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Risk factors associated with human Rift Valley fever infection:
systematic review and meta-analysis
Dennis E. Nicholas, Kathryn H. Jacobsen and Nigel M. Waters
George Mason University, Fairfax, VA, USA
Abstract objective To identify risk factors for human Rift Valley fever virus (RVFV) infection.
methods A systematic review identified 17 articles reporting on 16 studies examining risk factors
for RVFV. Pooled odds ratios (pOR) were calculated for exposures examined in four or more studies.
results Being male [pOR = 1.4 (1.0, 1.8)], contact with aborted animal tissue [pOR = 3.4 (1.6,
7.3)], birthing an animal [pOR = 3.2 (2.4, 4.2)], skinning an animal [pOR = 2.5 (1.9, 3.2)],
slaughtering an animal [pOR = 2.4 (1.4, 4.1)] and drinking raw milk [pOR = 1.8 (1.2, 2.6)] were
significantly associated with RVF infection after meta-analysis. Other potential risk factors include
sheltering animals in the home and milking an animal, which may both involve contact with animal
body fluids.
conclusions Based on the identified risk factors, use of personal protective equipment and
disinfectants by animal handlers may help reduce RVFV transmission during outbreaks. Milk
pasteurisation and other possible preventive methods require further investigation.
keywords meta-analysis, Rift Valley fever, risk factors, systematic review
Introduction
Rift Valley fever (RVF) is a zoonotic arboviral infection
that has caused outbreaks in Africa and parts of the Ara-
bian peninsula since at least the 1930s (Gerdes 2004;
Evans et al. 2008; Swanepoel & Paweska 2011). RVF out-
breaks have caused significant loss of human and animal
life (Gerdes 2004; Swanepoel & Paweska 2011) as well as
economic hardship for those who raise livestock (Rich &
Wanyoike 2010; Dar et al. 2013).
Livestock such as goats, sheep, camels and cattle can
become infected with RVF virus (RVFV) when bitten by
an infected mosquito, typically of the Aedes genus. In
more susceptible breeds, pregnant goats, sheep and cattle
infected with RVFV experience high rates of spontaneous
abortions, and there are high case fatality rates for young
animals (Davies 2003; Evans et al. 2008). Indigenous
breeds of livestock appear to be less susceptible than
imported breeds (Davies 2003; Evans et al. 2008). Most
infected humans are asymptomatic or experience a mild
febrile illness, but ocular damage, meningoencephalitis,
haemorrhagic fever or death may occur in a minority of
cases (Evans et al. 2008; World Health Organization
2008; Swanepoel & Paweska 2011). This possibility of
severe complications from infection makes identification
of human RVF risk factors a public health priority in
affected areas. Most of the likely risk factors relate to
modes of transmission of RVFV. Humans are thought to
become infected with RVFV when they handle the blood
or tissues of infected animals or inhale the aerosolised
body fluids of infected animals during slaughter or veteri-
nary procedures. Humans may also contract RVFV from
infected mosquitoes, and some studies suggest that raw
milk from infected animals and bites from infected hae-
matophagous (blood-consuming) flies may also be trans-
mission routes (World Health Organization 2008).
These potential transmission routes point towards
likely risk factors for contracting RVFV. However, no
previous meta-analysis has used a pooled analysis of RVF
field studies to measure the associations between various
possible risk factors and RVF infection. The goal of this
systematic review and meta-analysis is to identify the
RVF risk factors that are well-supported by the scientific
literature on RVF, with a particular goal of determining
which behavioural risk factors might be appropriate tar-
gets for preventive interventions.
Methods
In July 2014, we searched the Medline, Global Health,
CINAHL, AJOL (African Journals Online), SciELO and
ScienceDirect databases for reports of RVF risk factors.
To maximise the completeness of the search and reduce
selection bias, only two subject headers were used: ‘Rift
1420 © 2014 John Wiley & Sons Ltd
Tropical Medicine and International Health doi:10.1111/tmi.12385
volume 19 no 12 pp 1420–1429 december 2014
Valley fever’ and ‘risk factor OR seroprevalence’. (For
AJOL and SciELO, the only search term used was ‘Rift
Valley fever.’) All study locations, study and publication
years, and publication languages were eligible for inclu-
sion. All abstracts identified from the database searches
were screened for eligibility, and the full text of all poten-
tially relevant articles was read. Additionally, the refer-
ence lists of all full text articles, including review articles,
were scanned to identify non-indexed articles that might
meet the eligibility criteria. This search process yielded
128 potentially relevant articles.
To be eligible for inclusion, an article had to report on
primary studies of human risk factors for acute RVF
infection (as indicated by a positive IgM test or virologi-
cal methods) or past RVF infection (as indicated by an
IgG test). Articles were excluded if they did not report on
risk factors for RVF infection based on serological or
virological laboratory testing (n = 84), if they examined
animal RVF rather than human RVF (n = 14), if they
were review articles or secondary reports rather than pri-
mary research (n = 4), if they were RVF case reports that
did not include a comparison group of healthy controls
(n = 8), or if they did not report measures of association
for one or more potential risk factors (n = 1). Relevant
data from each of the 17 eligible articles (reporting on 16
studies) were extracted into a spreadsheet for further
analysis.
The odds ratio (OR) was the most frequently reported
measure of association in the eligible articles, so it was
used as the key measure for meta-analysis. The adjusted
OR was used for meta-analysis when one was available
for an exposure of interest. When an adjusted OR was
not available, the crude OR was used. When included
studies reported rate ratios (RRs) or chi-squared test
results rather than ORs, we used Comprehensive Meta-
Analysis 2.0 (Biostat, Englewood, NJ, USA) and/or Epi
Info 7.1.1.0 (Centers for Disease Control and Prevention,
Atlanta, GA, USA) along with descriptive statistics (such
as frequencies) to convert these statistics to ORs. When a
study reported a prevalence ratio (PR) or an RR without
reporting descriptive statistics that could be converted to
an OR, the study was not included in meta-analysis.
The repeated cross-sectional studies that were con-
ducted in 2006 and 2009 at the same site in Kenya were
treated as independent studies for analysis, even though
about half of the 2009 participants (102/194) had also
been surveyed in 2006 (LaBeaud et al. 2008, 2011). Sen-
sitivity analyses of each risk factor that was examined by
both of these studies demonstrated that the pooled effect
estimate was not significantly different when one or the
other study was removed and the OR recalculated. ORs
reported for only cases with haemorrhagic symptoms of
RVF (Anyangu et al. 2010) were not combined in pooled
analysis with studies that reported associations based on
broader RVF case definitions.
When the ORs for a risk factor were available for four
or more studies, a pooled effects estimate for the risk
factor was calculated using StatsDirect 2.7.9 (StatsDirect
Ltd, Cheshire, UK). A minimum criterion of four studies
was selected because the confidence intervals for pooled
estimates with fewer than four studies were generally too
wide to be useful.
Meta-analyses use either fixed effect or random effects
models to estimate pooled OR effects. A fixed effect
model is based on the assumption that all studies
included in the pooled analysis used comparable methods
and similar populations, and that as a result the variation
among the studies’ measures of association can be attrib-
uted to random differences in the composition of the
populations sampled for each study. A random effects
model uses the more realistic assumption that the
included studies sampled individuals from different popu-
lations and that the magnitude of association between an
exposure and disease in diverse populations may be dis-
similar. The random effects model adjusts for these
potential differences by including the between-studies var-
iance in the calculation of the pooled OR effect (Hedges
& Vevea 1998). Each meta-analysis in this investigation
includes studies from several independent populations,
and a random effects model is usually appropriate for
these analyses. However, random effects models may be
unreliable when fewer than five studies are included in
the pooled measure of association (Borenstein et al.
2009). When few studies are being pooled, the best
option is to perform a fixed effect meta-analysis with the
stipulation that the possible generalisability of results be
interpreted conservatively (Borenstein et al. 2009). In this
analysis, a conservatively-interpreted fixed effect model
was used to calculate a pooled OR effect when four stud-
ies without substantial between-studies variance were
included in the analysis; a random effects meta-analysis
model was used for all other analyses (Borenstein et al.
2009).
StatsDirect 2.7.9 was used to create forest plots of the
results of each meta-analysis (Figures 1a–f). I2 tests,
which estimate the proportion of total variability among
studies that can be explained by heterogeneity, were used
to examine the consistency of study results and the
appropriateness of pooled analysis (Higgins et al. 2003).
I2 values range from 0% to 100%, with lower values
indicating less heterogeneity (Higgins et al. 2003).
Kendall’s tau tests examine the possibility of the pooled
results being affected by publication bias, which may
occur when statistically significant associations are more
© 2014 John Wiley & Sons Ltd 1421
Tropical Medicine and International Health volume 19 no 12 pp 1420–1429 december 2014
D. E. Nicholas et al. Risk factors for Rift Valley fever infection
0.2 0.5 1 2 5 10 100
pooled OR (random effects) 1.36 (1.04, 1.79)
OR calculated by authors Lernout et al. (2013) 1.40 (0.80, 2.50)
OR Anyangu et al. (2010) 1.42 (1.03, 1.95)
OR calculated by authors LaBeaud et al. (2007) 0.60 (0.40, 0.90)
OR Pourrut et al. (2010) 1.75 (1.25, 2.45)
OR Hassanain et al. (2010) 2.80 (1.02, 7.60)
OR calculated by authors Marrama et al. (2005) 1.14 (0.73, 1.79)
OR calculated by authors Swai & Schoonman (2009) 3.69 (0.44, 30.63)
OR calculated by authors Jouan et al. (1989) 0.67 (0.34, 1.35)
OR calculated by authors Woods et al. (2002) 1.42 (0.65, 3.12)
OR LaBeaud et al. (2011) 2.33 (1.18, 4.61)
adjusted OR LaBeaud et al. (2008) 2.78 (1.18, 6.58)
adjusted OR Al-Azraqi et al. (2012) 1.25 (0.79, 1.99)
Odds ratio (95% confidence interval)
0.1 0.2 0.5 1 2 5 10 100 1000
pooled OR (random effects) 3.43 (1.61, 7.34)
OR calculated by authors Marrama et al. (2005) 0.96 (0.45, 2.03)
OR Lernout et al. (2013) 11.12 (1.10, 112.30)
OR calculated by authors Wilson et al. (1994) 4.66 (1.29, 16.82)
adjusted OR Al-Azraqi et al. (2012) 11.58 (6.95, 19.31)
OR calculated by authors Woods et al. (2002) 4.57 (2.02, 10.35)
OR calculated by authors Archer et al. (2011) 0.71 (0.11, 4.47)
OR LaBeaud et al. (2011) 3.49 (1.52, 8.00)
adjusted OR LaBeaud et al. (2008) 2.78 (1.03, 7.53)
Odds ratio (95% confidence interval)
1 2 5 10
pooled OR (fixed effect) 3.18 (2.38, 4.24)
OR Anyangu et al. (2010) 2.22 (1.40, 3.52)
OR calculated by authors Woods et al. (2002) 4.29 (1.86, 9.85)
OR calculated by authors LaBeaud et al. (2008) 4.08 (2.51, 6.65)
OR LaBeaud et al. (2011) 3.62 (1.61, 8.14)
Odds ratio (95% confidence interval)
(a)
(b)
(c)
Figure 1 (a) Forest plot for being male. (b) Forest plot for contact with aborted animal tissue. (c) Forest plot for birthing an animal.
(d) Forest plot for skinning an animal. (e) Forest plot for slaughtering an animal. (f) Forest plot for drinking raw milk.
1422 © 2014 John Wiley & Sons Ltd
Tropical Medicine and International Health volume 19 no 12 pp 1420–1429 december 2014
D. E. Nicholas et al. Risk factors for Rift Valley fever infection
1 2 5 10 100
pooled OR (fixed effect) 2.47 (1.90, 3.20)
OR calculated by authors Woods et al. (2002) 4.88 (2.14, 11.13)
OR calculated by authors LaBeaud et al. (2008) 2.53 (1.58, 4.04)
OR Anyangu et al. (2010) 2.19 (1.49, 3.22)
OR LaBeaud et al. (2011) 2.12 (1.06, 4.24)
Odds ratio (95% confidence interval)
0.01 0.1 0.2 0.5 1 2 5 10 100
pooled OR (random effects) 2.36 (1.37, 4.06)
OR Lernout et al. (2013) 2.15 (0.81, 5.70)
OR calculated by the authors LaBeaud et al. (2008) 1.51 (0.95, 2.38)
OR calculated by the authors Archer et al. (2011) 0.90 (0.08, 10.21)
OR Anyangu et al. (2010) 2.11 (1.43, 3.11)
adjusted OR Al-Azraqi et al. (2012) 5.52 (3.18, 9.58)
Odds ratio (95% confidence interval)
0.2 0.5 1 2 5 10 100 1000
pooled OR (random effects) 1.75 (1.19, 2.56)
OR calculated by authors Woods et al. (2002) 17.10 (2.20, 129.80)
OR Lernout et al. (2013) 0.88 (0.45, 1.72)
OR calculated by authors Jouan et al. (1989) 1.92 (0.99, 3.72)
OR calculated by authors LaBeaud et al. (2008) 1.50 (0.95, 2.37)
OR Anyangu et al. (2010) 1.71 (1.19, 2.46)
adjusted OR LaBeaud et al. (2011) 2.90 (1.32, 6.38)
Odds ratio (95% confidence interval)
(d)
(e)
(f)
Figure 1 (Continued).
© 2014 John Wiley & Sons Ltd 1423
Tropical Medicine and International Health volume 19 no 12 pp 1420–1429 december 2014
D. E. Nicholas et al. Risk factors for Rift Valley fever infection
likely than null results to be published. The values of Ken-
dall’s tau range from �1 to 1, with 0 indicating no evi-
dence of bias and absolute values near 1 demonstrating a
strong likelihood of bias (Rothstein et al. 2006). However,
Kendall’s tau requires a substantial number of included
studies (at least 10) in order to have the power to evaluate
a possible association between the effects and their stan-
dard errors (Higgins & Green 2011). Because so few possi-
ble risk factors for RVF were examined by 10 or more
studies, two additional methods were used to evaluate pos-
sible publication bias: the metafor package in R 3.0.1 soft-
ware (Viechtbauer 2010) was used to implement Duval
and Tweedie’s trim and fill method for calculating an
adjusted pooled effect estimate that imputes the effects of
missing studies (Duval & Tweedie 2000; Borenstein et al.
2009), and R 3.0.1 was used to apply Orwin’s method for
estimating the number of missing studies with null results
that would be required to reduce the overall summary
effect to a trivial OR of 0.95–1.05 (Borenstein et al. 2009).
Results
Table 1 briefly describes each of the 16 eligible studies,
which span 24 years of data collection (1987–2011) andmuch of the current geographic range of RVF. Ten of the
studies were descriptional cross-sectional studies, three
were case–control studies that compared those with and
without laboratory-confirmed RVF, and two were cohort
studies that followed participants forward in time to see
how many became infected with RVFV during the
follow-up period. The sample sizes for the cross-sectional
studies ranged from 171 to 4323, participant numbers
that generally provide sufficient statistical power for prev-
alence estimation. While one case–control study included
only about 50 participants, the others included 169–861participants. The cohort studies followed 273–685 partic-
ipants for 2 weeks to 3 months. All of the studies used
laboratory tests to confirm RVF diagnoses.
Ten potential risk factors were examined by three or
more studies. Figure 2 presents these findings graphically,
with statistically significant associations shown in the
upper half of the figure and non-significant results in the
lower half. The results are grouped into four categories:
demographic characteristics, animal-related factors, milk-
related factors and environmental factors (flooding).
Whenever possible, the measurement listed in each box is
the odds ratio and 95% confidence interval for the asso-
ciation. Preference was given to adjusted ORs listed in
the included studies. When no adjusted OR for an associ-
ation was available, the crude OR from the article is
listed. When no OR was provided but one could be
calculated from data provided in the article, a calculated
OR is provided. When no OR could be calculated a risk
ratio or prevalence ratio is listed.
Six (LaBeaud et al. 2007, 2008, 2011; Anyangu et al.
2010; Hassanain et al. 2010; Pourrut et al. 2010) of the
13 (Jouan et al. 1989; Woods et al. 2002; Marrama et al.
2005; Swai & Schoonman 2009; Al-Azraqi et al. 2012;
Heinrich et al. 2012; Lernout et al. 2013) studies that
investigated being male as a possible risk factor found a
statistically significant association with RVF infection.
ORs were available or able to be calculated for twelve of
these thirteen studies, so twelve studies were included in
a meta-analysis (Jouan et al. 1989; Woods et al. 2002;
Marrama et al. 2005; LaBeaud et al. 2007, 2008, 2011;
Swai & Schoonman 2009; Anyangu et al. 2010;
Hassanain et al. 2010; Pourrut et al. 2010; Al-Azraqi
et al. 2012; Lernout et al. 2013). The I2 test result
(I2 = 63.9%) suggested inconsistency in these studies’
measures of association. Because the available data could
not sufficiently explain the heterogeneity among sub-
groups (Higgins & Green 2011), the best analytic option
was to use a random effects meta-analysis model that
adjusted for these inconsistencies among studies. Ken-
dall’s tau (0.18, P = 0.46) indicated a low likelihood of
publication bias. Duvall and Tweedie’s trim and fill
method estimated that two missing studies would lower
the original pOR of 1.4 (1.0, 1.8) to 1.3 (1.0, 1.7).
Pooled analysis stratified by epidemicity for this associa-
tion [non-epidemic pOR = 1.4 (1.0, 2.0), epidemic
pOR = 1.3 (1.0, 1.7)] did not differ significantly from the
original pOR. Orwin’s method estimated that 96 missing
studies with an average null effect would be necessary to
lower the pooled effect estimate to a trivial OR of 1.05
or less. These results support being male as a risk factor
for RVF infection.
Seven (Woods et al. 2002; LaBeaud et al. 2007, 2008,
2011; Pourrut et al. 2010; Heinrich et al. 2012; Lernout
et al. 2013) of the 11 (Marrama et al. 2005; Anyangu
et al. 2010; Hassanain et al. 2010; Al-Azraqi et al. 2012)
studies that examined the association between age and
RVF infection concluded that older people had a greater
risk of infection. Because the age variables reported in
these studies were not measured in the same manner –some were continuous and some dichotomous, and they
used different age groups for categories – a meta-analysis
was not appropriate. More importantly, six of these stud-
ies (LaBeaud et al. 2007, 2008, 2011; Pourrut et al.
2010; Heinrich et al. 2012; Lernout et al. 2013) tested
for RVFV IgG seroprevalence, an indication of non-acute
exposure. Older people will, by definition, have greater
risk of past exposure than younger cohorts. A greater
lifetime prevalence of past exposure cannot be assumed
to translate to a greater risk for acute infection.
1424 © 2014 John Wiley & Sons Ltd
Tropical Medicine and International Health volume 19 no 12 pp 1420–1429 december 2014
D. E. Nicholas et al. Risk factors for Rift Valley fever infection
Table
1Characteristics
ofthe16eligible
studiesofhumanRVFrisk
factors
Country
Year(s)
ofdata
collection
Studydesign
Case
definition
Sample
size
Number
ofcases
Epidem
icReference
Mayo
tte
2011
Cross-sectional
IgG
seropositivity
1413
58
No
Lernoutet
al.(2013)
Kenya
2006,2009
Repeatedcross-sectional
surveys
IgG
seropositivityandplaquereduction
neutralisationtesting(PRNT)
194
44
No
LaBeaudet
al.(2011)
SaudiArabia
2008
Cross-sectional
IgG
seropositivity
2322
139
No
Al-Azraqiet
al.(2012,2013)
South
Africa
2008
Case–control
IgM
seropositivity,
RT-PCR
nucleicacid
detectionorvirusisolation
51
8Yes
Archer
etal.(2011)
Tan
zania
2007–2
008
Cross-sectional
IgG
seropositivity
1228
64
No
Heinrich
etal.(2012)
Gab
on
2005–2
008
Cross-sectional
IgG
seropositivity
4323
145
No
Pourrutet
al.(2010)
Kenya
2007
Case–control
IgM
orRT-PCR
seropositivity,
RT-PCR
nucleicaciddetectionorhaem
orrhagic
symptoms
861
202
Yes
Anyan
guet
al.(2010)
Sudan
2007
Cross-sectional
IgG
seropositivity
149
122
Yes
Hassan
ain
etal.(2010)
Kenya
2006
Cross-sectional
IgG
seropositivity
248
33
No
LaBeaudet
al.(2008)
Tan
zania
2004
Cross-sectional
IgG
seropositivity
199
8No
Swai&
Schoonman(2009)
Senegal
1999
Cross-sectional
IgG
seropositivity
1520
79
No
Marramaet
al.(2005)
Kenya
1997–1
998
Cross-sectional
IgM
seropositivity
171
31
Yes
Woodset
al.(2002)
Kenya
1994,1996,
1997,1998
Cross-sectional
IgG
seropositivityandplaquereduction
neutralisationtesting(PRNT)
1263
143
No
LaBeaudet
al.(2007)
Egypt
1993
Cohort
(withnested
case–controlanalysis)
IgM
seropositivity
685
69
Yes
Centers
forDisease
Control
&Prevention(C
DC)(1994)
Senegal
1989
Cohort
IgG
seropositivity
273
61
No
Wilsonet
al.(1994)
Mauritania
1987
Case–control
IgM
seropositivityorvirusisolation
169
116
Yes
Jouanet
al.(1989)
© 2014 John Wiley & Sons Ltd 1425
Tropical Medicine and International Health volume 19 no 12 pp 1420–1429 december 2014
D. E. Nicholas et al. Risk factors for Rift Valley fever infection
Seven (Wilson et al. 1994; Woods et al. 2002; LaBeaud
et al. 2008, 2011; Anyangu et al. 2010; Al-Azraqi et al.
2012; Lernout et al. 2013) of the nine (Marrama et al.
2005; Archer et al. 2011) studies that examined contact
with aborted animal tissue found a statistically significant
association with RVF infection. Eight ORs for this associ-
ation were included in a meta-analysis (Wilson et al.
1994; Woods et al. 2002; Marrama et al. 2005; LaBeaud
et al. 2008, 2011; Archer et al. 2011; Al-Azraqi et al.
2012; Lernout et al. 2013). The I2 test result (I2 = 80.0%)
indicated inconsistency among the measures of association.
Duvall and Tweedie’s trim and fill method did not find evi-
dence of publication bias that would lower the point esti-
mate for the pOR, and Orwin’s method estimated that 194
missing studies with an average null effect would be neces-
sary to lower the pooled effect estimate to an OR of 1.05
or less. The random effects pOR of 3.4 (1.6, 7.3) supports
contact with aborted animal tissue as a risk factor for RVF
infection.
All four of the studies that examined birthing an ani-
mal found a statistically significant association with RVF
infection (Woods et al. 2002; LaBeaud et al. 2008, 2011;
Anyangu et al. 2010), and four ORs from these studies
were included in a meta-analysis. The I2 test result
(I2 = 23.9%) indicated a low likelihood of inconsistency
among the measures of association. Duvall and Tweedie’s
trim and fill method estimated that one missing study
would lower the original fixed effect pOR of 3.2 (2.4,
4.2) to 3.0 (2.3, 4.0). Orwin’s method estimated that 98
missing studies with an average null effect would be nec-
essary to lower the pooled effect estimate to an OR of
1.05 or less. This supports birthing an animal as a risk
factor for RVF infection.
All four studies that investigated skinning an animal
found a statistically significant association with RVF
infection (Woods et al. 2002; LaBeaud et al. 2008, 2011;
Anyangu et al. 2010), and the four ORs from these stud-
ies were included in a meta-analysis. The test for hetero-
geneity (I2 = 5.9%) indicated a low likelihood of
inconsistency in the reports. Duvall and Tweedie’s trim
and fill estimated that there were no missing studies in
the meta-analysis, and Orwin’s method estimated that 79
studies with an average null effect would be necessary to
lower the fixed effect pOR of 2.5 (1.9, 3.2) to 1.05 or
less. These results support skinning an animal as a risk
factor for RVF infection.
The four studies that investigated sheltering animals in
the home all found a statistically significant association
with RVF infection (Woods et al. 2002; LaBeaud et al.
2008, 2011; Al-Azraqi et al. 2012), and four ORs from
these studies were included in a meta-analysis. The I2 test
result (56.5%) suggested possible inconsistency in these
studies’ findings. As neither a fixed effect nor a random
effects model was appropriate, a pOR was not calcu-
lated.
Three (Al-Azraqi et al. 2012; Anyangu et al. 2010;
Centers for Disease Control & Prevention (CDC) 1994)
of the six (LaBeaud et al. 2008; Archer et al. 2011;
*OR = 16.6 (2.2,121.0) Lernout et al. (2013)
≥15 years old
OR = 11.1 (1.1, 112.3) Lernout et al. (2013) births or abortions
OR = 1.4 (1.0, 2.0) Anyangu et al. (2010)
acute cases
*OR 3.3 (2.1, 5.1) LaBeaud et al. (2007)
≥16 years old
*OR = 4.7 (1.3, 16.8) Wilson et al. (1994)births or abortions
OR = 1.8 (1.3, 2.5) Pourrut et al. (2010)
OR = 0.5 (0.3, 0.8) Pourrut et al. (2010)
15-33 years old
OR = 3.5 (1.5, 8.0) LaBeaud et al. (2011)
OR = 2.8 (1.0, 7.6) Hassanain et al. (2010)
PR = 1.02 (1.01, 1.04) Heinrich et al. (2012)
per year
aOR = 3.8 (1.7, 9.1) Anyangu et al. (2010)
severe cases
OR = 2.2 (1.4, 3.5) Anyangu et al. (2010)
acute cases
*OR = 4.9 (2.1, 11.1) Woods et al. (2002)
aOR = 2.0 (1.1, 3.6) Al-Azraqi et al. (2012)
aOR = 2.8 (1.2, 6.6) LaBeaud et al. (2008)
aRR = 0.3 (0.1, 1.0) Woods et al. (2002)
< 15 years old
*OR = 4.6 (2.0, 10.4) Woods et al. (2002)
OR = 3.6 (1.6, 8.1) LaBeaud et al. (2011)
OR = 2.1 (1.1, 4.2) LaBeaud et al. (2011)
OR = 3.8 (1.5, 9.4) LaBeaud et al. (2011)
cow only
RR = 2.5 (1.2, 5.1) CDC (1994)
*OR = 17.1 (2.2, 129.8) Woods et al. (2002)
OR = 2.1 (1.5, 2.9) Anyangu et al. (2010)
acute cases
OR = 2.3 (1.2, 4.6) LaBeaud et al. (2011)
aOR = 1.04 (1.02, 1.06) LaBeaud et al. (2011)
aOR = 2.8 (1.0, 7.5) LaBeaud et al. (2008)
*OR = 4.3 (1.9, 9.9)Woods et al. (2002)
OR = 2.2 (1.5, 3.2) Anyangu et al. (2010)
acute cases
*OR = 8.3 (2.7, 24.8) Woods et al. (2002)
aOR = 5.5 (3.2, 9.6) Al-Azraqi et al. (2012)
aOR = 2.9 (1.3, 6.4) LaBeaud et al. (2011)
*OR = 5.7 (2.2, 14.8) Woods et al. (2002)
OR = 1.6 (1.1, 2.2) Anyangu et al. (2010)
acute cases*OR = 0.6(0.4, 0.9)
LaBeaud et al. (2007)male is protective
aOR = 1.05 (1.03, 1.07) LaBeaud et al. (2008)
aOR = 11.6 (7.0, 19.3) Al-Azraqi et al. (2012)
*OR = 4.1 (2.5, 6.7) LaBeaud et al. (2008)
*OR = 2.5 (1.6, 4.0) LaBeaud et al. (2008)
*OR = 2.0 (1.3, 3.2) LaBeaud et al. (2008)
OR = 2.1 (1.4, 3.1) Anyangu et al. (2010)
acute cases
OR = 1.7 (1.2, 2.5) Anyangu et al. (2010)
acute cases
*OR = 2.6 (1.7, 4.2) LaBeaud et al. (2008)
*OR = 1.7 (1.1, 2.7) LaBeaud et al. (2008)
*OR = 1.4 (0.7, 3.1) Woods et al. (2002)
aOR = 1.2 (0.6, 2.3)Al-Azraqi et al. (2012)
20 years old
*OR = 0.7 (0.1, 4.5) Archer et al. (2011)
*OR = 1.5 (1.0, 2.4) LaBeaud et al. (2008)
*OR = 1.5 (1.0, 2.4) LaBeaud et al. (2008)
*OR = 1.5 (0.6, 3.9)Woods et al. (2002)
*OR = 0.7 (0.3, 1.4) Jouan et al. (1989)
*OR = 0.8 (0.5, 1.3) Marrama et al. (2005)
15 years old
*OR = 1.0 (0.5, 2.0) Marrama et al. (2005)
*OR = 0.9 (0.1, 10.2) Archer et al. (2011)
*OR = 1.9 (1.0, 3.7) Jouan et al. (1989)
all participants
aOR = 1.3 (0.8, 2.0) Al-Azraqi et al. (2012)
OR = 1.0 (0.9, 1.0) Hassanain et al. (2010)
OR = 2.2 (0.8, 5.7) Lernout et al. (2013)
OR = 0.9 (0.5, 1.7) Lernout et al. (2013)
PR = 1.1 (0.7, 1.8) Heinrich et al. (2012)
*OR = 1.3 (0.8, 2.2) Anyangu et al. (2010) ≥ 15 years acute cases
*OR = 3.7 (0.4, 30.6) Swai & Schoonman
(2009)
*OR = 1.1 (0.7, 1.8) Marrama et al. (2005)
*OR = 1.4 (0.8, 2.5) Lernout et al. (2013)
Being Male Older Age Contact with Aborted Animal
Tissue
Birthing an Animal
Skinning an Animal
Sheltering Animals in the
Home
Slaughtering an Animal
Drinking Raw Milk Milking an Animal Home Flooding
Sta
tistic
ally
Sig
nific
ant
Not
Sta
tistic
ally
Sig
nific
ant
Figure 2 The risk factors for RVF reported in three or more studies. *OR calculated by the authors.
1426 © 2014 John Wiley & Sons Ltd
Tropical Medicine and International Health volume 19 no 12 pp 1420–1429 december 2014
D. E. Nicholas et al. Risk factors for Rift Valley fever infection
Lernout et al. 2013) studies that examined slaughtering
an animal found a statistically significant association with
RVF infection. Five ORs for this association were included
in a meta-analysis (LaBeaud et al. 2008; Anyangu et al.
2010; Archer et al. 2011; Al-Azraqi et al. 2012; Lernout
et al. 2013). The I2 test result (71.0%) suggested incon-
sistency in these studies’ findings. Duvall and Tweedie’s
trim and fill method did not find evidence of publication
bias that would lower the point estimate for the pOR,
and Orwin’s method estimated that 68 missing studies
with an average null effect would be necessary to lower
the pooled effect estimate to an OR of 1.05 or less. The
random effects pOR of 2.4 (1.4, 4.1) supports slaughter-
ing an animal as a risk factor for RVF infection.
Additionally, three studies that looked at general con-
tact with various types of animals (cattle, sheep, goats
and camels) found that exposure to animals was associ-
ated with increased risk of RVF (Woods et al. 2002;
LaBeaud et al. 2008; Anyangu et al. 2010). However, the
non-specific nature of this exposure means that it is of
limited use in identifying particular risks. Some analyses
may also be incomplete because they combined exposures
to multiple animals. Risk factors for RVFV transmission
to humans may vary for different species of livestock, as
was observed in the analyses of exposure to aborted
animal tissue [cow OR = 4.5 (1.5, 13.3), goat OR = 3.0
(1.3, 7.1), sheep OR = 3.6 (1.5, 8.6)] and birthing an
animal [cow OR = 8.5 (2.7, 26.4), goat OR = 3.4 (1.4,
7.9), sheep OR = 3.4 (1.4, 7.9)] reported in stratified
analysis in one study (LaBeaud et al. 2011) (not shown
in Figure 2).
Three (Woods et al. 2002; Anyangu et al. 2010;
LaBeaud et al. 2011) of the six studies (Jouan et al.
1989; LaBeaud et al. 2008; Lernout et al. 2013) that
examined drinking raw milk found a statistically signifi-
cant association with RVF infection. The six ORs from
these six studies were included in a meta-analysis. The
test for heterogeneity (I2 = 53.6%) suggested possible
inconsistency among the measures of association. Duvall
and Tweedie’s trim and fill method estimated that one
missing study would lower the original random effects
pOR of 1.8 (1.2, 2.6) to 1.6 (1.1, 2.5). Orwin’s method
estimated that 105 missing studies with an average null
effect would be necessary to lower the pooled effect esti-
mate to an OR of 1.05 or less. These results support
drinking raw milk as a risk factor for RVF infection.
Other exposures were investigated too infrequently to
allow for meta-analysis. The three studies that examined
milking an animal as a possible risk factor all found a
statistically significant association with RVF infection
(Woods et al. 2002; LaBeaud et al. 2008; Anyangu et al.
2010), as did two (LaBeaud et al. 2008; Anyangu et al.
2010) of the three (Woods et al. 2002) studies that inves-
tigated the association between home flooding and RVF
infection.
Discussion
Almost two-thirds (28/44) of the statistically significant
associations reported by the eligible studies were for
exposures related to contact with animals or consump-
tion of animal products: contact with aborted animal
tissue, birthing an animal, skinning an animal, sheltering
animals in the home, slaughtering an animal, drinking
raw milk and milking an animal. Based on the meta-
analyses, contact with aborted animal tissue, birthing an
animal, skinning an animal and slaughtering an animal
can be considered confirmed risk factors for RVF. The
results of the meta-analysis also confirm drinking raw
milk as a risk factor for infection. However, a recent study
found that raw milk consumption was not a significant
predictor of RVF infections in South Africa between 2008
and 2011 (Archer et al. 2013), suggesting that additional
studies are needed to further evaluate this association in
different contexts. Contact with aborted tissue, birthing,
skinning and slaughtering involve contact with infected
animal blood or tissue in ways that may allow the virus to
enter into wounds in the skin or be inhaled (World Health
Organization 2008; Swanepoel & Paweska 2011). Small
amounts of RVFV have been reported in the milk, saliva
and nasal discharges of infected sheep and cattle (Swane-
poel & Paweska 2011), so consuming infected raw milk
could represent another pathway for the virus to be intro-
duced into the body. Additionally, being male appears to
be a risk factor for RVF, likely because of occupational
exposure, but additional confirmatory studies are required.
More research is also necessary to further examine
whether birthing an animal (or particular types of live-
stock), sheltering animals in the home, slaughtering an ani-
mal, milking an animal and home flooding increase the
risk of contracting RVFV.
While it is possible that some of these results were influ-
enced by various types of bias (Jacobsen 2011), we were
careful to minimise bias when identifying relevant articles
and to interpret our results cautiously when tests sug-
gested the possible presence of bias in pooled estimates.
To minimise search bias, the search terms were minimally
restrictive. To minimise selection bias, all publication
languages and all study designs were eligible for inclusion
in the review. When the sample size was sufficiently large,
we used Kendall’s tau to test for the likelihood of publica-
tion bias in each meta-analysis. Two additional statistical
tests (Duvall and Tweedie’s trim and fill and Orwin’s
method) were used to evaluate the impact of potentially
© 2014 John Wiley & Sons Ltd 1427
Tropical Medicine and International Health volume 19 no 12 pp 1420–1429 december 2014
D. E. Nicholas et al. Risk factors for Rift Valley fever infection
unpublished studies on the pooled effect. Thus, the conclu-
sions from this analysis should be valid even with the
small sample size for some potential risk factors. How-
ever, the findings of some studies may be affected by recall
bias resulting when notable events such as home flooding
may have been more easily recalled than less notable
potential exposures such as an insect bite.
These findings point to potentially effective RVF infec-
tion control policies and practices. As contact with
animal tissue appears to be an important mode of trans-
mission of RVFV, especially during outbreaks, increased
use of personal protective equipment (such as shoulder-
length polyethylene gloves) and disinfectants (such as
alcohol-based hand sanitisers) may help to reduce trans-
mission during times when RVF is endemic or epidemic
within a community (Archer et al. 2011; Swanepoel &
Paweska 2011; Fyumagwa et al. 2012). These control
strategies may be more feasible to implement in a com-
mercial setting like an abattoir than in a rural farm set-
ting. If drinking raw milk is a risk factor, pasteurising
milk through boiling could aid in control efforts. Addi-
tional research on behavioural risk factors and on modes
of transmission may help to identify other targets for pre-
vention activities. Ideally, future studies should seek to
use common definitions for exposure variables, which
would allow for easier comparisons of studies and would
facilitate further meta-analysis. Subsequent research
should explore the effect of the intensity of exposure
(such as the amount of milk consumed or number of
animals slaughtered or birthed) in addition to the pres-
ence or absence of exposure.
RVF has demonstrated the capacity to expand into
new geographical regions and cause outbreaks in suscep-
tible populations, and climate change may further expand
the range of RVF (Chevalier et al. 2010). RVF studies
that definitively characterise the behavioural and demo-
graphic risk factors for infection are vitally important for
preparing to address future outbreaks of this emerging
viral infection.
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Corresponding Author Dennis E. Nicholas, 4400 University Dr 5B7, Fairfax, VA 22030, USA. E-mail: [email protected]
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Tropical Medicine and International Health volume 19 no 12 pp 1420–1429 december 2014
D. E. Nicholas et al. Risk factors for Rift Valley fever infection