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A 13-year Study of Japanese Cedar Pollinosis in Japanese Schoolchildren
Allergology International. 2008;57:175-180 DOI: 10.2332! allergolint.O-07-513
ORIGINAL ARTICLE
A 13-year Study of Japanese Cedar Pollinosis in Japanese Schoolchildren Kotaro Ozasa1, Takemitsu Hama2, Kenji Dejima3, Yoshiyuki Watanabe1, Sawako Hyo4, Tetsuya Terada4, Natsuko Araki4 and Hiroshi Takenaka4 ABSTRACT Background: Japanese cedar pollen (JCP) sensitization and Japanese cedar pollinosis (JCPS) appear to be increasingly prevalent in younger children. The present study investigated factors affecting JCP sensitization and JCPS development in school children. Methods: In May or June each year from 1994 to 2006, 275―510 children were assessed for serum JCP-IgE and house dust mite (HDM)-IgE levels, and surveyed regarding rhinoconjunctival symptoms. Results: Strong JCP sensitization (IgE " 17.5 UA!ml ) was associated with age (odds ratio (OR) = 2.65), the amount of dispersed pollen in the observed year (OR = 2.03) and in the year following birth (OR = 1.51), the month of birth (OR = 2.18), and the recent birth cohort (OR = 1.96). Symptoms were negatively correlated with the recent birth cohort (OR = 0.69) after adjusting for JCP-IgE levels. Strong HDM sensitization was associated with gender (OR = 0.65 for girls) and the recent birth cohort (OR = 1.76). Conclusions: JCP sensitization appeared to be associated with the recent birth cohort and to increases in dispersed pollen just after birth and in the observed season. Although the recent birth cohort was more easily sensitized, they were not more likely to develop symptoms. In contrast to JCP sensitization, strong HDM sensitization appeared to develop prior to commencement of primary school and was more likely to affect boys.
KEY WORDS allergy, epidemiology, IgE, Japanese cedar pollinosis, month of birth
INTRODUCTION Japanese cedar pollinosis (JCPS) is a common type of allergic rhinoconjunctivitis in Japan during spring. The prevalence of JCPS has increased over recent decades, and it is estimated to affect 10―30% of various populations.1 JCPS is more common in adolescents and adults in their forties than in the elderly population.1-3 The prevalence of JCPS is linked to the amount of dispersed pollen in the areas and seasons. The amount of dispersed Japanese cedar pollen (JCP) has increased in Japan since the 1980s.1 In addition, other environmental factors that may affect allergic sensitization have changed in Japan in recent decades.1-8 This combination of conditions may cause a cohort effect in younger generations in terms of allergic sensitization to JCP and development of JCPS. The present study involved a 13-year observation of 1Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, 2Department of Otorhinolaryngology―Head and Neck Surgery, Kyoto Prefectural University of Medicine, 3Kyoto Second Red Cross Hospital, Kyoto and 4Department of Otorhinopharyngolaryngology, Osaka Medical College, Osaka, Japan. Correspondence: Kotaro Ozasa, MD, Department of Epidemiology
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schoolchildren in order to identify factors affecting sensitization to JCP and development of JCPS.
METHODS The study examined children from primary and junior-high schools in a rural town in the southern Kyoto Prefecture of Japan. Most children in the town attended the schools. Study samples comprised 275― 510 children who underwent serum antibody concentration analysis and completed a questionnaire survey from 1994―2006. The participation rate was 79.0― 87.0% for primary and junior-high school children from 1995―2006, and 98.0% for primary school children in 1994. There were a total of 5069 observations taken from a total of 1094 children during the study period. Serum levels of antigen-specific IgE antibodies against Japanese cedar pollen (JCP-IgE) and house dust mite (HDM-IgE) were measured in May for Community Health and Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602−8566, Japan. Email: [email protected]−m.ac.jp Received 3 September 2007. Accepted for publication 22 November 2007. !2008 Japanese Society of Allergology
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Ozasa K et al. or June every year using the Pharmacia CAP System at SRL Inc. (Japan) during 1994―2001, and at the Osaka Medical College during 2002―2006. Both measurements were conducted under standard quality control conditions. Parents of the children were asked about their children’s health conditions and environments using a self-administered questionnaire which asked: “Did you have any of the following symptoms this March or April?” The symptoms listed were sneezing, nasal discharge, nasal obstruction, itching of nasal mucosa, itching of conjunctiva, watering eyes, and eye irritation. Subjects were also asked whether symptoms lasted 3 weeks or longer. For analysis, symptoms had to last for longer than 3 weeks in March or April of the surveyed year before they were classified as “symptoms of JCPS”. Subjects positive for JCP-IgE ml ) and with JCPS symptoms were (i.e., "0.70 UA! diagnosed as having JCPS. The 1994 responses were not used in the present analysis as the questions about symptoms were asked in a different fashion. The amount of pollen in the town air was determined using the Durham method9 in 1994―2006. A Vaseline-coated glass slide was left outside for 24 hours using a Durham sampler, and the number of naturally fallen pollen grains were collected and counted. These data were expressed as the number of pollen grains per square centimeter of glass (grains! cm2). The amount of JCP in the surveyed year was shown as the sum of the numbers from February 1 to April 30. This analysis showed that the town air pollen counts ranged from 165―8369 grains! cm2 during the study period, and the median, oneand two-third points were 1796, 1258 and 4733 grains! cm2, respectively. Such dispersed pollen counts have also been taken at the Kyoto Prefectural University of Medicine in Kyoto City by the Department of Otorhinopharyngolaryngology since 1982. The university is approximately 25 km from the town. The university air pollen counts ranged from 148― 8798 grains! cm2, and the index was 1310, 695 and 1665 grains! cm2, respectively. Spearman’s correlation coefficient between town and university measurements from 1994―2006 was 0.95, p < 0.01. The relationship between the dispersed pollen count and prevalence of sensitization to JCP-IgE and JCPS was examined using the Cochrane-Armitage test. The influence of sex, age, amount of dispersed pollen in an observation year, the amount of dispersed pollen just after birth, the birth year, and the month of birth was evaluated using logistic regression. The odds ratios (ORs) for sensitization to JCP-IgE were ml (CAP scores 2―3) or " determined (0.70―17.4 UA! ml (CAP scores 4+) relative to 0). To evalu17.5 UA! ate the effect of JCP exposure just after birth, children born in May or later were analyzed in terms of the amount of dispersed pollen in the following season. The amounts of dispersed pollen in the observed
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year, in the year following birth, and the year of birth were used as tertiles in the analysis. The subjects’ parents were informed of the purpose of the survey and blood examination, and their written consent was obtained. Individual laboratory results and advise on their health was given to the subjects after the blood examination every year. Data were anonymously processed in the analysis. These procedures were in accordance with the principles embodied in the Declaration of Helsinki of 1995. This study was approved by the Ethical Board of Kyoto Prefectural University of Medicine every year from 2002.
RESULTS The JCPS prevalence rates ranged from 12.7―23.6% during the observation period (Fig. 1). Prevalence ml ) were rates for JCP-IgE-positivity (i.e., "0.70 UA! 39.0―56.8%, excluding 1994 (pollen count of 165 grains! cm2) in which year junior-high school children were not examined. In addition, 11.4―29.5% of subjects were found to have serum JCP-IgE concenml (i.e., highly sensitized). All of trations "17.5 UA! these prevalence rates were found to be associated with the amount of JCP in the air in the observed season (p < 0.001). The association between JCP sensitization and pollen count in the season following birth is shown in Figure 2. Although sensitization to JCP (both >0.70 ml ) was associated with the pollen and 17.5 UA! count (p < 0.01), the prevalence of JCPS was not (p = 0.84). The month of birth corresponded to the period of JCP exposure after birth. A lower prevalence of sensitization and pollinosis was observed in children born in summer, which is after the pollen dispersion season. In contrast, a higher prevalence was observed in those born in winter who were exposed to pollen dispersion just after birth (Fig. 3). Demographic and environmental factors were mutually analyzed (Table 1). Sex, age, the amount of dispersed pollen in the observed year, the amount of dispersed pollen in the year following birth, and the year and month of birth were found to be independent factors for strong sensitization (i.e., JCP-IgE >17.5 UA! ml). That is, strong sensitization was linked to male children, older children, when there was a large amount of dispersed pollen in the observed year and in the year following birth, recent birth cohorts, and children born between autumn and winter. Moderate ml JCP-IgE) was found sensitization (0.70―17.5 UA! to be associated with a large amount of dispersed pollen in the observed year and birth in November to January. The effect of age, amount of dispersed pollen in the observed year and in the year following birth, and the recentness of birth cohorts appeared to be dose-dependent. Older children, a large amount of dispersed pollen in the observed year and in the year following birth,
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Cedar Pollinosis in Schoolchildren
70 60
Prevalence (%)
50 40 30 20 10 0 100
1,000
10,000
Count of dispersed pollen (/cm2), total of February to April JCP-IgE >= 0.70 UA/ml
Japanese cedar pollinosis
JCP-IgE >= 17.5 UA/ml Fi g.1 Theef f ectoft heamountofdi s per s edpol l eni nt heobs er v at i ons eas onon Japanese cedarpol l en sensi t i z at i on and J apanes ec edarpol l i nos i spr ev al enc e. Fr om Febr uar yt oApr i l 30,Vas el i nec oat edgl as ss l i deswer epl ac edout s i def or24hourper i odsusi ngaDur ham s ampl er .Thex ax i ss howst henumberofpol l en gr ai nspersquar ecent i met erofgl as ss l i de. . 70UA/ mlpr ev al enc er at e;▲＝ t heJ CPI gE＞ 7. 5UA/ ml ●＝ t heJCPI gE＞ ＿0 ＿1 ( hi ghl ysensi t i zed)pr eval encer at e;○＝ J apanes ec edarpol l i nos i s .Ther anges show 95% conf i dencei nt er val s( onl yones i dei ss hownt oav oi dc onf us i onf ort he l at t ert womeasur ement s) .
and birth in November to January were linked to the development of JCPS symptoms. When adjusted for JCP-IgE levels, the recent birth cohort showed a decreased risk of developing symptoms, and the effect of other factors diminished. Male children and a recent birth cohort were both associated with strong sensitization to HDM (HDMml), while sex, age, and a large JCP disIgE >17.5 UA! persion were associated with moderate sensitization ml HDM-IgE). (0.70―17.4 UA!
DISCUSSION The increase in JCP in Japan since the 1980s is believed to result from the maturation of cedar forests planted after World War II.3 The prevalence of JCPS depends on the amount of dispersed pollen in an observed area and the season. The prevalence rates in various districts of Japan in 2001 correlated well with the pollen counts for the districts.3 Annual differences in the pollen count affect the prevalence, and a correlation between pollen count and prevalence was observed in the present study area.7 It has been suggested that a number of other environmental factors which have changed in Japan over recent decades may have also contributed to enhance
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allergic sensitization, such as air pollution (especially diesel exhaust particles), urbanization or Western lifestyles, exposure to allergens just after birth, and less exposure to a microbial environment (the hygiene hypothesis).1-8 Exposure to allergens just after birth was presented as month of birth and amount of dispersed pollen in the next season from birth. The effect of exposure in early life on sensitization to aeroallergens was reported for some pollen in Western countries4,10-12 and also for Japanese cedar pollen in Japan.5,6 There seemed to be a cohort effect such that younger generations have a high prevalence of pollinosis, which may derive from a combination of the factors above. Such a theory is supported by findings showing pollinosis is more common in the age range from adolescents to adults in their forties than in the elderly population.1,3 The present multivariate analysis showed that the calendar year of birth was an independent factor for JCP sensitization, especially strong sensitization. These data suggest that the calendar year may indicate factors other than JCP exposure in an observation year or just after birth, such as changes in lifestyle or other environmental factors. It is not likely that the association is due to changes in air pollution
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Ozasa K et al.
70
Prevalence (%)
60 50 40 30 20 10 0 100
1,000
10,000
Count of dispersed pollen (/cm2), total of February to April, in the next season from birth JCP-IgE >= 0.70 UA/ml
Japanese cedar pollinosis
JCP-IgE >= 17.5 UA/ml Fi g. 2 Theef f ectoft heamountofdi s per s edpol l eni nt hes eas onf ol l owi ngbi r t h onJapanesecedarpol l ensens i t i z at i onandJ apanes ec edarpol l i nos i spr ev al enc e. SeeFi gur e1f orexpl anat i onsoft hex ax i sands y mbol s .
60
Prevalence (%)
50 40 30 20 10 0 1
2
3
4
5
6
7
8
9
10
11
12
Month of birth JCP-IgE >= 0.70 UA/ml
Japanese cedar pollinosis
JCP-IgE >= 17.5 UA/ml Fi g.3 Theef f ectoft hemont hofbi r t honJ apanes ec edarpol l ens ens i t i z at i on andJapanesecedarpol l i nosi spr ev al enc e. SeeFi gur e1f orexpl anat i onsoft hex ax i sands y mbol s .
as the study area remains rural and mainly agricultural, and the relatively light amount of traffic did not appear to change over the study period. Domestic environments and lifestyles may have changed over the
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study period. Sensitization may increase in houses that are poorly ventilated and warm in winter. However, such domestic environments may have more influence on sensitization to HDM than to JCP.
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Allergology International Vol 57, No2, 2008 www.jsaweb.jp!
Mal e 1. 00 Femal e 0. 94( 0. 82,1. 07) 6t o8 1. 00 9t o11 1. 31( 1. 10,1. 56) 12t o14 1. 65( 1. 36,1. 99) ＜1258§ 1. 00 1258t o4732 1. 01( 0. 85,1. 20) ＞ 733 1. 37( 1. 15,1. 64) ＿4 ＜695§ 1. 00 695t o1664 1. 10( 0. 93,1. 30) ＞ 665 0. 94( 0. 78,1. 12) ＿1 ＜1987§ 1. 00 1987t o1990 0. 88( 0. 73,1. 07) ＞ 991 0. 95( 0. 78,1. 16) ＿1 Mayt oJ ul y 1. 00 Augustt oOc t ober 1. 03( 0. 85,1. 25) Nov embert oJ anuar y1. 21( 1. 00,1. 45) Febr uar yt oApr i l 1. 10( 0. 83,1. 24)
‡
† OR( 95%CI )
1. 00 0. 83( 0. 71,0. 98) 1. 00 1. 80( 1. 46,2. 22) 2. 65( 2. 12,3. 32) 1. 00 1. 53( 1. 25,1. 87) 2. 03( 1. 64,2. 52) 1. 00 1. 42( 1. 16,1. 73) 1. 51( 1. 22,1. 87) 1. 00 1. 30( 1. 03,1. 64) 1. 96( 1. 55,2. 46) 1. 00 1. 46( 1. 16,1. 85) 2. 18( 1. 74,2. 73) 1. 43( 1. 11,1. 83)
ORsand95%CI swer emul t i v ar i at el yc al c ul at ed. Countofpol l enonac m2ofgl as s ,s ummedf r om Febr uar y1t oApr i l30. § Ter t i l eofobs er v at i ons .
†
Mont hofbi r t h
Yearofbi r t h
Numberofdi s per s ed pol l en i n t he nex t y earofbi r t h‡
Numberofdi s per s ed pol l eni nt heobsev ed ‡ year
Age
Sex
† OR( 95%CI )
Sens i t i z at i ont oJ apanes ec edar pol l en ( 0. 70t o17. 4UA/ ml ) ( ＞ 7. 5UA/ ml ) ＿1 1. 00 0. 87( 0. 74,1. 02) 1. 00 1. 24( 1. 00,1. 52) 1. 33( 1. 07,1. 66) 1. 00 1. 23( 1. 01,1. 50) 1. 51( 1. 23,1. 87) 1. 00 1. 22( 1. 01,1. 48) 1. 27( 1. 03,1. 57) 1. 00 0. 86( 0. 68,1. 07) 0. 97( 0. 77,1. 22) 1. 00 1. 19( 0. 95,1. 48) 1. 24( 1. 00,1. 55) 1. 14( 0. 90,1. 45)
† OR( 95%CI )
1. 00 0. 91( 0. 75,1. 09) 1. 00 0. 95( 0. 74,1. 22) 0. 86( 0. 65,1. 12) 1. 00 1. 01( 0. 79,1. 27) 1. 05( 0. 82,1. 36) 1. 00 1. 06( 0. 85,1. 33) 0. 95( 0. 73,1. 22) 1. 00 0. 69( 0. 53,0. 91) 0. 69( 0. 52,0. 91) 1. 00 1. 01( 0. 78,1. 31) 0. 79( 0. 61,1. 03) 0. 87( 0. 66,1. 16)
† OR( 95%CI )
1. 00 0. 56( 0. 48,0. 66) 1. 00 1. 63( 1. 30,2. 04) 2. 35( 1. 85,2. 98) 1. 00 1. 13( 0. 92,1. 38) 1. 12( 0. 90,1. 40) 1. 00 1. 11( 0. 90,1. 37) 1. 33( 1. 07,1. 65) 1. 00 1. 05( 0. 83,1. 31) 0. 92( 0. 72,1. 17) 1. 00 0. 80( 0. 64,1. 00) 0. 69( 0. 55,0. 86) 0. 71( 0. 55,0. 90)
† OR( 95%CI )
1. 00 0. 65( 0. 56,0. 76) 1. 00 1. 11( 0. 92,1. 33) 1. 16( 0. 95,1. 42) 1. 00 1. 04( 0. 87,1. 25) 1. 08( 0. 89,1. 31) 1. 00 0. 86( 0. 72,1. 03) 1. 03( 0. 85,1. 25) 1. 00 1. 06( 0. 86,1. 32) 1. 76( 1. 43,2. 17) 1. 00 1. 09( 0. 89,1. 34) 1. 02( 0. 83,1. 25) 0. 98( 0. 78,1. 22)
† OR( 95%CI )
Dev el opmentofs y mpt omsofJapanese Sensi t i zat i ont ohousedustmi t e c edarpol l i nos i s ( Adj us t edf orJCPI gE) ( 0. 70t o17. 4UA/ ml ) ( ＞ 7. 5UA/ ml ) ＿1
Tabl e 1 Oddsr at i os( ORs)and95% c onf i denc ei nt er v al s( CI s )ofenv i r onment alanddemogr aphi cf ac t or sf ors ens i t i zat i ont oJapanesecedarpol l enandhousedustmi t e, anddev el opmentofJ apanesec edarpol l i nos i s.
Cedar Pollinosis in Schoolchildren
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Ozasa K et al. The development of JCPS was associated with age, amount of dispersed pollen in the observed year and in the year following birth, and the month of birth. However, all such factors became insignificant after adjusting for JCP-IgE. This finding indicates that the effect of these factors on JCPS development appears to be mediated through JCP sensitization. After adjustment, the recent cohort factor was associated with a decreased risk of JCPS development. These data indicate that subjects born in recent years may be easily sensitized to JCP, but are not more likely to develop JCPS symptoms. Strong HDM sensitization was not associated with pollen dispersion in the observed year, or in the year following birth. This finding appears to indicate the specificity of the associations observed between JCP sensitization and various factors. Strong HDM sensitization appeared to develop before the commencement of primary school since the age at school was not associated with the risk of strong sensitization. Being in a recent cohort was also associated with strong HDM sensitization. Strong HDM sensitization may be associated with changes in the domestic environment. We think that the data indicate that moderate HDM sensitization accelerated as the children became older during school age. While boys were more likely to be sensitized to HDM, there was no difference between sexes in terms of JCP sensitization. From the viewpoint of prevention of sensitization to JCP and development of JCPS, it is difficult to discuss such demographic and environmental factors examined in this study. For example, both month of birth and amount of dispersed pollen in the next season from birth presented the effect of exposure to aeroallergens in early life. Keeping windows and doors closed was reported to considerably reduce the amount of pollen entering a house.2,13 Therefore, sensitization to JCP could be reduced by keeping babies indoors during the JCP-dispersing season at least during days with dense dispersion. However, is it really best for babies to be shut into such a closed room in spring? In conclusion, the data indicate that JCP sensitization is associated with age, the amount of dispersed pollen in the observed year and in the year following birth, and the month of birth. The recent birth cohort had an increased risk of JCP sensitization after adjustment for relevant factors. Although JCPS development was thought to be mediated through JCP sensitization, we found that while subjects in the recent birth cohort were more easily sensitized they were not more likely to develop JCPS symptoms. Strong HDM sensitization appeared to develop prior to commencement of primary school and was more likely to occur in boys than in girls, and these factors distinguished HDM sensitization from JCP sensitization.
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ACKNOWLEDGEMENTS We thank Drs. S. Itakura and K. Ochi, and Drs. T. Kiriyama and M. Yanagisawa (the school doctors), and the nursing teachers of the primary and juniorhigh schools in the town. We also thank Mr. J. Kubo, the chief pharmacist of the town clinic, and the nurses in the relevant clinics for assistance with surveys and measuring pollen dispersal. We are grateful to the Education Board of the town and the school principals for their permission to conduct the surveys. This study was supported in part by a Grant-in-aid for Scientific Research (C) (No.08670448, 11670382, 13670380, 16590510, 18590608) from the Ministry of Education, Science, Culture and Sports of Japan.
REFERENCES 1. Kaneko Y, Motohashi Y, Nakamura H, Endo T, Eboshida A. Increasing prevalence of Japanese cedar pollinosis. Int. Arch. Allergy Immunol. 2005;136:365-371. 2. Okuda M, Shida T. Clinical aspect of Japanese cedar pollinosis. Allergol. Int. 1998;47:1-8. 3. Okuda M. Epidemiology of Japanese cedar pollinosis throughout Japan. Ann. Allergy Asthma Immunol. 2003; 91:288-296. 4. Björkstén B. Risk factors for sensitization and development of allergic diseases. In: Blumental MN, Björkstén B. (eds). Genetics of Allergy and Asthma. New York: Dekker, 1997; 171-195. 5. Ozasa K, Dejima K, Hama T, Watanabe Y, Takenaka H. Exposure to Japanese cedar pollen in early life and subsequent sensitization to Japanese cedar pollen. J. Epidemiol. 2000;10:42-47. 6. Saitoh Y, Dake Y, Shimizu S et al. Month of birth, atopic diseases and atopic sensitization. J. Investig. Allergol. Clin. Immunol. 2001;11:183-187. 7. Ozasa K, Dejima K, Takenaka H. Prevalence of Japanese cedar pollinosis among schoolchildren in Japan. Int. Arch. Allergy Immunol. 2002;128:165-167. 8. Vandenbulcke L, Bachert C, Van Cauwenberge P, Claeys S. The innate immune system and its role in allergic disorders. Int. Arch. Allergy Immunol. 2006;139:159-165. 9. Durham OC. The volumetric incidence of atmospheric allergens. 5. A proposed standard method of gravity sampling, counting, and volumetric interpolation of result. J. Allergy 1946;79:79-86. 10. Wjst M, Dold S, Peitmeir P, Stiepel E, von Mutiuse E. Month of birth and allergic disease at the age of 10. Clin. Exp. Allergy 1992;22:1026-1031. 11. Karachaliou FH, Panagiotopoulou K, Manousakis M, Sinaniotis K, Papageorgiou F. Month of birth, atopic disease, and sensitization to common aeroallergens in Greece. Pediatr. Allergy Immunol. 1995;6:216-219. 12. Graf N, Johansen P, Schindler C et al. Analysis of the relationship between pollinosis and date of birth in Switzerland. Int. Arch. Allergy Immunol. 2007;143:269-275. 13. D’Amato G, Russo M, Liccardi G et al. Comparison between outdoor and indoor airborne allergenic activity. Ann. Allergy Asthma Immnol. 1996;77:147-152.
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ORIGINAL ARTICLE
A 13-year Study of Japanese Cedar Pollinosis in Japanese Schoolchildren Kotaro Ozasa1, Takemitsu Hama2, Kenji Dejima3, Yoshiyuki Watanabe1, Sawako Hyo4, Tetsuya Terada4, Natsuko Araki4 and Hiroshi Takenaka4 ABSTRACT Background: Japanese cedar pollen (JCP) sensitization and Japanese cedar pollinosis (JCPS) appear to be increasingly prevalent in younger children. The present study investigated factors affecting JCP sensitization and JCPS development in school children. Methods: In May or June each year from 1994 to 2006, 275―510 children were assessed for serum JCP-IgE and house dust mite (HDM)-IgE levels, and surveyed regarding rhinoconjunctival symptoms. Results: Strong JCP sensitization (IgE " 17.5 UA!ml ) was associated with age (odds ratio (OR) = 2.65), the amount of dispersed pollen in the observed year (OR = 2.03) and in the year following birth (OR = 1.51), the month of birth (OR = 2.18), and the recent birth cohort (OR = 1.96). Symptoms were negatively correlated with the recent birth cohort (OR = 0.69) after adjusting for JCP-IgE levels. Strong HDM sensitization was associated with gender (OR = 0.65 for girls) and the recent birth cohort (OR = 1.76). Conclusions: JCP sensitization appeared to be associated with the recent birth cohort and to increases in dispersed pollen just after birth and in the observed season. Although the recent birth cohort was more easily sensitized, they were not more likely to develop symptoms. In contrast to JCP sensitization, strong HDM sensitization appeared to develop prior to commencement of primary school and was more likely to affect boys.
KEY WORDS allergy, epidemiology, IgE, Japanese cedar pollinosis, month of birth
INTRODUCTION Japanese cedar pollinosis (JCPS) is a common type of allergic rhinoconjunctivitis in Japan during spring. The prevalence of JCPS has increased over recent decades, and it is estimated to affect 10―30% of various populations.1 JCPS is more common in adolescents and adults in their forties than in the elderly population.1-3 The prevalence of JCPS is linked to the amount of dispersed pollen in the areas and seasons. The amount of dispersed Japanese cedar pollen (JCP) has increased in Japan since the 1980s.1 In addition, other environmental factors that may affect allergic sensitization have changed in Japan in recent decades.1-8 This combination of conditions may cause a cohort effect in younger generations in terms of allergic sensitization to JCP and development of JCPS. The present study involved a 13-year observation of 1Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, 2Department of Otorhinolaryngology―Head and Neck Surgery, Kyoto Prefectural University of Medicine, 3Kyoto Second Red Cross Hospital, Kyoto and 4Department of Otorhinopharyngolaryngology, Osaka Medical College, Osaka, Japan. Correspondence: Kotaro Ozasa, MD, Department of Epidemiology
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schoolchildren in order to identify factors affecting sensitization to JCP and development of JCPS.
METHODS The study examined children from primary and junior-high schools in a rural town in the southern Kyoto Prefecture of Japan. Most children in the town attended the schools. Study samples comprised 275― 510 children who underwent serum antibody concentration analysis and completed a questionnaire survey from 1994―2006. The participation rate was 79.0― 87.0% for primary and junior-high school children from 1995―2006, and 98.0% for primary school children in 1994. There were a total of 5069 observations taken from a total of 1094 children during the study period. Serum levels of antigen-specific IgE antibodies against Japanese cedar pollen (JCP-IgE) and house dust mite (HDM-IgE) were measured in May for Community Health and Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602−8566, Japan. Email: [email protected]−m.ac.jp Received 3 September 2007. Accepted for publication 22 November 2007. !2008 Japanese Society of Allergology
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Ozasa K et al. or June every year using the Pharmacia CAP System at SRL Inc. (Japan) during 1994―2001, and at the Osaka Medical College during 2002―2006. Both measurements were conducted under standard quality control conditions. Parents of the children were asked about their children’s health conditions and environments using a self-administered questionnaire which asked: “Did you have any of the following symptoms this March or April?” The symptoms listed were sneezing, nasal discharge, nasal obstruction, itching of nasal mucosa, itching of conjunctiva, watering eyes, and eye irritation. Subjects were also asked whether symptoms lasted 3 weeks or longer. For analysis, symptoms had to last for longer than 3 weeks in March or April of the surveyed year before they were classified as “symptoms of JCPS”. Subjects positive for JCP-IgE ml ) and with JCPS symptoms were (i.e., "0.70 UA! diagnosed as having JCPS. The 1994 responses were not used in the present analysis as the questions about symptoms were asked in a different fashion. The amount of pollen in the town air was determined using the Durham method9 in 1994―2006. A Vaseline-coated glass slide was left outside for 24 hours using a Durham sampler, and the number of naturally fallen pollen grains were collected and counted. These data were expressed as the number of pollen grains per square centimeter of glass (grains! cm2). The amount of JCP in the surveyed year was shown as the sum of the numbers from February 1 to April 30. This analysis showed that the town air pollen counts ranged from 165―8369 grains! cm2 during the study period, and the median, oneand two-third points were 1796, 1258 and 4733 grains! cm2, respectively. Such dispersed pollen counts have also been taken at the Kyoto Prefectural University of Medicine in Kyoto City by the Department of Otorhinopharyngolaryngology since 1982. The university is approximately 25 km from the town. The university air pollen counts ranged from 148― 8798 grains! cm2, and the index was 1310, 695 and 1665 grains! cm2, respectively. Spearman’s correlation coefficient between town and university measurements from 1994―2006 was 0.95, p < 0.01. The relationship between the dispersed pollen count and prevalence of sensitization to JCP-IgE and JCPS was examined using the Cochrane-Armitage test. The influence of sex, age, amount of dispersed pollen in an observation year, the amount of dispersed pollen just after birth, the birth year, and the month of birth was evaluated using logistic regression. The odds ratios (ORs) for sensitization to JCP-IgE were ml (CAP scores 2―3) or " determined (0.70―17.4 UA! ml (CAP scores 4+) relative to 0). To evalu17.5 UA! ate the effect of JCP exposure just after birth, children born in May or later were analyzed in terms of the amount of dispersed pollen in the following season. The amounts of dispersed pollen in the observed
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year, in the year following birth, and the year of birth were used as tertiles in the analysis. The subjects’ parents were informed of the purpose of the survey and blood examination, and their written consent was obtained. Individual laboratory results and advise on their health was given to the subjects after the blood examination every year. Data were anonymously processed in the analysis. These procedures were in accordance with the principles embodied in the Declaration of Helsinki of 1995. This study was approved by the Ethical Board of Kyoto Prefectural University of Medicine every year from 2002.
RESULTS The JCPS prevalence rates ranged from 12.7―23.6% during the observation period (Fig. 1). Prevalence ml ) were rates for JCP-IgE-positivity (i.e., "0.70 UA! 39.0―56.8%, excluding 1994 (pollen count of 165 grains! cm2) in which year junior-high school children were not examined. In addition, 11.4―29.5% of subjects were found to have serum JCP-IgE concenml (i.e., highly sensitized). All of trations "17.5 UA! these prevalence rates were found to be associated with the amount of JCP in the air in the observed season (p < 0.001). The association between JCP sensitization and pollen count in the season following birth is shown in Figure 2. Although sensitization to JCP (both >0.70 ml ) was associated with the pollen and 17.5 UA! count (p < 0.01), the prevalence of JCPS was not (p = 0.84). The month of birth corresponded to the period of JCP exposure after birth. A lower prevalence of sensitization and pollinosis was observed in children born in summer, which is after the pollen dispersion season. In contrast, a higher prevalence was observed in those born in winter who were exposed to pollen dispersion just after birth (Fig. 3). Demographic and environmental factors were mutually analyzed (Table 1). Sex, age, the amount of dispersed pollen in the observed year, the amount of dispersed pollen in the year following birth, and the year and month of birth were found to be independent factors for strong sensitization (i.e., JCP-IgE >17.5 UA! ml). That is, strong sensitization was linked to male children, older children, when there was a large amount of dispersed pollen in the observed year and in the year following birth, recent birth cohorts, and children born between autumn and winter. Moderate ml JCP-IgE) was found sensitization (0.70―17.5 UA! to be associated with a large amount of dispersed pollen in the observed year and birth in November to January. The effect of age, amount of dispersed pollen in the observed year and in the year following birth, and the recentness of birth cohorts appeared to be dose-dependent. Older children, a large amount of dispersed pollen in the observed year and in the year following birth,
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Cedar Pollinosis in Schoolchildren
70 60
Prevalence (%)
50 40 30 20 10 0 100
1,000
10,000
Count of dispersed pollen (/cm2), total of February to April JCP-IgE >= 0.70 UA/ml
Japanese cedar pollinosis
JCP-IgE >= 17.5 UA/ml Fi g.1 Theef f ectoft heamountofdi s per s edpol l eni nt heobs er v at i ons eas onon Japanese cedarpol l en sensi t i z at i on and J apanes ec edarpol l i nos i spr ev al enc e. Fr om Febr uar yt oApr i l 30,Vas el i nec oat edgl as ss l i deswer epl ac edout s i def or24hourper i odsusi ngaDur ham s ampl er .Thex ax i ss howst henumberofpol l en gr ai nspersquar ecent i met erofgl as ss l i de. . 70UA/ mlpr ev al enc er at e;▲＝ t heJ CPI gE＞ 7. 5UA/ ml ●＝ t heJCPI gE＞ ＿0 ＿1 ( hi ghl ysensi t i zed)pr eval encer at e;○＝ J apanes ec edarpol l i nos i s .Ther anges show 95% conf i dencei nt er val s( onl yones i dei ss hownt oav oi dc onf us i onf ort he l at t ert womeasur ement s) .
and birth in November to January were linked to the development of JCPS symptoms. When adjusted for JCP-IgE levels, the recent birth cohort showed a decreased risk of developing symptoms, and the effect of other factors diminished. Male children and a recent birth cohort were both associated with strong sensitization to HDM (HDMml), while sex, age, and a large JCP disIgE >17.5 UA! persion were associated with moderate sensitization ml HDM-IgE). (0.70―17.4 UA!
DISCUSSION The increase in JCP in Japan since the 1980s is believed to result from the maturation of cedar forests planted after World War II.3 The prevalence of JCPS depends on the amount of dispersed pollen in an observed area and the season. The prevalence rates in various districts of Japan in 2001 correlated well with the pollen counts for the districts.3 Annual differences in the pollen count affect the prevalence, and a correlation between pollen count and prevalence was observed in the present study area.7 It has been suggested that a number of other environmental factors which have changed in Japan over recent decades may have also contributed to enhance
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allergic sensitization, such as air pollution (especially diesel exhaust particles), urbanization or Western lifestyles, exposure to allergens just after birth, and less exposure to a microbial environment (the hygiene hypothesis).1-8 Exposure to allergens just after birth was presented as month of birth and amount of dispersed pollen in the next season from birth. The effect of exposure in early life on sensitization to aeroallergens was reported for some pollen in Western countries4,10-12 and also for Japanese cedar pollen in Japan.5,6 There seemed to be a cohort effect such that younger generations have a high prevalence of pollinosis, which may derive from a combination of the factors above. Such a theory is supported by findings showing pollinosis is more common in the age range from adolescents to adults in their forties than in the elderly population.1,3 The present multivariate analysis showed that the calendar year of birth was an independent factor for JCP sensitization, especially strong sensitization. These data suggest that the calendar year may indicate factors other than JCP exposure in an observation year or just after birth, such as changes in lifestyle or other environmental factors. It is not likely that the association is due to changes in air pollution
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Ozasa K et al.
70
Prevalence (%)
60 50 40 30 20 10 0 100
1,000
10,000
Count of dispersed pollen (/cm2), total of February to April, in the next season from birth JCP-IgE >= 0.70 UA/ml
Japanese cedar pollinosis
JCP-IgE >= 17.5 UA/ml Fi g. 2 Theef f ectoft heamountofdi s per s edpol l eni nt hes eas onf ol l owi ngbi r t h onJapanesecedarpol l ensens i t i z at i onandJ apanes ec edarpol l i nos i spr ev al enc e. SeeFi gur e1f orexpl anat i onsoft hex ax i sands y mbol s .
60
Prevalence (%)
50 40 30 20 10 0 1
2
3
4
5
6
7
8
9
10
11
12
Month of birth JCP-IgE >= 0.70 UA/ml
Japanese cedar pollinosis
JCP-IgE >= 17.5 UA/ml Fi g.3 Theef f ectoft hemont hofbi r t honJ apanes ec edarpol l ens ens i t i z at i on andJapanesecedarpol l i nosi spr ev al enc e. SeeFi gur e1f orexpl anat i onsoft hex ax i sands y mbol s .
as the study area remains rural and mainly agricultural, and the relatively light amount of traffic did not appear to change over the study period. Domestic environments and lifestyles may have changed over the
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study period. Sensitization may increase in houses that are poorly ventilated and warm in winter. However, such domestic environments may have more influence on sensitization to HDM than to JCP.
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Mal e 1. 00 Femal e 0. 94( 0. 82,1. 07) 6t o8 1. 00 9t o11 1. 31( 1. 10,1. 56) 12t o14 1. 65( 1. 36,1. 99) ＜1258§ 1. 00 1258t o4732 1. 01( 0. 85,1. 20) ＞ 733 1. 37( 1. 15,1. 64) ＿4 ＜695§ 1. 00 695t o1664 1. 10( 0. 93,1. 30) ＞ 665 0. 94( 0. 78,1. 12) ＿1 ＜1987§ 1. 00 1987t o1990 0. 88( 0. 73,1. 07) ＞ 991 0. 95( 0. 78,1. 16) ＿1 Mayt oJ ul y 1. 00 Augustt oOc t ober 1. 03( 0. 85,1. 25) Nov embert oJ anuar y1. 21( 1. 00,1. 45) Febr uar yt oApr i l 1. 10( 0. 83,1. 24)
‡
† OR( 95%CI )
1. 00 0. 83( 0. 71,0. 98) 1. 00 1. 80( 1. 46,2. 22) 2. 65( 2. 12,3. 32) 1. 00 1. 53( 1. 25,1. 87) 2. 03( 1. 64,2. 52) 1. 00 1. 42( 1. 16,1. 73) 1. 51( 1. 22,1. 87) 1. 00 1. 30( 1. 03,1. 64) 1. 96( 1. 55,2. 46) 1. 00 1. 46( 1. 16,1. 85) 2. 18( 1. 74,2. 73) 1. 43( 1. 11,1. 83)
ORsand95%CI swer emul t i v ar i at el yc al c ul at ed. Countofpol l enonac m2ofgl as s ,s ummedf r om Febr uar y1t oApr i l30. § Ter t i l eofobs er v at i ons .
†
Mont hofbi r t h
Yearofbi r t h
Numberofdi s per s ed pol l en i n t he nex t y earofbi r t h‡
Numberofdi s per s ed pol l eni nt heobsev ed ‡ year
Age
Sex
† OR( 95%CI )
Sens i t i z at i ont oJ apanes ec edar pol l en ( 0. 70t o17. 4UA/ ml ) ( ＞ 7. 5UA/ ml ) ＿1 1. 00 0. 87( 0. 74,1. 02) 1. 00 1. 24( 1. 00,1. 52) 1. 33( 1. 07,1. 66) 1. 00 1. 23( 1. 01,1. 50) 1. 51( 1. 23,1. 87) 1. 00 1. 22( 1. 01,1. 48) 1. 27( 1. 03,1. 57) 1. 00 0. 86( 0. 68,1. 07) 0. 97( 0. 77,1. 22) 1. 00 1. 19( 0. 95,1. 48) 1. 24( 1. 00,1. 55) 1. 14( 0. 90,1. 45)
† OR( 95%CI )
1. 00 0. 91( 0. 75,1. 09) 1. 00 0. 95( 0. 74,1. 22) 0. 86( 0. 65,1. 12) 1. 00 1. 01( 0. 79,1. 27) 1. 05( 0. 82,1. 36) 1. 00 1. 06( 0. 85,1. 33) 0. 95( 0. 73,1. 22) 1. 00 0. 69( 0. 53,0. 91) 0. 69( 0. 52,0. 91) 1. 00 1. 01( 0. 78,1. 31) 0. 79( 0. 61,1. 03) 0. 87( 0. 66,1. 16)
† OR( 95%CI )
1. 00 0. 56( 0. 48,0. 66) 1. 00 1. 63( 1. 30,2. 04) 2. 35( 1. 85,2. 98) 1. 00 1. 13( 0. 92,1. 38) 1. 12( 0. 90,1. 40) 1. 00 1. 11( 0. 90,1. 37) 1. 33( 1. 07,1. 65) 1. 00 1. 05( 0. 83,1. 31) 0. 92( 0. 72,1. 17) 1. 00 0. 80( 0. 64,1. 00) 0. 69( 0. 55,0. 86) 0. 71( 0. 55,0. 90)
† OR( 95%CI )
1. 00 0. 65( 0. 56,0. 76) 1. 00 1. 11( 0. 92,1. 33) 1. 16( 0. 95,1. 42) 1. 00 1. 04( 0. 87,1. 25) 1. 08( 0. 89,1. 31) 1. 00 0. 86( 0. 72,1. 03) 1. 03( 0. 85,1. 25) 1. 00 1. 06( 0. 86,1. 32) 1. 76( 1. 43,2. 17) 1. 00 1. 09( 0. 89,1. 34) 1. 02( 0. 83,1. 25) 0. 98( 0. 78,1. 22)
† OR( 95%CI )
Dev el opmentofs y mpt omsofJapanese Sensi t i zat i ont ohousedustmi t e c edarpol l i nos i s ( Adj us t edf orJCPI gE) ( 0. 70t o17. 4UA/ ml ) ( ＞ 7. 5UA/ ml ) ＿1
Tabl e 1 Oddsr at i os( ORs)and95% c onf i denc ei nt er v al s( CI s )ofenv i r onment alanddemogr aphi cf ac t or sf ors ens i t i zat i ont oJapanesecedarpol l enandhousedustmi t e, anddev el opmentofJ apanesec edarpol l i nos i s.
Cedar Pollinosis in Schoolchildren
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Ozasa K et al. The development of JCPS was associated with age, amount of dispersed pollen in the observed year and in the year following birth, and the month of birth. However, all such factors became insignificant after adjusting for JCP-IgE. This finding indicates that the effect of these factors on JCPS development appears to be mediated through JCP sensitization. After adjustment, the recent cohort factor was associated with a decreased risk of JCPS development. These data indicate that subjects born in recent years may be easily sensitized to JCP, but are not more likely to develop JCPS symptoms. Strong HDM sensitization was not associated with pollen dispersion in the observed year, or in the year following birth. This finding appears to indicate the specificity of the associations observed between JCP sensitization and various factors. Strong HDM sensitization appeared to develop before the commencement of primary school since the age at school was not associated with the risk of strong sensitization. Being in a recent cohort was also associated with strong HDM sensitization. Strong HDM sensitization may be associated with changes in the domestic environment. We think that the data indicate that moderate HDM sensitization accelerated as the children became older during school age. While boys were more likely to be sensitized to HDM, there was no difference between sexes in terms of JCP sensitization. From the viewpoint of prevention of sensitization to JCP and development of JCPS, it is difficult to discuss such demographic and environmental factors examined in this study. For example, both month of birth and amount of dispersed pollen in the next season from birth presented the effect of exposure to aeroallergens in early life. Keeping windows and doors closed was reported to considerably reduce the amount of pollen entering a house.2,13 Therefore, sensitization to JCP could be reduced by keeping babies indoors during the JCP-dispersing season at least during days with dense dispersion. However, is it really best for babies to be shut into such a closed room in spring? In conclusion, the data indicate that JCP sensitization is associated with age, the amount of dispersed pollen in the observed year and in the year following birth, and the month of birth. The recent birth cohort had an increased risk of JCP sensitization after adjustment for relevant factors. Although JCPS development was thought to be mediated through JCP sensitization, we found that while subjects in the recent birth cohort were more easily sensitized they were not more likely to develop JCPS symptoms. Strong HDM sensitization appeared to develop prior to commencement of primary school and was more likely to occur in boys than in girls, and these factors distinguished HDM sensitization from JCP sensitization.
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ACKNOWLEDGEMENTS We thank Drs. S. Itakura and K. Ochi, and Drs. T. Kiriyama and M. Yanagisawa (the school doctors), and the nursing teachers of the primary and juniorhigh schools in the town. We also thank Mr. J. Kubo, the chief pharmacist of the town clinic, and the nurses in the relevant clinics for assistance with surveys and measuring pollen dispersal. We are grateful to the Education Board of the town and the school principals for their permission to conduct the surveys. This study was supported in part by a Grant-in-aid for Scientific Research (C) (No.08670448, 11670382, 13670380, 16590510, 18590608) from the Ministry of Education, Science, Culture and Sports of Japan.
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