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Published: December 28, 2012 DOI:
10.1371/journal.pone.0052986
Clinical Manifestations and Case Management of Ebola
HaemorrhagicCaused by a Newly Identified Virus Strain, Bundibugyo,
Uganda, 2007Paul Roddy , Natasha Howard, Maria D. Van Kerkhove,
Julius Lutwama, Joseph Wamala,Esther Sterk, Benjamin Jes, Michel
Van Herp, Matthias Borchert
AbstractA conrmed Ebola haemorrhagic fever (EHF) outbreak in
Bundibugyo, Uganda, November 2007February 20(Bundibugyo
ebolavirus). It included 93 putative cases, 56 laboratory-conrmed
cases, and 37 deaths (CFR =manifestations and case management for
26 hospitalised laboratory-conrmed EHF patients. Clinical
ndinginfections. The most frequently experienced symptoms were
non-bloody diarrhoea (81%), severe headache reported or were
observed with haemorrhagic symptoms, six of whom died. Ebola care
remains dicult due tinfection-control procedures required. However,
quality data collection is essential to evaluate case
denitionimprovement in future epidemics. Organizations usually
involved in EHF case management have a particular
Figures
Citation: Roddy P, Howard N, Van Kerkhove MD, Lutwama J, Wamala
J, et al. (2012) Clinical ManifestationFever Caused by a Newly
Identied Virus Strain, Bundibugyo, Uganda, 20072008. PLoS ONE
7(12): e52
Editor: Malcolm Gracie Semple, University of Liverpool, United
Kingdom
Received: August 31, 2012; Accepted: November 23, 2012;
Published: December 28, 2012
Copyright: 2012 Roddy et al. This is an open-access article
distributed under the terms of the Creativeunrestricted use,
distribution, and reproduction in any medium, provided the original
author and source a
Funding: MDVK acknowledges funding from the Medical Research
Council UK and the Bill and Melinda Gadesign, data collection and
analysis, decision to publish, or preparation of the
manuscript.
Competing interests: The authors have declared that no competing
interests exist.
IntroductionFiloviridae family members are characterised by
lamentous enveloped particles with a negative-sense singlegenera,
Ebolavirus and Marburgvirus, respectively causing Ebola and Marburg
haemorrhagic fever (EHF, MHF
Aliation: Department of Clinical Sciences, Institute oMedicine
Antwerp and Department of Epidemiology aMedicine, University of
Antwerp, Antwerp, Belgium
-
haemorrhagic fever (FHF) outbreaks are characterised by
secondary transmission and high case fatality (CFR) vary
considerably: Zaire ebolavirus (ZEBOV; 8090%) [2], [4], [5], Sudan
ebolavirus[6][8], Cte d'Ivoire ebolavirus (CIEBOV; 0%; based on a
single patient) [9][11], Reston ebolavirus[12][16], and Lake
Victoria marburgvirus (MARV; 2088%) [17][20]. To date, 35 FHF
outbreaks are knownMHF), all in or originating from sub-Saharan
Africa [2], [21][27].
Suspect and laboratory-conrmed patient categorisationIn
sub-Saharan Africa, when a medical professional suspects a lovirus
infection, the patient's blood sample(BSL-4) laboratory for
diagnostic conrmation. If positive, an outbreak is declared and an
international respocontact tracing, with isolation and treatment of
suspect and laboratory-conrmed patients in a lovirus wardDue to
delays between outbreak onset, recognition, and response, some
individuals potentially infected with to follow-up before having
their blood sampled for disease conrmation. Likewise, if clinical
disease and outcfunctionality, not all patients are hospitalised
and treated on a lovirus ward. Outbreaks therefore habitually
conrmed patient categorisations, with only some patients receiving
supportive treatment on a lovirus wardOnce case identication and
contact tracing activities commence, individuals matching
epidemiological and clovirus ward for clinical assessment and, when
appropriate, categorised as a suspected FHF patient while
aconrmation. Diagnostic results are typically available within four
hours from an on-site laboratory, 48 hoursweek for samples sent
abroad [33], [34]. Patients with negative test results are
discharged and assessed forre-tested if FHF clinical suspicion
remains. Laboratory-conrmed patients remain hospitalised on the
loviru
Standard case managementIn the absence of specic antiloviral
therapy, lovirus ward clinicians provide suspect and
laboratory-conradministered during the 1995 EHF outbreak in Kikwit,
Democratic Republic of the Congo and subsequent outrehydration,
nutritional supplementation, and psychosocial support [26],
[29][31]. Oral medication includeas nausea and vomiting (e.g.
metoclopramide and promethazine), dyspepsia (e.g. aluminium
hydroxide, cimeagitation, or confusion (e.g. diazepam,
chlorpromazine), and pain (e.g. paracetamol, tramadol, and
morphineoral artemether/lumefantrine for uncomplicated malaria and
an oral antibiotic (e.g. amoxicillin, cotrimoxazoladministered due
to the customary absence of an on-site laboratory capable of safely
processing biological sexpanded, supportive care may also include
prevention and treatment of dehydration via intravenous (IV)
usupplementation, and IV administration of medication for optimum
drug delivery when clinically indicated
Improving knowledge of human clinical manifestations and case
managementLimited quality FHF clinical data from human outbreaks
have been collected, analysed, and published, partly paper-based
clinical records outside the lovirus ward [26]. Records have been
destroyed as potential fomiteresult, most detailed descriptions of
clinical manifestation have been from laboratory-based studies of
non-hhuman patients (e.g. ZEBOV [28], [40][52], SEBOV [53][56],
CIEBOV [9], and MARV Substantial uncertainties remain regarding
human FHF incubation periods and symptom frequency, onset, andata
are of questionable validity and reliability due to reporting and
recall biases [41], symptom frequency and duration [9], [19], [40],
[49], [53], [55], numerous others yielded only frequency daand
period prevalence of symptoms (e.g. at admission to the lovirus
ward, during hospital stay) fail to docuhuman FHF symptomatology is
crucial for advancing outbreak control measures and administering
supportivdisease severity [33].Although anecdotal evidence suggests
supportive treatment increases FHF survival, its eectiveness has
not[46]. More data on human clinical manifestations and treatment
eectiveness are needed to improve respons
The 20072008 Bundibugyo outbreak
-
On 29 November 2007, the Uganda Ministry of Health (MoH) and the
World Health Organization (WHO) conwestern Uganda, and responded in
collaboration with Mdecins Sans Frontires (MSF), the Uganda Virus
Resfor Disease Control and Prevention (CDC), and others [68]. On 20
February 2008, the outbreak concluded wi(30 of whom were
hospitalised) and 37 deaths, yielding a 25% CFR [69], [70]. Most
cases originated from B16,000 and 5,700 inhabitants respectively.
Bundibugyo is situated at the base of the Rwenzori Mountains, anwas
set up and maintained at each location throughout the outbreak
response [70]. Genetic sequencing of vthe virus causing the
Bundibugyo outbreak diered from any known ebolavirus (EBOV) species
and was, althproposed as a new EBOV species provisionally named
Bundibugyo ebolavirus (BEBOV)
Study rationale and objectivesThis outbreak is the rst known
observation of human disease caused by this putatively novel EBOV
species. BEBOV infection furthers knowledge of human FHF
symptomatology, while describing the implemented FHF cshortcomings,
a baseline imperative for improving and assessing the eectiveness
of supportive case managthis may be the only way for future
patients to receive better care. The objectives of this secondary
analysis odemographics and contact histories; (ii) document
symptoms from onset to clinical outcome; (iii) describe carecommend
strategies for improving data collection in future FHF
outbreaks.
MethodsEthics statementThe Uganda National Health Research
Organization and the Ethics Review Boards of Mdecins Sans
FrontireMedicine provided ethics approval for a posteriori analyses
of the outbreak's anonymous and routinely collecadditional data
were collected for research purposes and all data were anonymous
before analysis, the ethicconsent.
Study population and data collectionStudy subjects were patients
hospitalised on Bundibugyo or Kikyo Ebola wards with subsequent EHF
laboratosuspected EHF cases in Bundibugyo District were: (i) an
epidemiological link to an individual potentially infec(i.e.
asthenia, anorexia, myalgia/arthralgia, diarrhoea, abdominal pain,
nausea, vomiting, headache, dysphag(ii) fever plus at least three
of the general symptoms listed above; or (iii) fever plus
unexplained haemorrhagaccompanied to an Ebola ward and clinically
assessed. Suspected cases further corroborated by clinical
assedrawn and sent to the UVRI/CDC laboratory in Entebbe, Uganda
for biological conrmation by polymerase chlinked immunosorbent
assay (ELISA), or IgM-capture ELISA [69], [71]. Laboratory results
were available thrThe makeshift Bundibugyo and Kikyo Ebola wards
became fully functional following implementation of WHO a[3], [31].
Study subjects were hospitalised on (i) a makeshift ward for the
entirety of their stay; (ii) a makeshstay; or (iii) a fully
functional ward for the entirety of their stay. Dierences between
fully functional and makmanagement as described in the
introduction, and standardised data collection [48]. Data were
recorded by MSF sta on fully functional wards (Figure 1).
-
Figure 1. Filovirus ward clinicians administering supportive
treatment while concurrently recording clin200708 Ebola
haemorrhagic fever outbreak.Photo by Claude
Mahoudeau.doi:10.1371/journal.pone.0052986.g001
Study variables and data analysisData were collected on patient
demographics, contact history, symptoms (self-reported from disease
onset uhealthcare workers from admission until clinical outcome),
treatment, patient monitoring, and clinical outcomDemographic
variables were age, gender, residence, occupation, and Ebola ward.
Contact history with an indcategorized as none, indirect (i.e. via
fomite), direct, and direct during funeral practices Supportive
treatment was categorised as EHF-related symptom alleviation,
antibiotics, antimalarials, and dehpsychosocial support data were
not collected. Patient monitoring data were axillary body
temperature (i.e. feCelsius), heart rate (beats per minute),
respiratory rate (breaths per minute), and blood pressure (mmHg).
Cdischarge from the Ebola ward.Data were analysed using Microsoft
Excel and Stata 11.0 (StataCorp Texas) to describe symptom
frequencassociations between demographics, symptoms, or treatment
and clinical outcome using exact logistic regreregression was used
to determine probability of death by number of symptoms. Fisher's
exact p-values of
-
Table 1. Self-reported demographics, days before seeking
treatment at an Ebola ward, and contact histEbola haemorrhagic
fever, Bundibugyo District, Uganda (November 2007February
2008).doi:10.1371/journal.pone.0052986.t001
Course of disease and clinical manifestationsEleven of the 26
patients died (CFR = 42%). The median duration of disease was 9
days (range 3 to 20) frompatients and 9.9 days (range 2 to 21) from
self-reported onset to last recorded symptom prior to discharge
fEbola ward after a mean self-reported delay of 3.5 days (range 0
to 8) following symptom onset. Available daincreased probability of
death (e.g. dierences were not signicant for patients who died
after being admittethree days (4/13; 31%) after symptoms reportedly
commenced [Fisher's exact p-value 0.66; Table 2 presents all
recorded patient symptoms. The left side shows frequency, usual day
of onset, and mean15 patients. The most frequently reported general
symptoms were fever, nausea/vomiting and non-bloody di(9/15; 60%),
and conjunctivitis (5/15; 33%). Each self-reported symptom was
experienced for a median of no individual self-reported symptom was
associated with clinical outcome (Fisher's exact p-value range
0.23signicantly doubled the odds of death (OR 2.14; 95%CI:
1.028.18).
Table 2. Self-reported symptoms (15 patients), clinically
observed symptoms (21 patients), and combihospitalised
laboratory-conrmed EHF patients with known clinical outcome for
whom data were recor2007February
2008).doi:10.1371/journal.pone.0052986.t002
The centre of Table 2 presents frequency, pattern (continuous
versus intermittent), and mean duration in daypatients, from
presentation to the Ebola ward until clinical outcome. Frequent
symptoms included severe heamyalgia (16/21; 76%), dysphagia and
appetite loss (15/21; 71% each), and non-bloody diarrhoea (14/21;
3.58 days (range 113). Less frequent clinically observed general
symptoms (conjunctivitis, chest pain, cou
-
protracted duration (mean 47 days). Of ten patients whose body
temperature was recorded at least once wfever for one day.The right
of Table 2 and Figure 2 present symptom frequency from
self-reported onset to clinical outcome (i.study-patients. The most
frequently experienced symptoms were non-bloody diarrhoea (81%),
severe headapresents their median duration.
Figure 2. Frequency of non-haemorrhagic symptoms from
self-reported day of symptom onset to clinicpercentages, among
symptomatic (9 deceased and 12 surviving) laboratory-conrmed Ebola
haemorrUganda, November 2007February 2008.Note changes in
denominator between self-reported and clinically observed
sections.doi:10.1371/journal.pone.0052986.g002
Figure 3. Median duration in days of symptoms from self-reported
onset until clinical outcome among 2haemorrhagic fever patients,
Bundibugyo District, Uganda (November 2007February 2008).Blue and
red bars indicate general and haemorrhagic symptoms, respectively.
*Day 0 = presentation to thduration of the self-reported symptoms
prior to presentation to the Ebola ward for patient observations
>clinician-assessed symptoms at presentation to and during
hospitalisation on the Ebola ward for patient o
-
patients only (n = 9).doi:10.1371/journal.pone.0052986.g003
No self-reported or clinically observed symptom or combination
of symptoms, other than any haemorrhage (clinical outcome (Fisher's
exact p-value range: 0.371.00). However, similarly to self-reported
symptoms, foodds of death increased by approximately 31% (OR 1.31;
95%CI: 1.041.82).
Haemorrhagic symptomsSeven patients experienced self-reported
and/or clinically observed haemorrhagic symptoms, six of whom
dtimes greater odds of dying than those not experiencing any
haemorrhagic symptom (86% versus 33%; OR Three patients
self-reported haemorrhagic symptoms prior to admission while ve
patients were clinically obhospitalisation. The one surviving
patient self-reported and was clinically observed with epistaxis
(and later died, one reported melaena, while the other reported
haematemesis, epistaxis, and postpartum blehaemorrhagic symptoms
clinically observed during hospitalisation. Of the three patients
who self-reported award within 24 hours of self-reported bleeding
onset, while one tolerated melaena for three days prior to
preself-reported median of one day of fever prior to Ebola ward
presentation.Clinically observed haemorrhagic symptoms (Table 2;
Figure 4) included melaena and prolonged bleeding athaematemesis,
bleeding gums, haemoptysis, haematuria, haematoma, and postpartum
vaginal bleeding (1/2clinically observed with haemorrhagic
symptoms, the rst was observed with bleeding gums; the second
withthird with melaena, haematemesis, and prolonged bleeding from
an injection site; and the fourth with melaenpostpartum bleeding.
Petechiae were not observed.
Figure 4. Frequency of haemorrhagic symptoms from self-reported
day of symptom onset to clinical ouamong symptomatic (9 deceased
and 12 surviving) laboratory-conrmed Ebola haemorrhagic fever
paNovember 2007February 2008.Note changes in denominator between
self-reported and clinically observed
sections.doi:10.1371/journal.pone.0052986.g004
Case managementOf the 19 laboratory-conrmed patients with
treatment details recorded, 18 (95%) were administered
paracreceived cimetidine for dyspepsia (Table 3). No other
medication was administered to alleviate Ebola-relatedpatients
(37%) for potential concomitant infections. Antimalarials were
administered to 11 patients (58%), borderline signicant positive
association between antimalarial administration and fatal outcome
(OR 5.93, 9However, two of these patients received quinine,
indicating more severe infection. When these two were remo
-
patients receiving presumptive artemether/lumefantrine, the
dierence in clinical outcome was no longer sigwas administered to
16 patients (84%), while four patients (21%) received IV-uids.
Vitamin supplementatiantimalarial treatment, there was no signicant
dierence in clinical outcome for any treatment component (
Table 3. Treatment recorded for 19 hospitalised
laboratory-conrmed Ebola haemorrhagic fever
patiendoi:10.1371/journal.pone.0052986.t003
Of the ten patients whose axillary body temperature was recorded
at least once during hospitalisation, ve (5daily for 80% of their
stay, while seven (70%) had their temperature recorded at least
once daily for 50% ofrate, and blood pressure were not recorded for
any patients.
DiscussionThis study documents clinical manifestations of human
BEBOV infection among hospitalised patients and desclinical
manifestations from a putatively novel EBOV species furthers
knowledge of human lovirus infection,for improvement and
accentuates the need to assess eectiveness of supportive treatment
in future outbrea
Case fatality ratioTo date, the 25% crude CFR of the 20072008
Bundibugyo outbreak is the lowest of recorded major
humanlaboratory-conrmed patients the CFR increases to 42%, similar
to that found by MacNeil and colleagues forand observed
consistently in SEBOV [53][55], [72] and occasionally in ZEBOV
[41], [73]among putative cases [8] or more accurate due to
inclusion of less severe cases who did not attend hospitalspecies
merits caution, as disease recognition often requires a functioning
surveillance system and case-fataspecies, including route and dose
of infection, genetic susceptibility, and underlying prevalence of
immunode
Patient demographics and contact historiesSimilar to some
previous lovirus outbreaks, this study population only comprised
adults (2066 years) reported direct contact (11/14) or direct
contact with a potentially infected corpse during funeral practices
opportunities for disease transmission in previous lovirus
outbreaks [33], [49], [75]contact history. This may be due to
non-rigorous patient interviews during high-workload periods on the
Ebowere missing (e.g. 54%, or 14/26 of study subjects did not have
their occupation recorded), indicating shortunnoticed secondary
transmission could have occurred. Available data preclude decisive
conclusions.Regrettably, incubation periods were not measured for
this study population. Albeit challenging to establish with a
source case, it is possible to obtain quality contact history and
incubation-period data Contact history data facilitate outbreak
control eorts and further understanding of transmission
patterns
-
understanding of disease course in humans [35], [80]. Without
complete and accurate data, interpretation odicult. Authors are,
for example, precluded from explaining why 73% of the study
population were male.
Clinical manifestationsEbola-ward clinicians working on the
fully functional ward employed a standardised prospective case
reportiprioritised data transfer outside the ward [19], [81], [82].
Subsequent analyses (Tables 2human disease caused by this
putatively novel EBOV species and further knowledge of FHF clinical
manifestaobserved and reported from human ZEBOV [28], [40][52],
SEBOV [53][55], CIEBOV clinical data. A more detailed comparison is
not feasible due to substantial variations in FHF reporting methoAs
lovirus ward clinicians often use personal discretion to decide
whether an individual should proceed to acommunity [33], these
documented BEBOV clinical manifestations could potentially assist
future FHF clinicalsupposed lovirus disease hallmarks (fever plus
haemorrhage) were observed relatively infrequently (3/26; 1prior to
hospitalization reported fever plus haemorrhage, no individual
whose axillary temperature was recorand one or more haemorrhagic
symptom was observed in only ve hospitalised patients. The most
frequent population (i.e. severe headache, asthenia, myalgia) are
subjective and could equally indicate typhoid, shigelsettings,
authors recommend continued rigorous study of human FHF clinical
manifestations to increase the crucial aspect of outbreak control
[28][33]. Further improvements to diagnostic accuracy beyond that
achirequire the consistent and timely dispatch of eld laboratories
to lovirus outbreak settings and an eventual test).Comprehensive
documentation and understanding of FHF clinical manifestations is
needed, as the administrapresentation, anticipated symptomatology,
and disease severity. Authors recommend that future clinical
repoform, further justication of which is delineated below
[19].
Case managementData indicate that components of standard
treatment were not comprehensively administered and monitorinshould
have received antibiotics and antimalarials, but these were
recorded for only 27% and 42% of patienthis was warranted or rather
demonstrate sub-standard treatment, incomplete data recording, or
both. Lack 74% increased odds of death, suggesting a possible
relationship between data recording and outcome, thou1.74; 95%CI:
0.2315.06).Measurement of axillary body temperature, a basic
non-invasive procedure, was recorded sporadically, if at
atemperature recorded at least once per day for 80% of their
hospital stay. This indication of sub-standard panding that only
one patient developed fever for one day during hospitalisation. It
is questionable whether thinfection, which seems likely to have
been more frequent than data indicate. Sub-standard patient
monitoringrespiratory rate, blood pressure and laboratory-based
biochemical patient monitoring data. Since the use of prevented by
safety concerns, it is important to develop a protocol for safe
usage of such basic monitoring tohigh-biosafety eld laboratory to
be located near-by future outbreak epicentres so that diagnostic
results aredesirable if laboratory testing additionally included
the monitoring of patient's biochemical parameters. Patietreatment
regimens are to incorporate additional elements of intensive care
(e.g. correcting electrolyte and mhaemodynamics, supplementing
oxygen, and mitigating strong inammatory responses and disseminated
intevaluation.While antibiotics and antimalarial administration and
standard patient monitoring are deliverables for all patias
indicated by symptomatology or disease severity. However, as in
other data collection initiatives 69% of patients experience mild
pain and appropriately receive paracetamol for its alleviation, or
did other prelief? This diculty in interpretation also applies to
administration of cimetidine, IV-uids, and ORS
receivedOrganizations responsible for lovirus patient management
should, prior to the next outbreak, consider thescollection
accordingly.
Study limitations
-
Data were collected from laboratory-conrmed EBOV hospitalised
patients on the two Ebola wards and not fridentied in the community
[69]. Individuals receiving hospital care may dier from those not
seeking and reless severe disease and survive more frequently, thus
explaining the overall lower CFR compared to the one opatients (25%
versus 42%). Moreover, limited data were collected from patients
hospitalised early in the outAuthors were limited to describing
administered treatment rather than assessing its impact on clinical
outcommonitoring data precluded adjusting for potential confounding
(e.g. by disease severity) of any association binstance, the
borderline association of antimalarial treatment with fatal outcome
could be explained by patiewith malaria or Ebola than those who did
not.
Recommendations for improving data collection in lovirus
outbreaksLikely reasons for incomplete patient monitoring and
possible sub-standard treatment delivery include: (i) nocollection
due to heavy workloads, particularly during the height of the
outbreak, (ii) recording of patient datlikelihood of data
mismanagement or loss, and (iii) lack of sta awareness of the
importance and reasons formanagement during lovirus outbreaks.
Organizations responsible for lovirus patient management thus
neesupplies to improve data collection and case management
components, similar to those used for intensive caThose responsible
for lovirus case management must ensure that sucient supplies and
equipment (e.g. thstethoscope, and sphygmomanometer, as used for
previous lovirus patients [9], [19], available at outbreak response
initiation. Together with appropriate training and comprehensive
supportive tclinicians' eorts to deliver optimal care to future
patients and enhance analyses of accurate epidemiologicaoutbreak
control and treatment eorts for poorly understood lovirus
diseases.Finally, laboratory tests (e.g. haemoglobin, complete and
white blood cell counts) performed in past outbreaincluded in
routine lovirus patient monitoring. On-site laboratory capacity
would greatly facilitate case mandiagnostic and patient status
results. The authors recommend on-site diagnostic and biochemical
laboratory[29], [33], [34].
ConclusionsAuthors did not nd important dierences between the
symptomatology of BEBOV and other FHF strains. fatality reported
initially [8], but are similar to MacNeil and colleague's ndings
among conrmed BEBOV cassignicantly increased the probability of
patient death. Each additional symptom increased the odds of
deathfactor.Recordkeeping and data collection were poor in both
makeshift and fully functional Ebola wards.
Standardisirecordkeeping on Ebola wards will help address the
uncertainties discussed in this paper. Improved documenintensifying
supportive care in future outbreaks. Safety protocols should be
reviewed where they appear to csignicantly improving safety.
AcknowledgmentsFor their invaluable contributions to outbreak
containment, authors thank the Uganda Ministry of Health,
UgOutbreak Alert and Response Network (GOARN), Mdecins Sans
Frontires, Uganda Virus Research Institute,African Field
Epidemiology Network, International Federation of Red Cross and Red
Crescent Societies (IFRCWorld Food Programme (WFP).
Author ContributionsPerformed the experiments: PR NH MDVK PPP ES
BJ JL JW ZY RC MVH MB. Analyzed the data: PR NH MDVK M
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PR NH MDVK PPP ES BJ JL JW ZY RC MVH MB. Wrote the paper: PR NH
MDVK PPP ES BJ JL JW ZY RC MVH MB.
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