International Journal of Epidemiology © International Epidemiological Association 1992
Vol. 21, No. 2 Printed in Great Britain
The Prevalence and Regional Distribution of Antibodies against Chlamydia pneumoniae (Strain TWAR) in Finland in 1958 M KARVONEN,* J TUOMILEHTO.* A NAUKKARINEN** AND P SAIKKUt
A newly discovered human pathogen, recently named Chlamydia pneumoniae (strain TWAR), has been found to be a causative agent in respiratory tract infections, particularly in pneumonia.1'2 Infection due to C pneumoniae is thought to be transmitted directly from person to person without the need for an animal vector, including avian contacts.3"6 C pneumoniae infection spreads slowly and the interval between cases is long.1'2'7-8 In Scandinavia, an epidemic cycle of 6 years has been suggested consisting of about a 2.5-year period of high incidence and a 3-4 year interval.8-9 Until now, the antibody prevalence in healthy populations has been studied only sporadically. Recently, the IgG antibody prevalences of C pneumoniae in healthy adult populations has been reported for the period 1963-1989. It was shown to be 40-52% in US, Finland and Japan and 60% in Panama. 210 " Antibody prevalence has been shown to be very low among children under 5 years but it begins to increase at school age reaching the level in the adult population in the late teens.9
At the end of the 1950s, numerous reports of ornithosis outbreaks were published in Scandinavia.12"16 Many showed the rarity of avian contacts in these outbreaks and the name of 'para-ornithosis' was suggested. In Finland, the occurrence of an acute respiratory illness, considered to be ornithosis, was reported between 1958 and I960.17 Contact with birds was reported by only 36% of patients and 46% of those in the neighbourhood also reported similar symptoms. Interhuman transmission, nowadays thought to be typical for Cpneumoniae, was proposed.17 Since then a serological distinction between ornithosis due to C psittaci and infection due to C pneumoniae has been possible using micro-immunofluorescence. Thus it has been demonstrated that some occurrences of ornithosis believed to be caused by C psittaci were in fact C pneumoniae infections.9'18"20 In order to find out whether C pneumoniae was present in Finland in 1958, we examined the IgG antibody prevalence in samples representing the whole rural population of Finland. We examined this series of sera using micro-immunofluorescence, which can differentiate between Cpneumoniae and Cpsittaci antibodies.
* Department of Epidemiology, National Public Health Institute, Elimaenkatu 25, SF-00510 Helsinki, Finland. •* Department of Geography, University of Oulu, Linnanmaa, SF-90570 Oulu, Finland. f Department of Virology, University of Helsinki, Haartmaninkatu 3, SF-00260 Helsinki, Finland.
MATERIALS AND METHODS Study Population The study included the whole population living in rural areas and rural municipalities in Finland in 1958. The 391
Downloaded from http://ije.oxfordjournals.org/ at University of California, San Diego on June 5, 2015
Karvonen M (Department of Epidemiology and Department of Bacteriology, National Public Health Institute, Elimaenkatu 25, SF-00510, Helsinki, Finland), Tuomilehto J, Naukkarinen A and Saikku P. The prevalence and regional distribution of antibodies against Chlamydia pneumoniae (strain TWAR) in Finland in 1958. International Journal of Epidemiology 1992; 21: 391-398. The occurrence of nonavian 'ornithosis' was reported in Scandinavia at the end of the 1950s. In order to find out whether Chlamydia pneumoniae had been present in Finland, we examined the IgG antibody prevalence to C pneumoniae in samples representing the whole rural population of Finland in 1958. The total number of sera studied using micro-immunofluorescence was 2000. Trend-surface analysis was used to examine the regional patterns of antibody prevalence. C pneumoniae antibodies were present throughout the country. The mean antibody prevalence was 56% among adults and 27% among children. Thus the possible role of C pneumoniae in nonavian 'ornithosis' in Finland between 1958 and 1960 cannot be excluded.
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INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
inhabitants of larger towns were excluded. Finland's total population was 4.4 million and that living in rural municipalities 2.8 million. The number of children aged 14 years and under was 1.3 million in the whole of Finland and 900000 in rural municipalities. Of the total population 50% lived in the southern part of the country, in an area covering one-seventh of the whole land area (Figure IB). Rural population density in this area was about 20 inhabitants per km2. In the rest of southern Finland the population density was 10-20 inhabitants per km2. In the northern part of the country it was less than two inhabitants per km2.21'22
FIGURE I Administrative regions (A) (provinces of: Lapland = L, Oulu = O, Vaasa = V, Kuopio = Ku, Turku and Pori = T, Hame = H, Mikkeli = M, Uusimaa = U, and Kymi = Ky) and population density (B) (inhabitants/km2) in Finland in 1958.
Downloaded from http://ije.oxfordjournals.org/ at University of California, San Diego on June 5, 2015
Sample Sera from 8010 people aged 5 years or more living in rural areas of Finland were collected by random sampling in connection with a study on the quality of household water, which was carried out during September and October 1958.23 The number of pupils in the fourth grade of elementary schools was used as
the sampling frame in every rural municipality of Finland. Elementary school districts representing about 1000 individuals of rural population were defined. The sampling point in each district was the home of the pupil whose name was centremost in the alphabetical list of pupils in the fourth grade of the school. A blood specimen was drawn from this child and one of the parents (if the child was a boy, from the mother, and if a girl, from the father). A third sample was drawn from one person about 15-30 years old, who was not a member of the same household, but who was living in the same neighbourhood. Each sample represented 333 rural inhabitants, 8292 subjects altogether. Blood specimens were obtained from 8010 subjects (96.6%). A small majority, (56%) of the sample population were females. The proportion of females in the Finnish rural population at that time was51%.22-24 The sera had been stored in glass tubes with rubber plugs at -20°C since 1958. They were stored in the
CPNEUMONIAE PREVALENCE IN FINLAND IN 1950s
C pneumoniae Antibody Test IgG antibodies against C pneumoniae were determined by micro-immunofluorescence (micro-IF), 6 using the elementary body of strain TW 183 (Washington University Research Foundation, Seattle) as antigen. Antibodies were detected with fluorescein-conjugated anti-human IgG (Kallestad). Diagnosis of a past infection was made when the IgG antibody titres were at least 1:32.6'10'25 Due to their lengthy storage measurement of IgM antibodies in the sera, indicating recent infection, was not possible. The micro-IF assay was blind because it was performed by one person but the sera were collected by another person randomly from different regions. Map Generalization Although administrative division was used for stratification of the sampling areas, it was too broad for data analysis. However, using a municipality as the study unit would have been too detailed and resulted in large random variation, because the country was divided into 482 municipalities in 1958. Smoothed Maps. A choroplethic mapping technique (the name comes from the Greek words, choros meaning place and plethos meaning quantity.26) was used as the method for representing the geographical distribution of the observed C pneumoniae antibody prevalence. Distribution of the sample population and individuals with a positive antibody titre were mapped on a regular grid (each square equal to 1600 km2)
covering the whole study area. The prevalence in each cell of the grid was calculated using spatial averaging, by applying a four-cell local operator. Statistically, the generated value is a four-cell moving average in a 6400 km2 four-cell square.26 Regional Trend. Using the smoothing method and the four-cell moving average will lead to the loss of local detail in the map. The regional trend of antibody prevalence was determined using regionally smoothed maps. This technique begins with a calculation of the measure of centrality for every row and column of the lattice, in this case the arithmetic mean. The map of the regional trend, an 'expected' map, is formed by defining the cell value in a given row and column as the average of the corresponding row and column means. In the generated 'expected' map the average distribution of the antibody prevalence is defined as its expected value, which is statistically the value most likely to occur.26"29 Local Residuals. The loss of local details, in the regionally smoothed 'expected' maps were determined as local residuals, the residual differences between the actual observations and the regional trend (observed minus expected values in each cell of the lattice). The positive residuals, the departure from the broad regional trend of antibody prevalences, were represented on the isoplethic map by connecting the places of equal data value by isolines.26"29 The northernmost part of Lapland (area above broken line in Figures 2B and 3B) has been processed as one unit, since the population density in the area was very low (14 years) from each area. The sera from seven municipalities in the region of Mikkeli and Kuopio and seven municipalities in the province of Lapland were not found. The sample population was divided into two age groups; children (5-14 years) and adults (>14 years) because the original personal identification data was only available for this classification.
393
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INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
TABLE 1 Chlamydia pneumoniae antibody prevalences in Finland in 1958 Children (5-14 years)
Adults ( > 14 years) Province
Uusimaa Turku and Pori Ahvenanmaa Hame Kymi
Mikkeli
Total (average)
No. positive8 (%)
Serum samples (No.)
positive8
118 111 6 83 82 78 122 200 143 57
64(54) 76 (68) • 3 (50) 55(66) 54(66) 38 (49) 63 (52) 110(55) 62 (43) 34(60)
122 115 2 83 78 73 127 200 146 54
28 (23) 38 (33) 0 (0) 34(41) 22 (28) 20 (27) 20(16) 57 (28) 29 (20) 18 (33)
1000
559 (56)
1000
' An IgG antibody titre 1:32 or higher, measured by the micro-lF test, was considered positive.
O
FIGURE 2
BO k m
C pneumoniae antibody prevalence (A) and positive residuals (B) among adults in Finland in 1958.
W
266 (27)
Downloaded from http://ije.oxfordjournals.org/ at University of California, San Diego on June 5, 2015
Kuopio Vaasa Oulu Lapland
No.
Serum samples (No.)
C PNEUMONIAE PREVALENCE IN FINLAND IN 1950s
Children Among children the antibody prevalence ranged from 0 to 56% in the 6400 km2 four-cell squares within the study area (Figure 3A). The map of the actual antibody prevalence did not create such a clear impression of low and high prevalence zones as the map for the adult population did. The high prevalence (49-60%) areas were in the Southwest about 100 kilometres from the coast, and in three separate tracts in northern Finland. However, in the southern part of the country the high-prevalence areas were different from those for the adult population. The lowest antibody prevalence
(
Vol. 21, No. 2 Printed in Great Britain
The Prevalence and Regional Distribution of Antibodies against Chlamydia pneumoniae (Strain TWAR) in Finland in 1958 M KARVONEN,* J TUOMILEHTO.* A NAUKKARINEN** AND P SAIKKUt
A newly discovered human pathogen, recently named Chlamydia pneumoniae (strain TWAR), has been found to be a causative agent in respiratory tract infections, particularly in pneumonia.1'2 Infection due to C pneumoniae is thought to be transmitted directly from person to person without the need for an animal vector, including avian contacts.3"6 C pneumoniae infection spreads slowly and the interval between cases is long.1'2'7-8 In Scandinavia, an epidemic cycle of 6 years has been suggested consisting of about a 2.5-year period of high incidence and a 3-4 year interval.8-9 Until now, the antibody prevalence in healthy populations has been studied only sporadically. Recently, the IgG antibody prevalences of C pneumoniae in healthy adult populations has been reported for the period 1963-1989. It was shown to be 40-52% in US, Finland and Japan and 60% in Panama. 210 " Antibody prevalence has been shown to be very low among children under 5 years but it begins to increase at school age reaching the level in the adult population in the late teens.9
At the end of the 1950s, numerous reports of ornithosis outbreaks were published in Scandinavia.12"16 Many showed the rarity of avian contacts in these outbreaks and the name of 'para-ornithosis' was suggested. In Finland, the occurrence of an acute respiratory illness, considered to be ornithosis, was reported between 1958 and I960.17 Contact with birds was reported by only 36% of patients and 46% of those in the neighbourhood also reported similar symptoms. Interhuman transmission, nowadays thought to be typical for Cpneumoniae, was proposed.17 Since then a serological distinction between ornithosis due to C psittaci and infection due to C pneumoniae has been possible using micro-immunofluorescence. Thus it has been demonstrated that some occurrences of ornithosis believed to be caused by C psittaci were in fact C pneumoniae infections.9'18"20 In order to find out whether C pneumoniae was present in Finland in 1958, we examined the IgG antibody prevalence in samples representing the whole rural population of Finland. We examined this series of sera using micro-immunofluorescence, which can differentiate between Cpneumoniae and Cpsittaci antibodies.
* Department of Epidemiology, National Public Health Institute, Elimaenkatu 25, SF-00510 Helsinki, Finland. •* Department of Geography, University of Oulu, Linnanmaa, SF-90570 Oulu, Finland. f Department of Virology, University of Helsinki, Haartmaninkatu 3, SF-00260 Helsinki, Finland.
MATERIALS AND METHODS Study Population The study included the whole population living in rural areas and rural municipalities in Finland in 1958. The 391
Downloaded from http://ije.oxfordjournals.org/ at University of California, San Diego on June 5, 2015
Karvonen M (Department of Epidemiology and Department of Bacteriology, National Public Health Institute, Elimaenkatu 25, SF-00510, Helsinki, Finland), Tuomilehto J, Naukkarinen A and Saikku P. The prevalence and regional distribution of antibodies against Chlamydia pneumoniae (strain TWAR) in Finland in 1958. International Journal of Epidemiology 1992; 21: 391-398. The occurrence of nonavian 'ornithosis' was reported in Scandinavia at the end of the 1950s. In order to find out whether Chlamydia pneumoniae had been present in Finland, we examined the IgG antibody prevalence to C pneumoniae in samples representing the whole rural population of Finland in 1958. The total number of sera studied using micro-immunofluorescence was 2000. Trend-surface analysis was used to examine the regional patterns of antibody prevalence. C pneumoniae antibodies were present throughout the country. The mean antibody prevalence was 56% among adults and 27% among children. Thus the possible role of C pneumoniae in nonavian 'ornithosis' in Finland between 1958 and 1960 cannot be excluded.
392
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
inhabitants of larger towns were excluded. Finland's total population was 4.4 million and that living in rural municipalities 2.8 million. The number of children aged 14 years and under was 1.3 million in the whole of Finland and 900000 in rural municipalities. Of the total population 50% lived in the southern part of the country, in an area covering one-seventh of the whole land area (Figure IB). Rural population density in this area was about 20 inhabitants per km2. In the rest of southern Finland the population density was 10-20 inhabitants per km2. In the northern part of the country it was less than two inhabitants per km2.21'22
FIGURE I Administrative regions (A) (provinces of: Lapland = L, Oulu = O, Vaasa = V, Kuopio = Ku, Turku and Pori = T, Hame = H, Mikkeli = M, Uusimaa = U, and Kymi = Ky) and population density (B) (inhabitants/km2) in Finland in 1958.
Downloaded from http://ije.oxfordjournals.org/ at University of California, San Diego on June 5, 2015
Sample Sera from 8010 people aged 5 years or more living in rural areas of Finland were collected by random sampling in connection with a study on the quality of household water, which was carried out during September and October 1958.23 The number of pupils in the fourth grade of elementary schools was used as
the sampling frame in every rural municipality of Finland. Elementary school districts representing about 1000 individuals of rural population were defined. The sampling point in each district was the home of the pupil whose name was centremost in the alphabetical list of pupils in the fourth grade of the school. A blood specimen was drawn from this child and one of the parents (if the child was a boy, from the mother, and if a girl, from the father). A third sample was drawn from one person about 15-30 years old, who was not a member of the same household, but who was living in the same neighbourhood. Each sample represented 333 rural inhabitants, 8292 subjects altogether. Blood specimens were obtained from 8010 subjects (96.6%). A small majority, (56%) of the sample population were females. The proportion of females in the Finnish rural population at that time was51%.22-24 The sera had been stored in glass tubes with rubber plugs at -20°C since 1958. They were stored in the
CPNEUMONIAE PREVALENCE IN FINLAND IN 1950s
C pneumoniae Antibody Test IgG antibodies against C pneumoniae were determined by micro-immunofluorescence (micro-IF), 6 using the elementary body of strain TW 183 (Washington University Research Foundation, Seattle) as antigen. Antibodies were detected with fluorescein-conjugated anti-human IgG (Kallestad). Diagnosis of a past infection was made when the IgG antibody titres were at least 1:32.6'10'25 Due to their lengthy storage measurement of IgM antibodies in the sera, indicating recent infection, was not possible. The micro-IF assay was blind because it was performed by one person but the sera were collected by another person randomly from different regions. Map Generalization Although administrative division was used for stratification of the sampling areas, it was too broad for data analysis. However, using a municipality as the study unit would have been too detailed and resulted in large random variation, because the country was divided into 482 municipalities in 1958. Smoothed Maps. A choroplethic mapping technique (the name comes from the Greek words, choros meaning place and plethos meaning quantity.26) was used as the method for representing the geographical distribution of the observed C pneumoniae antibody prevalence. Distribution of the sample population and individuals with a positive antibody titre were mapped on a regular grid (each square equal to 1600 km2)
covering the whole study area. The prevalence in each cell of the grid was calculated using spatial averaging, by applying a four-cell local operator. Statistically, the generated value is a four-cell moving average in a 6400 km2 four-cell square.26 Regional Trend. Using the smoothing method and the four-cell moving average will lead to the loss of local detail in the map. The regional trend of antibody prevalence was determined using regionally smoothed maps. This technique begins with a calculation of the measure of centrality for every row and column of the lattice, in this case the arithmetic mean. The map of the regional trend, an 'expected' map, is formed by defining the cell value in a given row and column as the average of the corresponding row and column means. In the generated 'expected' map the average distribution of the antibody prevalence is defined as its expected value, which is statistically the value most likely to occur.26"29 Local Residuals. The loss of local details, in the regionally smoothed 'expected' maps were determined as local residuals, the residual differences between the actual observations and the regional trend (observed minus expected values in each cell of the lattice). The positive residuals, the departure from the broad regional trend of antibody prevalences, were represented on the isoplethic map by connecting the places of equal data value by isolines.26"29 The northernmost part of Lapland (area above broken line in Figures 2B and 3B) has been processed as one unit, since the population density in the area was very low (14 years) from each area. The sera from seven municipalities in the region of Mikkeli and Kuopio and seven municipalities in the province of Lapland were not found. The sample population was divided into two age groups; children (5-14 years) and adults (>14 years) because the original personal identification data was only available for this classification.
393
394
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
TABLE 1 Chlamydia pneumoniae antibody prevalences in Finland in 1958 Children (5-14 years)
Adults ( > 14 years) Province
Uusimaa Turku and Pori Ahvenanmaa Hame Kymi
Mikkeli
Total (average)
No. positive8 (%)
Serum samples (No.)
positive8
118 111 6 83 82 78 122 200 143 57
64(54) 76 (68) • 3 (50) 55(66) 54(66) 38 (49) 63 (52) 110(55) 62 (43) 34(60)
122 115 2 83 78 73 127 200 146 54
28 (23) 38 (33) 0 (0) 34(41) 22 (28) 20 (27) 20(16) 57 (28) 29 (20) 18 (33)
1000
559 (56)
1000
' An IgG antibody titre 1:32 or higher, measured by the micro-lF test, was considered positive.
O
FIGURE 2
BO k m
C pneumoniae antibody prevalence (A) and positive residuals (B) among adults in Finland in 1958.
W
266 (27)
Downloaded from http://ije.oxfordjournals.org/ at University of California, San Diego on June 5, 2015
Kuopio Vaasa Oulu Lapland
No.
Serum samples (No.)
C PNEUMONIAE PREVALENCE IN FINLAND IN 1950s
Children Among children the antibody prevalence ranged from 0 to 56% in the 6400 km2 four-cell squares within the study area (Figure 3A). The map of the actual antibody prevalence did not create such a clear impression of low and high prevalence zones as the map for the adult population did. The high prevalence (49-60%) areas were in the Southwest about 100 kilometres from the coast, and in three separate tracts in northern Finland. However, in the southern part of the country the high-prevalence areas were different from those for the adult population. The lowest antibody prevalence
(
