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Dispatch
Puumala hantavirus Infection
in Humans and in the Reservoir Host, Ardennes Region, France
F. Sauvage,* C. Penalba,† P. Vuillaume,‡ F. Boue,§ D. Coudrier,#
D. Pontier,* and M. Artois**
*Université C. Bernard Lyon 1, France; †Centre Hospitalier, Charleville-Mézières,
France; ‡Entente Interdépartementale de Lutte contre la Rage, Malzéville,
France; §AFSSA Nancy, Domaine de Pixerécourt, Malzéville, France; #Institut
Pasteur, Paris, France; and **Ecole nationale vétérinaire de Lyon, Marcy
l'Etoile, France
Suggested
citation for this article: Sauvage
F, Penalba C, Vuillaume P, Boue F, Coudrier D, Pontier D, et al. Puumala
hantavirus infection in humans and in the reservoir host, Ardennes
Region, France. Emerg Infect Dis [serial online] 2002 Dec [date cited];8.
Available from: URL: http://www.cdc.gov/ncidod/EID/vol8no12/01-0518.htm
We compared the
occurrence of nephropathia epidemica cases, over a multi-annual population
cycle, in northeastern France with the hantavirus serology for bank
voles captured in the same area. We discuss hypotheses to explain the
pattern of infection in both humans and rodents and their synchrony.
In Eurasia, hantaviruses (family Bunyaviridae) are the etiologic
agents of hemorrhagic fever with renal syndrome (HFRS) in humans (1).
In France, the HFRS-endemic area is the northeastern quarter of the country
(2–4). The Ardennes massif at the Belgian border hosted
244 recorded human cases during 1991–1999 and accounted for two thirds
of the total number of French cases during the 1996–1999 regional bank
vole (Clethrionomys glareolus) demographic cycle. Historically,
40% of all recorded French cases occur in this region. Human cases of
nephropathia epidemica (NE), a milder form of HFRS caused by Puumala
virus (PUUV), are routinely recorded at the Centre Hospitalier Régional
(CHR) of Charleville, (Ardennes) France, which has the largest number
of clinical cases in the country. Epidemic outbreaks of acute infection
have been observed every third year since 1991. We hypothesize that the
risk of human infection results from an increase in the mass shedding
of virus, after a population increase of infected voles over a threshold
density. In this case, the prevalence of infection in rodents may rise
some time before the outbreak occurs in humans.
To test this hypothesis, we set up a surveillance protocol to investigate
if increased densities of bank vole populations would amplify anti-PUUV
antibody prevalence in the reservoir, reflecting an increased risk for
infection by human beings. We determined the prevalence of anti-hantavirus
antibodies in a population of bank voles, the rodent reservoir (5),
within the disease-endemic area. During the 3 years before the last peak
of disease (1997–1999), we monitored bank vole populations by trapping
and screening antibodies. Animals were trapped in the Elan and Hazelles
forests near the city of Charleville by using 100-m trap lines, each containing
34 nonbaited small rodent INRA box traps (6) in the spring,
summer, and autumn of 1997, 1998 (plus one session in December 1998),
and 1999. The forests were divided into equal sectors, and 12 trap lines
by forest (13 in 1997) were set in randomly chosen sectors for each capture
session. Traps were checked daily for 3 successive days, and captured
rodents were removed for further virologic studies. If lines were reset
in the same sector on successive occasions, they were moved to reduce
bias caused by the removal of animals trapped in the previous session.
Serum samples of blood from the trapped animals were withdrawn by cardiac
puncture and evaluated by enzyme-linked immunosorbent assay (ELISA) on
plaques directly coated with antigen from cells infected with PUUV or
controls, lysed in triton-borate buffer, and then sonicated. Antibody
uptake was estimated with peroxidase-tagged anti-mouse immunoglobulin
(Ig) G, which cross-reacts with bank vole Ig (not shown). Positive serum
samples were confirmed by immunofluorescence on PUUV or Haantan
virus-infected Vero E6 cells at serial doubling dilutions. We did not
use direct detection of the virus by reverse transcriptase polymerase
chain reaction (RT-PCR). Therefore, a discrepancy between our estimates
of infected voles and the true number of potentially infectious animals
may have occurred but should not affect the temporal trends over a 3-month
intervals (7,8).
During the study, we observed a fourfold increase in the density index
of the monitored vole population, with seasonal fluctuations (highest
in September and lowest in spring). A total of 550 animals were trapped
during 25,092 trap nights for an overall trap success rate of 2.19% (3.25%
in Elan, with 408 captures and 1.13% in Hazelles, with 142 captures).
Five species of rodents and two species of insectivores were captured.
Overall, C. glareolus was most commonly collected (49.8%); however,
the proportion of the different species varied greatly between the two
forests: bank voles accounted for 57.6% of captures in Elan but only for
27.5% of captures in Hazelles (chi-square =13.65, p = 2.10-4),
where they were overtaken in frequency by Apodemus flavicollis
(29.6%). Twenty-nine rodents were seropositive for hantaviruses; 25 were
bank voles (23 in Elan and 2 in Hazelles) and 4 were A. sylvaticus
(3 in Elan and 1 in Hazelles). Seropositive wood mice were detected during
the peak of prevalence in bank voles, which suggests a spillover infection
similar to that seen in humans. We focused on bank voles in Elan because
the number of infected voles from Hazelles is too small to allow statistical
analysis. Among the 235 bank voles captured, 113 were male, 119 were female,
and 3 were undetermined. The overall seroprevalence was 9.8% (23 seropositive
voles), with 13 males (prevalence of 11.5%), 9 females (7.6%), and 1 undetermined.
Prevalence did not differ between sexes (chi-square = 0.64, p = 0.42).
Hantavirus antibody prevalence reached a maximum of 29% (4 of 14 bank
voles tested) during the spring of 1999 from 8.9% (5/56) in the previous
fall. Prevalence then fell to 11% (4/36) the next summer and remained
at this level (7/76) until the population peak in September 1999. One
might hypothesize that the amount of virus available for human contamination
reached its highest level between September 1998 and September 1999.
We observed an irregular distribution of seropositive animals among the
captures from the Elan forest (Figure 1); many trap lines did not have
positive voles from a large number of captures, whereas others had higher
rates (up to 3 of 3 captured voles). No clear correlation exists between
host density (as estimated by capture frequency) and seropositivity, but
seropositive animals were more often taken on northerly facing trap lines
(chi-square = 12.68, p = 4.10-4) than southerly facing ones
(chi-square = 0.86, p = 0.35). This difference is probably due to the
higher humidity of northerly facing slopes, which are less often exposed
to the sun. Verhagen et al. (9) have reported that the
probability that a bank vole will be infected increases with the humidity
of its territory. The lower number of observations from the Hazelles forest
also showed a variation in population density and antibody prevalence
in synchrony with the Elan voles.
At least 40 human cases of NE (range 40–74) were recorded at the Charleville
CHR in 1993, 1996, and 1999, whereas no more than 14 NE cases were seen
in the intervening years (Figure 2). If the sampled
rodents are representative of the whole reservoir population to which
humans are exposed, our findings suggest a synchrony of infection rates
in humans and reservoir rodents over the 3-year epidemiologic cycle. In
accordance with previous records, the greatest number of HFRS cases were
registered at Charleville CHR during the periods of highest prevalence
in the reservoir host (1993, 1996, and 1999). Provided that the data from
this preliminary study are accurate, the temporal correlation between
infection rates in human victims and in the reservoir host (Spearman's
rank correlation, z = 2.55, p = 0.01 p = 0.86) strongly suggests a common
process of infection. The assumption that the vole demographic population
peak precedes the epidemic outbreak in humans is not supported by our
data. If our study is representative of the actual situation, our results
suggest that the maximum infection rate is reached simultaneously in both
the human and reservoir hosts. These results could be explained if the
proportion of newly infected voles is more important than the total number
of infected voles. In fact, the amount of virus shed during the first
month of infection is far higher than during the consecutive chronic phase
(10). In this case, the increased mass shedding of virus
would not necessitate a very high prevalence. To attain the observed high
proportion of infected voles for less than 1 month, even with a stable
prevalence, the transmission between voles must be rapid in the increasing
population.
We hypothesize that the mechanism of virus circulation is related to
the social structure of the reservoir: bank voles are territorial and
avoid encounters with conspecifics during the breeding season but share
nests during winter. Direct transmission seems difficult during the reproductive
season. We have previously examined a possible role of the environment
in the survival of the virus outside its host to explain its observed
patchy distribution (11). Human contamination occurs
mainly by this indirect route (12). The bank vole social
component, in combination with an indirect transmission route, can explain
the rapid spread of infection through a population of increased density.
The voles may become infected through the sniffing of contaminated excreta
marks, even though these animals avoid direct encounters. This activity
could result in a high proportion of newly contaminated voles. A change
in the population dynamics of the bank vole reservoir, leading to a low
incidence of newly infected individuals as seen in the more stable populations,
could explain the transition from an epidemic to a sporadic pattern of
HFRS in regions of France south of the Ardennes (2).
This hypothesis will be tested in ongoing epidemiologic studies.
Acknowledgments
We are grateful to the French Army Bureau of Health, and particularly
to Commandant Perraudin, for logistic support and help from army veterinary
surgeons; all the personnel of AFSSA Nancy and “Entente Interdépartementale
de Lutte Contre la Rage” who participated in data collection in the field,
and in particular Jean-Michel Demerson for his high commitment; Evelyne
Cain-Jouquelet for serologic analyses; and Tim Greenland for his constructive
comments.
This work was financed by grants from AFSSA Nancy and the “Entente Interdépartementale
de Lutte Contre la Rage.”
Mr. Sauvage is a doctoral student under the supervision of Dominique
Pontier. His main interests are ecological field studies on the epidemiology
of hantaviruses in France and modeling approaches to these studies.
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