Download related (Pogosta) virus in different parts of Finland

Rheumatology 2003;42:632–636
doi:10.1093/rheumatology/keg143, available online at www.rheumatology.oupjournals.org
Advance Access publication 31 March 2003
The prevalence of antibodies against Sindbisrelated (Pogosta) virus in different parts of
Finland
M. Laine1,2, R. Vainionpää3, J. Oksi1,2, R. Luukkainen4 and
A. Toivanen1
Objective. To study the occurrence of Sindbis-related (Pogosta) disease in Finland
by serological means.
Methods. A total of 2250 serum samples from five different areas were included in
the study. Four hundred samples were collected from healthy blood donors and
1850 samples from patients who were suspected to have some viral infection.
Antibodies of IgG and IgM classes against Pogosta virus were measured.
Results. Eleven per cent of 2250 samples were positive for IgG and 0.6% were
positive for IgM class antibodies against Pogosta virus. The antibody prevalence
in Finland was almost equally distributed, being highest in western Finland (17%)
and lowest in southern and northern Finland (9%). Of all samples with IgG class
antibodies, 25% were taken from children under 10 yr of age.
Conclusions. The prevalence of antibodies against Pogosta virus was much higher
than we expected. Additionally, they were detected from all locations studied and
not only in eastern Finland, which has been thought to be the main endemic area
for this disease. Pogosta disease has been considered to affect mainly middle-aged
persons, but our results indicate a high prevalence also among children.
KEY WORDS: Pogosta virus, Sindbis-related virus, Finland.
Pogosta disease, characterized by arthritis, rash and
occasionally fever, was first recognized in the eastern
parts of Finland in 1974 w1x. Since then there have been
several outbreaks in the country and they seem to occur
quite regularly every 7 years. A similar illness has been
described in Sweden (Ockelbo disease) and in Russia
(Karelian fever) w2, 3x. All three diseases are attributed
to Sindbis-related arboviruses w4–6x. The virus causing
Ockelbo disease has been isolated from pools of Culiseta,
Aedes and Culex mosquitoes, and it is supposed that these
late summer mosquitoes spread the Pogosta virus as well
w6, 7x. The transmission cycles of arboviruses are complex
w8x. Several factors, including viral, vector- and hostrelated, or environmental variations may contribute to its
geographical variation w9x. Vertical transmission appears
possible in the case of Ockelbo and Ross River viruses,
which are close relatives to Pogosta virus w10–12x. These
viruses are able to persist in the environment for a long
period in desiccation-resistant mosquito eggs; therefore, a
rapid onset of cases can occur if conditions become
suitable w10–12x.
In the case of Ross river virus, marsupials such as the
western grey kangaroo, wallabies and euros (Macropus
rotundus) are believed to be the major vertebrate hosts
of the virus w13x. A recent study has demonstrated that
migratory birds, mainly thrushes, on several continents
have a high prevalence of antibodies against the mosquitoborne alphaviruses, and in Sweden almost all passerine
species that were collected from forested wetlands and
humid forests had antibodies against Sindbis virus w14x.
Migratory birds may contribute to the spread of
arthropod-borne infections in at least two ways. First,
birds carrying infected ticks have been found to spread
Borrelia burgdorferi efficiently over long distances w15x.
Second, a latent borrelial infection may be reactivated
during the migratory restlessness of the birds w16x.
Departments of 1Medicine, 2Medical Microbiology and 3Virology, Turku University, Turku and 4Satalinna Hospital, Harjavalta, Finland.
Submitted 24 January 2002; revised version accepted 4 September 2002.
Correspondence to: A. Toivanen, Department of Medicine, Turku University, Kiinamyllynkatu 4–8, FIN-20520 Turku, Finland.
E-mail: auli.toivanen@utu.fi
632
ß 2003 British Society for Rheumatology
Antibodies against Pogosta virus in Finland
633
Many arthropod-borne diseases tend to occur in
certain areas. Thus, Lyme disease caused by Borrelia
burgdorferi is most common in the archipelago of southwestern Finland. Most cases of Ockelbo disease in
Sweden have been reported to occur between the 60th
and 64th parallels and Pogosta disease is thought to
occur only in the eastern parts of Finland w1, 17x. We
found a surprisingly high number of serologically
confirmed cases of Pogosta disease also in south-western
parts of Finland w18x. We also demonstrated that the
disease does not have as good a prognosis as believed,
but that the joint symptoms may persist for several years
w18, 19x. It may, therefore, be suspected that Pogosta
disease could be more common than thought at present,
and that it should be considered a diagnostic alternative
in patients with complaints of acute or chronic joint
symptoms. In order to analyse the occurrence of this
disease in Finland, we analysed samples collected from
different geographical parts of the country for the
presence of antibodies against Pogosta virus.
Material and methods
Serum specimens
A total of 2250 serum samples from five different areas
in Finland were analysed in this study. Of the samples, 1850
were selected to represent different parts of the country and
were otherwise taken randomly from the Finnish Red Cross
and the specimen libraries at the Department of Virology,
University of Turku and Department of Medical Microbiology,
University of Oulu. Therefore, various age groups were
included and this led, by chance, to inclusion of sera obtained
from very young individuals. Altogether, of these 1850
samples, 570 were from southern (Turku and Salo), 491
from eastern (Joensuu and Kuopio), 335 from western (Pori)
and 454 from northern Finland (Oulu). These sera were
mainly from hospitalized patients, and 90 samples were from
patients who had visited health centres and were suspected to
have some viral infection. The samples had been sent for
serological analysis for the possible presence of antibodies
against Mycoplasma pneumoniae, Chlamydia pneumoniae or
Chlamydia trachomatis. There were also a few samples sent for
testing of cytomegalovirus (CMV), herpes simplex (HSV),
varicella zoster (VZV), enterovirus, Epstein–Barr virus, herpes
virus 6 and parvovirus. Seventy-three samples were sent for
testing of Pogosta virus antibodies and four of them gave positive
results of Pogosta virus serology.
Four hundred sera included in the study were from healthy
blood donors in five cities: Kokkola (50), Joensuu (50),
Rovaniemi (100), Turku (100) and Maarianhamina in the
Åland Islands (100). The location of these cities is illustrated
in Fig. 1. Blood donation in Finland is organized by the
Finnish Red Cross. It is voluntary and strictly controlled, and
blood donors must be considered healthy and socially active.
All sera were stored at 2208C until tested for antibodies.
Antibody determination
Serum antibodies of IgG and IgM classes against Pogosta
(Sindbis) virus were detected by an enzyme immunoassay
method w4x. Briefly, the microtitre wells were coated with semipurified Sindbis virus antigen (strain 339). Serum dilutions
FIG. 1. Map illustrating the endemic areas of Pogosta and
Ockelbo diseases and Karelian fever. The cities from which
samples were obtained are marked.
(1:40–1:2560) were added to the wells and incubated for 2 h
at 378C, after which horseradish peroxidase (HRP)-conjugated
anti-human IgG or IgM antibodies at dilutions of 1:12 000
and 1:3000 (DAKO, Germany) were added. Orthophenylenediamine (OPD) was used as a colour substrate and the optical
density (OD) was measured at 492 mm by a Multiskan
Analyzer (Eflab OY, Helsinki, Finland). The last dilution,
which gave an OD value higher than 2.5 times the OD value of
negative controls, was considered positive. The sera positive
for IgM were tested for rheumatoid factor (RF) by latex
agglutination (RapiTex1RF, Dade Behring Marburg GmbH,
Germany). If the test was found to be positive, RF was removed
by absorption (GullSORB2, Gull Laboratories, Inc., SLC,
UT,USA) and the antibody titre was retested.
Results
Altogether 2250 serum samples collected from two
different sources were included in this study. The patient
material was chosen not only to represent typical highrisk areas but also those thought to be at low risk of
Pogosta disease. These 1850 sera were from people who
had visited health centres or had been hospitalized, and
in whom a viral disease was suspected. Their ages varied
from 2 days to 100 yr with a mean of 35 yr; 54% of them
were female and 46% male. Thirty-two per cent of the
1850 samples (594) came from persons under 20 yr
(Fig. 2), and 37 samples were from infants under 1 yr.
From the 400 healthy blood donors there was only
general information available. In general, blood donors
in Finland are healthy adults aged from 18 to 65; 51% of
them are female and 49% male.
We tested for IgG class antibodies against Pogosta
virus from all 2250 serum samples. Eleven per cent (248)
of these samples were positive for IgG class antibodies.
The distribution of Pogosta cases in different parts of
Finland is shown separately from the two serum donor
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M. Laine et al.
groups in Table 1 and together in Table 2. There were
significant differences (P=0.002) in proportions of IgG
class antibodies in different geographical areas. However,
when western Finland was excluded from the analysis,
the differences were not any more significant (P=0.465)
(Table 2). The exact P values calculated to test the
differences between the clinical and blood donor samples
at each geographical location have been shown in
Table 1. All IgG positive serum samples were tested
for IgM class antibodies and only 20 were found to be
positive. Five of them were positive for RF and they all
turned out negative after retesting. Thus, after removing
the RF by absorption, 15 sera were positive for Pogosta
virus antibodies of IgM class.
The prevalence of antibodies against Pogosta virus
among the 1850 persons who were suspected to have
some viral infection was highest in western Finland 15%
(51) and lowest in northern Finland 6% (26). In eastern
Finland 50 out of 491 samples (10%) were positive
(Joensuu 12%, Kuopio 9%) and in southern Finland 43
out of 570 patients (8%) (Turku 10%, Salo 5%) had
antibodies against Pogosta virus. Sera from persons aged
below 10 yr were positive in 19% of cases and all sera
from infants less than 1 yr old were negative.
The results from the 400 samples from healthy blood
donors were slightly different. The prevalence of IgG
class antibodies was almost equally distributed in
western (n=13, 26%), eastern (12, 24%) and in northern
Finland (24, 24%). In the archipelago of Finland 11 out
of 100 patients (11%) had IgG class antibodies and in
southern Finland (Turku) 18 (18%) samples were positive.
As a control we screened the result files of the
Department of Virology, University of Turku to see
which antibodies had been detected. The data of 1396
samples out of the 1850 which were included in the
present study were available for this. These results are
based on the tests carried out upon the request of clinicians, according to the clinical picture. Thirteen samples
out of 764 tested had IgM antibodies against Chlamydia
pneumoniae and 32 out of 354 tested against Mycoplasma
pneumoniae. Four of them also had antibodies of IgG
class against Pogosta virus. Also, 14 out of 179 tested
TABLE 1. Comparison of IgG class antibodies against Pogosta virus in
1850 clinical samples and in 400 samples from blood donors collected
by the Finnish Red Cross in different geographical areas in Finland
Geographical area
Eastern Finland
Clinical samples
Blood donors
Western Finland
Clinical samples
Blood donors
Southern Finland
Clinical samples
Blood donors
Northern Finland
Clinical samples
Blood donors
The Åland Islands
Total
Number of samples
IgGa n (%)
P valueb
491
50
50 (10)
12 (24)
0.007
335
50
51 (15)
13 (26)
0.067
570
100
43 (8)
18 (18)
0.002
454
100
100
2250
26
11
11
248
(6)
(11)
(11)
(11)
<0.001
a
Positive for antibodies of IgG class.
Exact P values were calculated to test differences between the
clinical and blood donor samples at each location by x2-test.
b
TABLE 2. Numbers and percentages of sera with antibodies against
Pogosta virus in all 2250 samples studied
Geographical area
Eastern Finland
Western Finland
Southern Finland
Northern Finland
The Åland Islands
Total
a
Number of samples
541
385
670
554
100
2250
IgGa (%)
IgMb (%)
11
17
9
9
11
11
2
1
0.4
0
0
0.6
Positive for antibodies of IgG class.
Positive for antibodies of IgM class.
b
patients had IgM antibodies against Epstein–Barr virus,
five out of 123 tested against parvovirus, two out of 38
tested against puumalavirus, three out of 227 tested
against cytomegalovirus and one out of 224 tested
against herpes simplex virus. None of these sera was
positive for Pogosta virus. The age and sex distribution
of the patients is shown in Figs 2 and 3.
Discussion
FIG. 2. Age and sex distribution of 1850 persons with
antibodies against Pogosta virus.
When we analysed the results of this study we found a
few surprises. First of all, the percentage of sera positive
for Pogosta virus was much higher than we expected.
Second, more of the positive samples were from other
parts of Finland than from eastern Finland, which is
considered the main endemic area for this disease. Third,
we were surprised by the high antibody prevalence among
children.
The critical question is whether the antibodies detected
are truly against Pogosta virus or whether they are due to
cross-reactivity against some other viruses. It is known
that Epstein–Barr virus is a strong polyclonal activator
and can cause cross-reactivity with other viruses. Still,
only five out of 123 samples tested for Epstein–Barr
Antibodies against Pogosta virus in Finland
samples were positive and none of them was positive for
Pogosta virus. There are no other known arboviruses
belonging to the genus alphaviruses in Finland that cause
diseases. Therefore cross-reactivity is very unlikely. We
also screened the result files of 1396 samples to look for
possible cross-reactivity against other viruses and bacteria
(collected from the Department of Virology of Turku
University). Only four samples positive for Pogosta
virus IgG antibodies had antibodies against other
micro-organisms. Thus, we consider the results reliable.
The most common symptoms of Pogosta disease are
arthralgia and polyarthritis, occurring in 93%, and rash
in 88% of the patients w20x. In children joint symptoms
are rare but rash is usually visible w20x. In this study 33%
of positive IgG antibody tests for Pogosta virus were
samples from patients younger than 20 yr. Thus, we
found Pogosta disease to be common in children, which
was quite striking because Pogosta disease is considered
to be an illness of middle-aged patients w1, 21x. In infants
aged less than 1 yr, antibodies were not detected and
therefore those observed in the older children cannot
be considered maternally derived. It might be that the
infection in children is mild or even asymptomatic, and
therefore until now neglected.
Sindbis-related viruses seem to affect patients’ lives
after infection and they should be considered as a differential diagnosis by doctors handling patients with
chronic symptoms. It is well established that Pogosta and
Ockelbo diseases can lead to chronic joint symptoms
635
lasting up to 4 yr w22x. The joint symptoms in Ockelbo
disease have been reported to cause absence from work
for up to 10 weeks (mean 3 weeks), being a true economic
problem w23x. In an earlier study we found that 50% of
patients still suffered from chronic joint and muscle pains
2.5 yr after Pogosta disease. After Ross River virus
infection, chronic musculoskeletal symptoms have been
reported w24x.
The present study was carried out to examine the prevalence of antibodies against Pogosta virus in different
parts of Finland. The serum samples were collected from
400 healthy blood donors and 1850 patients who were
suspected to have a viral infection. All the clinical samples were collected in 2000, but the samples from blood
donors were received in 1994. The fact that the two sets
of samples were collected at different times can hardly
explain the differences observed. The majority of
Pogosta disease cases occur in August and September
and for unknown reasons, at least in eastern Finland, the
disease has been thought to have a tendency to cause
outbreaks every 7 yr w1x. The reason for this variation is
not known.
Between the years 1989 and 2000 only one outbreak of
Pogosta disease occurred. In the study conducted in 1989
by Kroneld et al. w25x, the prevalence of antibodies
against Pogosta virus was 4.7% in southern Finland
(Turku), 5.7% in central Finland (Jyväskylä) and 2.7% in
the island of Iniö in the Finnish archipelago. Compared
with these results, the antibody prevalence in our study
FIG. 3. Age distribution of: (A) 335 persons with antibodies against Pogosta virus in western Finland, (B) 454 persons with
antibodies against Pogosta virus in northern Finland, (C) 491 persons with antibodies against Pogosta virus in eastern Finland, (D)
570 persons with antibodies against Pogosta virus in southern Finland.
636
M. Laine et al.
was higher, being 9% in southern Finland and 11% in the
archipelago. This could be explained by the fact that in
1995 there was an outbreak of Pogosta disease and after
that cases have been seen in southern Finland yearly
(National Public Health Institute report). The epidemiology of Pogosta disease may be changing to occur not
every 7 yr, but possibly every year, at least in southern
Finland. Furthermore, in this study only a few patients
(0.6%) had IgM antibodies against Pogosta virus, which
indicates that 1994 and 2000 were inter-epidemic years.
Formerly, Pogosta disease was considered to be endemic only in the eastern parts of Finland. Yet, in the light
of these new results, Pogosta disease is quite common at
all the locations studied.
Acknowledgements
We warmly thank the Department of Medical
Microbiology, University of Oulu and Finnish Red
Cross for providing serum samples for this study. This
study was financially supported by the Scandinavian
Rheumatology Research Foundation, Finnish Rheumatology Research Foundation, Turku Duodecim
Foundation and the EVO Foundation of the Turku
University Central Hospital.
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