic of Congo. After reports of a mysterious illness in Bundibugyo District, the presence of a novel, fi fth EBOV virus species, Bundibugyo ebolavirus (BEBOV), was identifi ed in diagnostic samples submitted to the Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, USA, in November 2007 (13). In response to detection of EBOV, an international outbreak response was initiated. In this report, we summarize fi ndings of laboratory-confi rmed cases of BEBOV infection.

The Study
Anecdotal reports suggested that human illness consistent with a viral hemorrhagic fever arose in Bundibugyo District as early as August 2007. After EHF was confi rmed (13), isolation wards were established at 2 medical facilities in the district. Diagnostic samples from hospitalized patients with acute illness and community residents who had febrile illnesses and multiple additional signs, symptoms, or epidemiologic exposures suggestive of EHF, were routinely collected for EBOV testing. These signs and symptoms included headache, vomiting, diarrhea, abdominal pain, conjunctivitis, skin rash, muscle pain, fatigue, diffi culty swallowing, diffi culty breathing, hiccups, bleeding, unexplained death, or contact with a patient with suspected EHF. A laboratory-confi rmed case of EHF was defi ned as illness in a person whose diagnostic samples were found positive for EBOV infection by any of the following tests: PCR (13), virus isolation, antigen detection, or immunoglobulin (Ig) M ELISA (14,15).
In addition, in a subset of surviving persons who had a history of illness consistent with EHF but no acute-phase blood samples available for testing, a convalescent-phase blood sample was collected for laboratory confi rmation by IgG ELISA (14,15). Laboratory testing was performed at the Uganda Viral Research Institute in Entebbe, and subsequent testing was performed on some samples at CDC, Atlanta. This analysis is limited to laboratory-confi rmed EHF cases, although additional suspected cases were identifi ed during the outbreak.
Fifty-six confi rmed cases of EHF were identifi ed; 43 of these were diagnosed on the basis of positive test results from acute-phase specimens (Figure). Twenty-six patients had a positive EBOV IgG titer in convalescent-phase serum, including 13 persons who had evidence of EBOV infection in acute-phase and convalescent-phase samples.
The proportion of deaths during this outbreak was calculated for case-patients confi rmed on the basis of an acute-phase diagnostic sample (those who only had a convalescent-phase sample are by defi nition surviving casepatients and represent a biased sample). Of the 43 cases confi rmed from acute-phase samples, 17 deaths occurred, for a proportion of 40%. The mean age of those who died (42 years, range 20-70 years) was signifi cantly higher than that of survivors (33 years, range 12-50 years; p = 0.0390).
No gender bias was observed between survivors and those who died (Table).
Signs and symptoms were reported by patients on standardized surveillance case-report forms at the time of case identifi cation, and in some instances, were examined further by chart review or follow-up interview. Common symptoms among patients with laboratory-confi rmed cases included fever, fatigue, headache, nausea/vomiting, abdominal pain, muscle/joint pain, diarrhea, and anorexia/weight loss (Table). No difference in the proportion of those reporting signs and symptom between those who survived and those who died was noted, except for diffi culty swallowing. This symptom was more common among case-patients who died (though marginally signifi cant, p = 0.0851). Bleeding of any type (bleeding from injection site, gums, eyes, nose, vagina; black or bloody stool; bloody vomitus; or hematuria) was reported among 54% of all patients with laboratory-confi rmed cases.
As part of the standardized surveillance case-report form, patients were also asked whether they had had contact with a sick person during the 3 weeks before development of illness. A large portion of the laboratory-confi rmed case-patients in this outbreak reported direct contact with a specifi c person, (case X), who died of a severe hemorrhagic febrile illness consistent with EHF (no diagnostic specimens were collected from this person) in November 2007. Using the date of last contact for those reporting contact with case X or reporting contact with another laboratoryconfi rmed case-patient to the date of symptom onset, we  calculated an average incubation period of 6.3 days among laboratory-confi rmed EHF case-patients (n = 24). No signifi cant difference was noted in the incubation period between survivors (5.7 days) and those who died (7.4 days).

Conclusions
The 2007 outbreak of EHF in Bundibugyo District, Uganda, was caused by a new EBOV species, Bundibugyo ebolavirus (13). Previous outbreaks of EHF have resulted in high proportion of deaths, ranging from 50% to 90% (1)(2)(3)(4)(5). The proportion of deaths among case-patients with EHF confi rmed by acute diagnostic specimens in this outbreak was 40%, a lower percentage than for other species of EBOV that have caused human outbreaks in Africa. However, we cannot exclude the possibility that the lower proportion of deaths in this outbreak is an artifact of differences in the severity of laboratory-confi rmed cases detected through outbreak surveillance or the quality of care received by hospitalized laboratory-confi rmed EHF casepatients in Bundibugyo District. Nonetheless, sustained person-to-person transmission was suffi cient to result in a sizeable outbreak, and death was clearly not uncommon. Thus, BEBOV should be considered a pathogen of serious public health concern.
As with previously documented EHF outbreaks, older age appeared to be a risk factor for death (3). The incubation period of EHF was ≈1 week, and signs and symptoms were largely nonspecifi c; infections frequently involved fever, fatigue, headache, gastrointestinal involvement, and muscle and joint pain. The nonspecifi c nature of these signs and symptoms, which may mimic other tropical diseases, made diagnosis of EHF based on clinical characteristics alone particularly challenging and underscores the importance of laboratory-based diagnostics to confi rm and monitor control and response efforts for EHF outbreaks. Notably, signs and symptoms described in this report are primarily based on information from patient surveillance case-report forms fi lled out at the time of triage, and they may not represent the full spectrum of illness experienced by all persons with EHF during this outbreak.
It is apparent that novel emerging infections continue to occur. The outbreak of EHF described in this report involved a previously unidentifi ed EBOV species, with a proportion of deaths of 40%. BEBOV represents the fourth EBOV species-associated disease in humans, and the third species to cause large human outbreaks of EHF. Although proportion of deaths was lower than that documented in previous EHF outbreaks, BEBOV is a severe human pathogen with epidemic potential. These fi ndings demonstrate the need for increased surveillance and diagnostic capabilities, as well as the capacity to respond quickly to emerging human infections.