The burden of allergic asthma in children: a landscape comparison based on data from Lithuanian, Latvian, and Taiwanese populations

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Pediatrics and Neonatology (2012) xx, 1e7

Available online at www.sciencedirect.com

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REVIEW ARTICLE

The Burden of Allergic Asthma in Children:A Landscape Comparison Based on Data fromLithuanian, Latvian, and Taiwanese Populations

Lawrence Shi-Shin Wu a, Tatjana Sjakste b, Raimundas Sakalauskas c,Brigita Sitkauskiene c, Natalia Paramonova b, Edita Gasiuniene c,Ren-Long Jan d,e, Jiu-Yao Wang e,*

a Institute of Medical Science, Tzu-Chi University, Hualian, TaiwanbGenomics and Bioinformatics, Institute of Biology of the University of Latvia, Salspils, LatviacDepartment of Pulmonology and Immunology, Lithuanian University of Health Sciences, Kaunas, LithuaniadDepartment of Pediatrics, Chi-Mei Medical Center, Lioying, Tainan, TaiwaneDivision of Allergy and Clinical Immunology, Department of Pediatrics, National Cheng Kung University Medical Center,Tainan, Taiwan

Received Jul 2, 2012; accepted Jul 2, 2012

Key Wordschildhood asthma;disease burden;prevalence

* Corresponding author. DistinguisheRoad, Tainan 70428, Taiwan.

E-mail address: [email protected]

Please cite this article in press as: WuLithuanian, Latvian, and Taiwanese P

1875-9572/$36 Copyright ª 2012, Taiwhttp://dx.doi.org/10.1016/j.pedneo.2

Asthma is one of the most common chronic respiratory diseases with an increasing prevalenceand financial burden worldwide. This disease affects individuals in all countries and all ethnicgroups; however, prevalence rates of asthma have been reported to vary significantly betweendifferent regions. To understand the origin of asthma and to manage it effectively, it is neces-sary to analyze the genetic and environmental factors that cause these geographic differ-ences. Therefore, we aimed to review published data from the investigations of asthmapatients in Eastern Europe, represented by Latvia and Lithuania, and of patients from EasternAsia represented by Taiwan. We hope that some of the common factors can be identified anddifferent variants can be compared among these three countries for development of a newstrategy to prevent childhood asthma.Copyright ª 2012, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rightsreserved.

d Professor of Pediatrics, College of Medicine, National Cheng Kung University, No. 138, Sheng-Li

du.tw (J.-Y. Wang).

LS-S, et al., The Burden of Allergic Asthma in Children: A Landscape Comparison Based on Data fromopulations, Pediatrics and Neonatology (2012), http://dx.doi.org/10.1016/j.pedneo.2012.08.001

an Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.012.08.001

2 L.S.-S. Wu et al

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1. Introduction

Asthma is one of the most common chronic respiratorydiseases with an increasing prevalence and financial burdenworldwide.1 This disease affects individuals in all countriesand all ethnic groups; however, prevalence rates of asthmahave been reported to vary significantly among differentregions.2 To understand the origin of asthma and to manageit effectively, it is necessary to understand the reasons forthese geographic differences. Therefore, we aimed toreview published data from the investigations of asthmapatients in Eastern Europe, represented by Latvia andLithuania, and of patients from Eastern Asia, representedby Taiwan.

2. Prevalence

A number of epidemiologic studies have been performed tocompare the burden of asthma, and these studies havereported striking differences in asthma prevalencebetween countries. Without doubt, ethnicity plays a role.The US Census Bureau, Population Estimates and Interna-tional Data Base, 2004 estimates that globally 373,847,408people suffer from asthma,3,4 and this number has beenrising notably during the past decades. The followingextrapolations are automated calculations and do not takeinto account any genetic, cultural, environmental, social,and racial or other differences across the various countriesand regions from which they are extrapolated (Table 1).These extrapolations may be highly inaccurate (especiallyfor developing or Third World countries) and only givea general indication as to the actual prevalence or inci-dence of asthma.

It has been shown that 5-15% European citizens areasthmatic. When assessing asthma prevalence in thedifferent European regions, it is evident that numbers arehigher in Northern Europe. However, in the Asia-Pacificregion, asthma prevalence is generally lower than that re-ported in Western countries as revealed by the recentfindings of the International Study of Asthma and Allergiesin Childhood (ISAAC). The key findings of the ISAAC includedthe high prevalence of reported asthma symptoms inEnglish-language countries, the high symptom prevalencein Latin America, the relatively high prevalence in WesternEurope, but much lower prevalence in Eastern Europe witha clear Northwest-Southeast gradient, and the relatively

Table 1 Prevalence of asthma in Lithuanian, Latvian and TaiwCensus Bureau, International Data Base, 2004.3,4

Country Taiwan

Population (2011) 22,749,838Density 642/km2 Z 1,664/sq miArea 36,193 km2 Z 13,974 sq miWater area % 10.34%GDP (nominal) total (2009) $466.8 billionGDP (nominal) per capita (2010) $20,100% of asthmatics 6.4%

GDP Z gross domestic product.

Please cite this article in press as: Wu LS-S, et al., The Burden of AllergLithuanian, Latvian, and Taiwanese Populations, Pediatrics and Neona

low prevalence in Africa and Asia.5 However, the ISAACphase III surprisingly showed a decrease in prevalence ofasthma symptoms in English-speaking countries andWestern Europe and an increase in prevalence in regionswhere prevalence had previously been low.6 In fact, it hasalso been observed that asthma prevalence has increased inWestern counties such as the United Kingdom, Australia,and New Zealand, but not in Eastern Europe, India, China,or Africa.7 Some studies, however, have revealed a levelingtrend,8,9 whereas others have reported a decliningprevalence.10,11

In Taiwan, according to Hsieh and Shen,12 the preva-lence of childhood asthma in Taipei, Taiwan was 1.3% in1974 and 5.0% in 1985. Using the ISAAC questionnaire in1994 and 2002 in 6- to 7-year-old schoolchildren in the sameplace, an increasing trend was observed for asthma prev-alence in 1994, but a leveling trend was detected for theperiod between 1994 and 2002.5,13 However, a phase IIIstudy conducted by Yan et al 14 in 2002 in 13- to 14-year-oldschoolchildren in Taipei showed an increasing prevalence ofsymptoms of asthma, allergic rhinitis, and atopic eczema.Recently, Wu et al15 showed that, from a total population of24,999 first-grade students from 153 elementary schools inTaipei who completed the questionnaire, the proportion ofchildren who have experienced wheezing and nocturnalcough in the past 12 months was significantly increased in2007 compared with results for 1994 and 2002. In contrast,no significant differences were detected in the prevalenceof current wheeze or physician-diagnosed asthma. Theprevalence of severe wheezing symptoms in the past 12months (four or more attacks of wheezing, � 1 night ofsleep disturbance due to wheezing per week, wheezing thatlimits speech, and exercise-induced wheezing) alsodecreased significantly. Alarmingly, the prevalence andseverity of rhinitis symptoms increased significantly duringthe 13-year period that was analyzed. The prevalence ofeczema symptoms, defined as recurrent itchy rash andtypical atopic eczema distribution in the past 12 months,also increased. The authors noted that increases in theprevalence and severity of allergic rhinitis and atopiceczema but not in asthma are multifactorial and need to beexplored further.

According to a 1998 survey of prevalence of childhoodasthma, rhinitis, and eczema in Scandinavia and EasternEurope in a total of 79,000children fromtwoage groups (13-14years and 6-7 years) using the ISAAC questionnaire, there isevidence that the prevalence of allergies and asthma differs

anese populations; extrapolated statistics, based on the US

Latvia Lithuania

2,306,306 3,607,89936/km2 Z 93/sq mi 52/km2 Z 134/sq mi64,589 km2 Z 24,937 sq mi 65,200 km2 Z 25,173 sq mi1.5% 1.35%$26.2 billion $37.2 billion$14,330 $16,9976.3% 6.4%

ic Asthma in Children: A Landscape Comparison Based on Data fromtology (2012), http://dx.doi.org/10.1016/j.pedneo.2012.08.001

The burden of childhood asthma in Lithuania, Latvia, and Taiwan 3

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between populations in western and eastern Europe.16 Theprevalence ofwheezing among the 13- to 14-year-old childrenwas 11.2-19.7% in Finland and Sweden, 7.6-8.5% in Estonia,Latvia, and Poland, and 2.6-5.9% in Albania, Romania, Russia,Georgia, and Uzbekistan. The prevalence of atopy-relateddisorders was higher in Scandinavia than in Estonia, Latvia,and Poland. This supports the hypothesis that "Western life-style" is associated with a high prevalence of childhoodallergy. According to the Lithuanian Health InformationCentre,17 approximately 15,000 children suffer from asthmain Lithuania, and almost 10% of them experience disability.From 2001 to 2003, the incidence of allergic rhinitis among10- to 14-year-old children has doubled in Lithuania. Kudzyteet al 18 used a Lithuanian version of the ISAAC core question-naire, which was completed by parents randomly selectedfrom Kaunas primary schools. A school-based sample of 1879participants in the 1994-1995 survey (response rate 94.0 %)and 2772 participants in the 2001-2002 survey (response rate92.4%) was included as the study population. When the resultof these two surveys are compared, there are significantincreases in the prevalence of asthma (0.9% vs. 2.6%), allergicrhinitis (1.4% vs. 2.4%), and atopic dermatitis (1.4% vs. 3.5%).There is also a tendency toward an increase in the prevalenceof current symptoms and diagnoses for all three conditions,but this increased prevalence was more pronounced in boys.The comorbidity among these three allergic diseases also rosesignificantly between 1994-1995 and 2001-2002. However,many allergic diseases remain undiagnosed.

2.1. The burden of childhood asthma

Maintenance medications and other therapies allow manypatients to control their asthma, but the cost of treatmentcan be high. In addition, the treatment of acute attacks andcomorbidities of asthma consume considerable medicalresources. As a leading chronic childhood illness in devel-oped countries, asthma places a large burden on affectedchildren and their families. According to Health and VitalStatistics, Taiwan, Republic of China,19 asthma mortality inTaiwan decreased from 8.17 per 100,000 in 1981 to 4.5 in2000, but the mortality rate in Taiwan is still greater thanthat in the United States (1.6 per 100,000).20 Althoughasthma is a major cause of childhood disability21,22 and inrare cases causes premature death, asthma morbidity andmortality are largely preventable if patients and theirfamilies are adequately educated about the disease andhave access to high-quality health care.23,24 Poor outcomesfor childhood asthma, such as hospitalizations and deaths,are at least partially sensitive to the quality of ambulatoryhealth care.25 Thus, it is important to monitor trends inasthma prevalence, health care utilization, and mortalitysimultaneously to estimate the burden of disease and tohelp assess the effect of asthma prevention programs andchanges in health care quality.

2.2. Health care utilization and medical costs ofchildhood asthma in Taiwan and Latvia

From 1985 to 1994, the estimated total cost of illness forpediatric (patients younger than 17 years) asthma in UnitedStates increased from $2.25 billion (in 1994 dollars) to $3.17

Please cite this article in press as: Wu LS-S, et al., The Burden of AllergiLithuanian, Latvian, and Taiwanese Populations, Pediatrics and Neona

billion despite a 15.5% decrease in the cost of care perchild.26 There are two types of costs contributing to thetotal cost of an illness–direct and indirect. Direct costsinclude both medical and nonmedical expenses associatedwith the disease. Medical direct costs include thoseexpenses generated in disease prevention, treatment, andrehabilitation. Nonmedical direct costs include trans-portation to and from the health care provider andpurchase of home health care. Indirect costs include daysmissed from work, school days lost (caretaker needs tosuspend usual daily activities to care for the child), andloss of future potential earnings as a result of prematuredeath.27 To investigate total health-care costs for pediatricpatients with asthma in Taiwan, Sun et al 27 enrolled data of33,461 patients age 3-17 years in the Taiwan NationalHealth Insurance Research Database (NHIRD) from January1 to December 31, 2002. Healthcare utilization and costs,including those related to office, outpatient hospital,emergency department, and inpatient hospital visits, werecompared between pediatric patients with and withoutasthma. Their findings revealed that, in 2002, the periodprevalence of treated asthma was 6.0%. Pediatric patientswith asthma used substantially more health services thandid those without asthma in all categories. Hospitaloutpatient visits and overall healthcare expenditure forpatients with asthma were 2.2-fold higher than those ofpatients without asthma. Almost three-fourths of allasthma-related costs were attributable to office andhospital outpatient visits; one-fourth was attributable tourgent care and hospitalizations. In detail, total directmedical expenditure is approximately $NTD (New Taiwandollar) NT$ 275 million (approximately $8.3 million USdollars) per year in this 1% (33,461) sample of generalpopulation enrollees age 3-17 years in Taiwan. Asthma careaccounted for 20-25% of all services that patients withasthma received. Therefore, patients with asthma incurredcosts of approximately NT$ 7.1 billion ($215 million in USdollars). In 2002, the exchange rate was NT$ 33.1 to $1.00in US dollars. The cost observed ($83.00 per asthmaticchildren per year) was far lower than reported in othernational surveys from Thailand ($216.00 in the year 2007),28

Singapore ($238.00 in the year 1999),29 and the USA($333.00 in the year 1994).30 The difference may have re-flected our provider payments (approximately $10.00 percase), patient copayments (approximately $ 3.00-$8.00 pervisit), and laboratory and radiology fees, which are lowerthan those of other countries. Despite the standards ofasthma control that international guidelines recommendshould be achieved,31 many patients continue to suffersuboptimal control of symptoms and experience exacer-bations (acute asthma attacks). In addition to being asso-ciated with reduced quality of life, asthma exacerbationsare a key cost driver in asthma management. However,asthma care still imposes a large economic burden onpatients’ families in Taiwan. In another study, Sun andLue32 evaluated 95,110 patients age 18-55 years who wereenrolled in the National Health Insurance Research Data-base in the same year of 2002, and they found that themean costs of hospitalization for patients with asthma were2.7-fold higher than for patients without asthma, and thatalmost one-half of all asthma-related costs were attribut-able to hospitalization.

c Asthma in Children: A Landscape Comparison Based on Data fromtology (2012), http://dx.doi.org/10.1016/j.pedneo.2012.08.001

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The same situation with asthma care and managementexists in European countries. A prospective study, con-ducted in 15 countries across Europe, including Latvia,assessed the local cost of asthma exacerbations managed ineither primary or secondary care.33 Multiple regressionanalysis of the asthma exacerbations showed that the costof exacerbations was significantly affected by country, caretype, and age. The results showed that asthma exacerba-tions are costly to manage, particularly in secondary care,suggesting that therapies able to reduce the frequency orseverity of exacerbations may bring economic benefits, aswell as improved quality of life.

2.3. The environmental factors for childhoodallergic asthma in Latvia, Lithuania, and Taiwan

From the ecologic point of view, the contrast betweenTaiwan and two Baltic countries is great, despite similarsized geographic areas (30,000 to 60,000 km2) (Table 1).Taiwan lies in the temperate zone of the tropic of Cancer,and its climate is marine tropical. The entire island experi-ences hot, humid weather from June through September.The northern part of the island has a rainy season that lastsfrom January through late March during the northeastmonsoon, and it experiences “meiyu” (seasonal rains) inMay. Themiddle and southern parts of the island do not havean extended monsoon season during the winter months. Incontrast, there is cold and humid weather in the Balticregion, except in summer seasons. Taiwan’s populationdensity is high,more than tenfold that of Latvia or Lithuania.Despite this environmental difference, the prevalence ofindividuals with asthma in the entire population is similar inthese three countries, i.e., approximately 6.4%. The“hygiene hypothesis” has been proposed as one explanationfor the increases in symptom prevalence, although it doesnot appear to explain the previously mentioned asthmaprevalence patterns. Other established asthma risk factors,such as exposure to airborne or industrial pollutants anddietary factors, may influence these discrepancies in theprevalence of asthma in different countries. Scientistsbelieve that rural environments are strongly protectiveagainst the disease, and increasing urbanization may becontributing to the rise in the numbers affected. A consis-tent body of literature shows that the Westernized lifestyle,increasing urbanization, and exposure to allergens may becontributing to the rise in the numbers affected.

A recent survey34 used an ISAAC questionnaire anddetecting of serum specific-immunoglobulin E (IgE) tocommon allergens in a total of 142 primary school children ofTaipei City, which included 25,094 students age 7-8 years. Theresults showed that a total of 1500 students (5.98%) hadconfirmed sensitivities to allergens. Dust mite sensitivityamong these children was almost 90%. The prevalence ofsensitivities to Dermatophagoides pteronyssinus (Der p),Dermatophagoides farinae (Der f), and Blomia tropicalis (Blot) were 90.79%, 88.24%, and 84.63%, respectively. Dog dander(29.95%)was the secondmost commonaeroallergen to inducesensitivity. Allergies to cat dander (8.69%) and to cockroach(15.48%) had decreased dramatically compared with previousanalyses.35 Among the food allergens studied, the mostcommonallergens that induced sensitizationwere (in order of

Please cite this article in press as: Wu LS-S, et al., The Burden of AllergLithuanian, Latvian, and Taiwanese Populations, Pediatrics and Neona

prevalence) crab, milk, egg white, and shrimp (88.08%,22.45%, 24.23%, and 21.44%, respectively). Mold and pollensensitization was identified in fewer than 2% of the school-children. Although new technology, using microfluidiccartridge immunoassay for in vitro IgE detection has beendeveloped for rapid and acute allergy diagnosis,36 clinicalinformation is essential for final confirmation of the sensiti-zation and allergy to certain allergens, particularly in foodallergy disorder. Wu et al37 conducted a nationwidequestionnaire-based survey on the prevalence of food allergyin Taiwan. A total of 30,018 individuals who met the inclusioncriteria were evaluated, and 6.95% were identified as victimsof food allergies. The prevalence was 3.44% in childrenyounger than 3 years, 7.65% in children age 4-18 years, and6.40% in adults, respectively. Approximately 77.33% of thefood allergy population had experienced recurrent allergicattacks. Systemic reactions occurred in approximately 4.89%of the food allergies group. Themost commonly reported foodallergen in Taiwan is seafood, including shrimp, crab, fish, andmollusk. Inaddition,mango,milk,peanuts, andeggswerealsoimportant food allergens in the general population, whereasmilk, shellfish, peanuts, and eggs were common allergens inchildren. The predisposing factors for the prevalence ofallergic diseases and allergic sensitization in Taiwanese chil-dren were investigated by Yao and the Prediction of Allergiesin Taiwanese Children (PATCH) study group.38 Their multi-variate analyses revealed that younger age, male sex, andobesity were significantly and independently associated withcurrent wheezing in children (all p < 0.01). The burden andcomorbidity of childhood allergies are substantial. There arestriking age-dependent sex differences in asthmaprevalence,exhibiting an inverted U-shaped curve for male-to-femaleprevalence ratios by age. Obesity is associated witha greater prevalenceofasthma inchildrenwithnoevidence ofa significant modulation by either sex or age.

To investigate the effect of prenatal, postnatal, andenvironmental characteristics of food allergen in younginfants among different regions of Europe, the EuroPrevallbirth cohort study, the largest study using gold-standarddiagnostic criteria for food allergy in children worldwide,found that self-reported adverse reactions to food everwere considerably more common in mothers from Germany(30%), Iceland, the United Kingdom, and the Netherlands(all 20e22%) compared with those from Italy (11%),Lithuania, Greece, Poland, and Spain (all 5e8%).39 TheLithuanian birth cohort “Alergemol” (n Z 1558), estab-lished as a part of the multicenter European birth cohort“EuroPrevall”, revealed 1.3% and 2.8% of symptomatic-sensitized patients at 6 and 12 months of age, respec-tively. This study also showed that maternal diet, disease,use of antibiotics, and tobacco smoking during pregnancyhad no significant effect on the early sensitization to foodallergens. However, infants of atopic mothers were signif-icantly more often sensitized to eggs in comparison withinfants of nonatopic mothers.40

2.4. Genetic predisposition of allergic asthma

Any chronic disease is caused by a complex interactionbetween environmental factors and individual genotypes.Asthma is no exception. However, the genetics of asthma

ic Asthma in Children: A Landscape Comparison Based on Data fromtology (2012), http://dx.doi.org/10.1016/j.pedneo.2012.08.001

The burden of childhood asthma in Lithuania, Latvia, and Taiwan 5

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are not well defined with many candidate genes, but nosingle gene or gene family stands out. One-third of patientswho have asthma have a family history of this condition,and a positive family history is one predictor of asthma risk.This is at least in part because family history capturesshared environmental risk factors, such as exposure toallergens and secondhand smoke, but it is also because weare only now beginning to dissect the genomic underpin-nings of the condition. Strong genetic components associ-ated with asthma were supported by family and twinstudies,41,42 and many genes have been identified or sus-pected to be involved in the pathogenesis of asthma.43,44

Although tremendous effort has been expended tolocalize the susceptibility genes in complex genetic disor-ders such as asthma, elucidation of the multigenic nature ofasthma has been greatly hampered by genetic heteroge-neity across populations, variability in disease expression,and uncontrolled environmental influences.45 Moreover,there may be various forms of asthma that involve differentcomponents of genes and environmental interactions.44

Currently more than 100 variants in candidate genes indifferent chromosomes have been reported to be associ-ated with different asthma phenotypes and several de novogenes or previously unidentified genes related to allergy orasthma have been identified using a positional approach.46

During past decades numerous genes have been studiedregarding the allele or haplotype association with asthma indifferent populations. However, the confirmation andreplication results of allergy- or asthma-related genes arestill lacking when compared across different populationsand ethnic backgrounds.

In the study of genetic susceptibility of childhoodasthma in Taiwan, we have conducted the genome-widelinkage disequilibrium screen for loci associated withgenetic difference between allergic and nonallergic asthmausing 763 autosomal short tandem repeat (STR) markers in190 unrelated asthmatic children47 The results showed thatevidence for association with difference between twoforms of asthma was observed in thirty-six STR markers.Twenty-one of these 36 STR markers were found to have atleast one meaningful genotype. Marker-to-marker syner-getic effect and simulation resampling tests revealed D5S2011, D6D1573, and D9S286 were important loci in allergicasthma, whereas D5S674, D6S1574, and D19S226 wereimportant in nonallergic asthma with odds ratios <0.14,and >7.1, respectively. These findings suggested that thereis a different set or sets of susceptible genes betweenallergic and nonallergic asthma in children based on totalserum IgE levels and responsiveness to common aero-allergens. It was also found that genetic susceptibility tochildhood asthma disease in Taiwan was associated withgenetic variant of innate immunity, such as CD14,48,49 andplatelet-derived growth factor receptor-alpha50 thatinteract with common environmental allergens or patho-gens. The polymorphisms of protein tyrosine phosphatereceptor-type delta,51 MD-1 gene,52 interleukin 17A,53 andinterleukin-7 receptor54 are reported to be associated withchildhood asthma in Taiwanese population. In anotherstudy, we also found that ABO/secretor blood group isassociated with childhood asthma.55 These results suggestthat there is some genetic discrepancy in disease suscep-tibility between Chinese and other ethnic populations.

Please cite this article in press as: Wu LS-S, et al., The Burden of AllergiLithuanian, Latvian, and Taiwanese Populations, Pediatrics and Neona

To determine whether this genetic information can haveany predictive value for allergic disorder and asthma, weassessed 13 single-nucleotide polymorphisms (SNPs) inseven well-known asthma susceptibility genes and lookedfor association with pediatric asthma using 449 asthmaticand 512 nonasthmatic patients in the Taiwanese pop-ulation.56 The results showed that CD14-159 C/T and MS4A2Glu237Gly were identified to have differences in genotype/allele frequencies between the control group and asthmapatients. Moreover, the genotype synergistic analysisshowed that the co-contribution of two functional SNPs wasriskier or more protective from asthma attack. Further-more, we also analyzed gene-gene interaction of thosegenes using different methods for developing predictivemodel(s) for asthma in children.57,58

3. Summary

Allergic asthma is one of the most common chronic respi-ratory diseases in childhood with an increasing prevalenceand burden worldwide. This disease affects individuals inall countries and all ethnic groups. It is well recognized thatallergic asthma in childhood is caused by a combination ofgenetic and environmental effects and increasing urbani-zation may be contributing to the rise in the numbersaffected. This theory indicated that the global change ofmodernization, regional development, and racial differ-ence may have strong influence on the rise of the preva-lence of allergic disorder. Hence, the collaboration andcomparison study between the Baltic nations, Latvia andLithuania, and Taiwan on the environmental and genetics ofchildhood asthma will provide a new insight and directionfor the preventive strategy of childhood asthma.

Acknowledgments

The authors wish to thank the data and published reportsprovided by the members of Taiwan Academic of PediatricAllergy, Asthma and Clinical Immunology. Authors receivedthe study grant from Mutual Funds of Taiwan-Latvia-Lithuania Cooperation Project sponsored by NationalScience Council, Taiwan (NSC 100-2923-B-006 -002 -MY3),Republic of China; Ministry of Education and Science, TheRepublic of Lithuania (TAP-100430, financial agreement Nr.TAP-06/2011); and Izglitibas un Zinatnes Ministrija, LatvijasRepublika (IZM financial agreement No 11-13-0501/3).

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