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1 pissn: eissn: (4): , September ORIGINAL ARTICLE 반복되는천명을주소로내원한 3 세미만의환아에서 25-hydroxyvitamin D 의혈청내농도와관련된인자 최은정 1, 박누리 2, 정진아 2, 김대철 3, 안혜성 4, 윤현진 1 1 일신기독병원소아청소년과, 동아대학교의과대학 2 소아과학교실 3 병리학교실, 4 온종합병원소아청소년과 Factors associated with serum vitamin D levels in children with recurrent wheezing less than 3 years old Eun-Jeong Choi 1, Nu-Ry Bag 2, Jin-A Jung 2, Dae-Cheol Kim 3, Hye-Sung Ahn 4, Hyun-Jin Yun 1 1 Department of Pediatrics, Ilsin Christian Hospital, Busan; Departments of 2 Pediatrics and 3 Pathology, Dong-A University College of Medicine, Busan; 4 Department of Pediatrics, On Hospital, Busan, Korea Purpose: We evaluated the relationship between laboratory/clinical factors and vitamin D levels in recurrent wheezers less than 3 years old. Methods: We retrospectively analyzed clinical data and laboratory factors (25-hydroxyvitamin D, complete blood count, C-reactive protein, glutamic oxaloacetic transaminase, glutamyl purovic transaminase, alkaline phosphatase [ALP], eosinophil counts, and serum IgE IgG, IgA, IgM) of 84 children less than 3 years who had experienced wheezing episodes at least 3 times. Results: Children in the normal group (1.4± 0.9 years) were younger than those in the deficient (2.2± 1.2 years) and insuffient (2.3± 1.0 years) groups (P= 0.010). Glutamyl purovic transaminase were higher in the normal group (24.5 ± 19.4 IU/L) than in the deficient (16.0 ± 4.7 IU/L) and insufficient (15.3 ± 4.5 IU/L) groups (P= 0.009). ALP were higher in the deficient (791.4 ± IU/L) and insufficient (770.4 ± IU/L) groups than in the normal group (631.9 ± IU/L, P= 0.034). Total IgE levels were higher in the deficient group (171.9 ± ku/l) than in the normal group (43.7 ± 58.3 ku/l, P< 0.05), and the rate of sensitization to aeroallergens was higher in the insufficient group (36.1%) than in the normal group (10%, P< 0.05). Conclusion: Among children with recurrent wheezing less than 3 years old, low vitamin D levels may be associated with older age, total IgE, ALP level, glutamic pyruvate transaminase level, and rate of sensitization to aeroallergens. ( 2014;2: ) Keywords: Vitamin D, Asthma, Wheezing, Young childhood 서론항구루병인자 (antirachitic factor) 로발견되어칼슘흡수에필수적이며부갑상선호르몬의작용을나타나게하는비타민 D는피부에서합성되는 7-dehydrocholesterol이자외선을받아비타민 D 3 (cholecalciferol) 로변환되며, 간과신장에서수산화 (hydroxylation) 되어최종활성형인 1,25-dihydroxycholecalciferol (1,25[OH] 2D 3, calcitriol) 로전환되는것으로알려져있다. 비타민 D의체내농도를가장잘반영하는형태는대사산물인 25-hydroxyvitamin D (25(OH)D) 로, 그농도는태양광선노출의정도와비타민 D의섭취에의해결정되며, 혈청내농도에영향을주는그밖의인자로는출생계절, 임부의 25(OH)D 섭취량, 체질량지수 (body mass index, BMI), 피부색, 나이및유전적인요인등이있다. 1-3) 비타민 D의주된생리기능인칼슘과인의항상성유지외에도최근에는 Keratinocyte나면역계세포를포함하는거의모든인체조직에서비타민 D 수용체가분포하고 4) 특히 25(OH)D 가염증유발사이토카인 (proinflammatory cytokines), 조절 T 세포 (T regulatory cell), 면역반응등에관여한다는것이알려지면서 5) 25(OH) Correspondence to: Hyun-Jin Yun Department of Pediatrics, Ilsin Christian Hospital, 27Jeonggongdan-ro, Dong-gu, Busan , Korea Tel: , Fax: , jinny198@hanmail.net Received: March 31, 2014 Revised: May 27, 2014 Accepted: July 27, The Korean Academy of Pediatric Allergy and Respiratory Disease The Korean Academy of Asthma, Allergy and Clinical Immunology This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (

2 Choi EJ, et al. Vitamin D in recurrent wheezers D의결핍이알레르기질환에미치는영향에대한관심이증가되었다. 또한제대혈청내 25(OH)D 의농도가소아의천명및호흡기감염과역의상관관계가있다는보고나비타민 D의보충으로천식을비롯한호흡기질환을예방또는호전시킬수있다는연구결과는 25(OH)D 농도가천식의발생및예방에중요한역할을할것을시사한다. 6,7) 3세미만의영유아에서반복되는천명 (wheezing) 은호흡기합포체바이러스 (respiratory syncytial virus), 리노바이러스 (rhinovirus) 등에의한호흡기감염에의해주로발생하며, 8,9) 천명또는소아천식의경과를조사하기위해시행된많은역학연구들은대부분의소아천식환자들이영유아기에이러한바이러스감염과관련된반복되는천명을경험하는것으로보고하였다. 10) 또한최근의연구들은낮은혈중의 25(OH)D 농도가천명의발생과연관이있음을보고한것들이많다. 11,12) 이에본연구자들은반복되는천명을주소로내원한 3세미만의환아에서 25(OH)D 의혈청내농도에따라혈청총 IgE, 특이 IgE, 말초혈액총호산구수등을포함한혈액검사와나이, 성별, 체질량지수등의임상적인자가연관성이있는지를확인하기위해본연구를시행하였다. 대상및방법 1. 연구대상 2011년과 2012년 3월에서 6월사이에동아대학교병원과일신기독병원소아청소년과에반복되는천명으로내원한 3세이하환아들중 25(OH)D 농도를검사한환아 84명을대상으로하여후향적으로의무기록지를조사하였다. 환아들중비타민 D를복용한경우는대상에서제외하였고, 이들중 25(OH)D 농도가 30 ng/ml 이상인경우를정상군 (n= 20), 20 ng/ml 이상 30 ng/ml 미만인경우를부족군 (n= 36), 20 ng/ml 미만인경우를결핍군 (n= 28) 으로분류하였다. 13) 2. 연구방법환아들의나이, 성별, 형제유무, 출생계절, 키, 몸무게, 체질량지수를조사였으며, 혈중 25(OH)D 농도, 백혈구수치및분획, 혈색소, 혈소판수치, C-반응단백 (C-reactive protein, CRP), 아스파라긴아미노트란스페라제 (glutamic oxalacetic transaminase, GOT), 알라닌아미노트란스페라제 (glutamic pyruvate transaminase, GPT), 알칼리성인산분해효소 (alkaline phosphatase, ALP), 총호산구수, 혈청총면역글로불린 E (IgE), 면역글로불린 G (IgG), 면역글로불린 A (IgA), 면역글로불린 M (IgM) 농도를조사하였다. Dermatophagoides farinae, Dermatophagoides pteronyssinus, cat dander, cockroach, alternaria alterance, tree mix에대한항원특이 IgE 항 체농도를조사하였다. 항원특이 IgE 항체농도는 ImmunoCAP (Phadia AB, Uppsala, Sweden) 으로측정하였고, 항원특이 IgE 항 체농도가 0.35 IU/mL 이상인경우를흡입항원에대한감작으로 정의하였다. 3. 통계분석 자료분석을위한통계처리는 IBM SPSS Statistics ver (IBM Co., Armonk, NY, USA) 을이용하여분석하였다. 세군간의평균 비교에는 one-way analysis of variance 를시행한후, 사후분석을위 해 Tukey multiple comparision 을수행하였다. 세군간정규분포를 보이지않는변수에대해서는다중비교를하였으며, median 값을 표시하였다. 각군간의빈도비교는 chi-square test 를사용하였다. P 값이 0.05 미만인경우를통계학적으로유의하다고판단하였다. 1. 대상환아의임상적특성 결과 연구대상중남아가 52 명, 여아가 32 명이었고, 평균연령은 2.0± 1.1 세였다. 대상군별나이는정상군의경우 1.4±0.9 세로결핍군의 2.2±1.2 세와부족군의 2.3±1.0 세에비해유의하게적었다. (P = 0.010) 성별, 체질량지수, 형제유무, 출생시계절은각군간 에유의한차이를보이지않았다 (Table 1) (OH)D 농도와알레르기검사 총호산구수는정상군, 결핍군, 부족군이각각 229.5±144.1/ mm 3, 228.1±184.8/mm 3, 236.8±208.9/mm 3 로유의한차이는없 었다 (P = 0.984). 혈청총 IgE 농도는정상군 43.7±58.3 ku/l (median, 23.0 ku/l), 부족군 104.8±178.6 ku/l (median, 56.0 ku/l), 결핍군 171.9±212.1 ku/l (median, 94.0 ku/l) 로결핍군이정상군 에비해유의하게높았다 (P<0.05). 또한, 한가지이상의흡입항원 Table 1. Clinical characteristics of the recurrent wheezers according to the levels of 25-hydroxyvitamin D Characteristic Normal (n= 20) Insufficiency (n= 36) Deficiency (n= 28) P-value Age (yr) 1.4± ± ± Male sex 12 (60.0) 23 (63.9) 17 (60.7) Body mass index (kg/m 2 ) 16.7± ± ± Having a siblings 7 (35.0) 23 (63.9) 20 (71.4) Season of birth Spring Summer Fall Winter 9 (45.0) 6 (30.0) 3 (15.0) 2 (10.0) 12 (33.3) 8 (22.2) 6 (16.7) 10 (27.8) Values are presented as mean± standard deviation or number (%). 25(OH)D, 25-hydroxyvitamin D. 9 (32.1) 9 (32.1) 4 (14.3) 6 (21.4)

3 최은정외 반복되는천명환아에서비타민 D 농도와관련된인자 Table 2. Comparisons of results of allergic tests according to the levels of 25-hydroxyvitamin D Variable Normal (n= 20) Insufficiency (n= 36) Deficiency (n= 28) P-value Total eosinophil count (/mm 3 ) 229.5± ± ± Total IgE (ku/l) 43.7± 58.3 (23.0) 104.8± (56.0) 171.9± 212.1* (94.0) Sensitization to aeroallergen 2 (10) 13 (36.1)* 6 (21.4) Values are presented as mean± standard deviation or number (%) unless otherwise indicated. *P< 0.05, compared to normal. Median. Table 3. Comparisons of results of laboratory tests according to the levels of 25-hydroxyvitamin D Laboratory test Normal (n= 20) Insufficiency (n= 36) Deficiency (n= 28) P-value WBC (/μl) 9,734.4± 3, ,551.9± 3, ,846.1± 3, Hemoglobin (g/dl) 12.5± ± ± Platelet (/μl) 324,944.4± 78, ,562.5± 86, ,565.2± 72, CRP (mg/dl) 1.3± ± ± GOT (IU/L) 39.8± ± ± GPT (IU/L) 24.5± ± ± ALP (IU/L) 631.9± ± ± IgG (mg/dl) 738.9± ± ± IgA (mg/dl) 66.9± ± ± IgM (mg/dl) 123.9± ± ± Values are presented as mean± standard deviation. WBC, white blood cell; CRP, C-reactive protein; GOT, glutamic oxalacetic transaminase; GPT, glutamic pyruvate transaminase; ALP, alkaline phosphatase. 에감작된비율은정상군 10%, 부족군 36.1%, 결핍군 21.4% 로부족군이정상군에비해유의하게높았다 (P<0.05) (Table 2) (OH)D 농도와임상검사백혈구, 혈색소, 혈소판, CRP, GOT, IgG, IgA, IgM 농도는세군사이에유의한차이가없었다. 하지만, GPT는정상군이 24.5±19.4 IU/L로결핍군 (16.0±4.7 IU/L) 과부족군 (15.3±4.5 IU/L) 에비해의미있게높았다 (P = 0.009). 또한, ALP의경우부족군 (770.4± IU/L) 과결핍군 (791.4±180.8 IU/L) 이정상군 (631.9±127.0 IU/L) 에비해유의하게높은수치를보였다 (P = 0.034) (Table 3). 고찰골격의성장과유지에필수적인호르몬으로알려져있던비타민 D가면역조절과정에도중요한역할을담당하고있음이밝혀지면서, 대표적인알레르기질환인천식과의연관성에대한연구들이보고되었다. 25(OH)D 와천식의중증도및알레르기의연관성확인을위해 6 14세아이들을대상으로하여시행된연구와 14) 25(OH)D 의보충이기관지과민성및이후천식의발생을예방할수있다는보고는비타민 D의부족이천식과같은대표적인알레르기질환의발생에기여함을시사한다고하겠다. 15) 또한임신중비타민 D를섭취할경우아동기천명발생이감소한다는보고도있다. 16,17) 세기관지염을포함한호흡기합포체바이러스감염은호흡기의 점막투과성과호흡기항원에대한알레르기감작을증가시켜천식의발달에기여하는것으로알려져있다. 18) 이과정에서 25(OH)D 농도가높을수록호흡기바이러스감염의소인을감소시키게되고, 19) 낮은 25(OH)D 농도는다른바이러스의공동감염의위험을증가시킨다. 특히호흡기합포체바이러스나리노바이러스감염의위험을증가시키는것으로알려져있다. 11) 이러한연구들은 25(OH) D 농도와호흡기바이러스로인한반복적인천명과의연관성이있음을알려준다. 본연구에서는호흡기바이러스에대한검사를일부환아에서만시행하였기에그결과를제시하지못하였다. 혈중 25(OH)D 농도에영향을미치는인자로출생계절, 임부의 25(OH)D 섭취량, 체질량지수, 피부색, 나이및유전적인요인등이보고되어있는데, 한연구에의하면출생계절에따라신생아의 25(OH)D 농도차이가있으며제대혈에서의 25(OH)D 농도는신생아의체내지방량을예측함에있어중요한인자가된다. 20) 또한, 정상체중을가진사람들보다비만한사람들에서 25(OH)D 농도가더낮다는보고가있으나 21,22) 정확한기전은밝혀지지않고있다. 본연구에서는대상군의체질량지수, 출생계절에있어서는다른연구와는달리세군사이에유의한차이는보이지않았다. 나이에따른피부의 7-dehydrocholesterol 농도차이에따라이차적으로 25(OH) D 농도또한나이에영향을받는것으로알려져있고, 23,24) 본연구에서도 25(OH)D 농도에따른나이의차이는통계학적으로의미가있었다. 하지만역으로나이에따른 25(OH)D 농도는통계학적으로유의한차이가없었다 (P = 0.24)

4 Choi EJ, et al. Vitamin D in recurrent wheezers 간질환이있는경우에는담즙산염의기능장애로비타민 D를포함한지용성비타민의흡수및수산화장애로인하여혈중 25(OH) D 농도가감소하게되고, 골연화증이나골감소증과같은대사성골질환이종종동반된다. 25) 최근의한연구에서통계학적유의성은없었지만 25(OH)D 농도가더낮은경우 GOT, GPT, GGT가더높은경향이있고 25(OH)D 농도가간질환의정도와역의상관관계가있다고하였다. 26) 본연구에서는 GOT와 ALP는다른연구와유사한결과를보였지만, GPT는정상군이부족군이나결핍군에비해서유의하게높아앞서언급한연구와는다른결과를보였다. 이러한결과의차이는 25(OH)D 농도가호흡기바이러스감염과같은염증상태와의연관성및 GPT와같은간효소수치의변화와상호관련되어있기때문으로추정된다. 25(OH)D 의농도와 GPT를비롯한간효소수치와의추후연구가더필요할것으로보인다. 코스타리카의천식환아 616명을대상으로시행한한연구에서혈중 25(OH)D 농도가감소할수록혈청총 IgE 농도, 호산구수, 병원입원빈도, 항염증약물사용빈도, 기관지과민성이증가하는것으로보고하였고, 27) 소아와성인을포함한 102명의정상대조군과 103 명의천식환자를대상으로시행한연구에서는천식이있는소아에서 25(OH)D 농도와혈청 IgE 농도사이에는역의상관관계가있음을보여주었다. 28) 본연구에서도혈청총 IgE 농도는결핍군이정상군에비해서유의하게높게나타났다. 그러나미국에서성인을대상으로한연구에서는낮은 25(OH)D 농도와알레르겐에대한 IgE 감작과는상관관계가없다고보고하였고, 29,30) Childhood Asthma Management Program Research Group (CAMP) 연구에서도연관성을발견하지못했다. 27) 이와같이상반된결과를보이는 25(OH)D 와혈청총 IgE 농도및알레르기질환과의관계에대해서는이후추가적인연구가필요할것으로생각된다. 25(OH)D 와흡입항원감작에대한연구들중 Brehm 등 14) 의연구에서는 25(OH)D 농도의감소와유럽집먼지진드기에대한특이 IgE, 피부반응검사양성이연관성을보였으나독일바퀴류에서는유의한결과를얻지못했다. 다른한연구에서는집먼지진드기양성률과낮은 25(OH)D 농도사이에연관성을보였으나, 고양이, 개, 곰팡이등에대해서는의미있는결과를얻지못했다. 26) 본연구에서는 25(OH)D 부족군에서만흡입항원에대해유의하게높은감작률을보였지만결핍군에서도정상군에비해감작률이높은경향을보여앞선연구들과유사한결과를보였다. 각흡입항원에대한감작정도를살펴보면집먼지진드기는 21명중 20명, 고양이털은 3명, 꽃가루혼합은 1명이양성이었다. 이번연구에서는검체채취시기에따른오류를최소화하기위해서 3월에서 6월까지 25(OH)D 농도를검사한환아만을대상으로하고, 3세이하의반복되는천명환아로나이를제한하였기에전체적으로연구대상환자수가적은제한점이있다. 또한, 호흡기바이러스검사를시행하지않았기에, 25(OH)D 농도와감염과의관계를 확인하지못하였다는제한점이있다. 천식을비롯한여러알레르기질환의예방과조절에있어 25(OH) D 의역할에대한많은연구가진행되었지만 3 세이하의반복되는 천명환아를대상으로한연구는보고된바가없어저자들은본연 구를시행하였다. 논문의결과를종합해보면, 3 세이하의반복되는 천명환아에서 25(OH)D 농도가부족하거나결핍되어있는경우 GPT 가낮고, ALP 와혈청총 IgE 수치, 그리고흡입항원에대한감 작률이높은것으로나타났다. 또한성별, 형제유무, 출생계절, 키, 몸무게, 체질량지수등과는통계학적인유의성을보이지않았지만 대규모환아를대상으로한전향적인추가연구가필요할것으로 생각된다. REFERENCES 1. Tsiaras WG, Weinstock MA. Factors influencing vitamin D status. Acta Derm Venereol 2011;91: Dror DK, King JC, Durand DJ, Allen LH. Association of modifiable and nonmodifiable factors with vitamin D status in pregnant women and neonates in Oakland, CA. J Am Diet Assoc 2011;111: Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D, et al. Common genetic determinants of vitamin D insufficiency: a genomewide association study. Lancet 2010;376: Benson AA, Toh JA, Vernon N, Jariwala SP. The role of vitamin D in the immunopathogenesis of allergic skin diseases. Allergy 2012;67: Hewison M. An update on vitamin D and human immunity. Clin Endocrinol (Oxf) 2012;76: Camargo CA Jr, Ingham T, Wickens K, Thadhani R, Silvers KM, Epton MJ, et al. Cord-blood 25-hydroxyvitamin D levels and risk of respiratory infection, wheezing, and asthma. Pediatrics 2011;127:e García de Tena J, El Hachem Debek A, Hernandez Gutierrez C, Izquierdo Alonso JL. The role of vitamin D in chronic obstructive pulmonary disease, asthma and other respiratory diseases. Arch Bronconeumol 2014; 50: Blanken MO, Rovers MM, Bont L; Dutch RSV Neonatal Network. Respiratory syncytial virus and recurrent wheeze. N Engl J Med 2013;369: van der Gugten AC, van der Zalm MM, Uiterwaal CS, Wilbrink B, Rossen JW, van der Ent CK. Human rhinovirus and wheezing: short and long-term associations in children. Pediatr Infect Dis J 2013;32: El-Gamal YM, El-Sayed SS. Wheezing in infancy. World Allergy Organ J 2011;4: Jartti T, Ruuskanen O, Mansbach JM, Vuorinen T, Camargo CA Jr. Low serum 25-hydroxyvitamin D levels are associated with increased risk of viral coinfections in wheezing children. J Allergy Clin Immunol 2010; 126:1074-6, 1076.e Miyake Y, Sasaki S, Tanaka K, Hirota Y. Dairy food, calcium and vitamin D intake in pregnancy, and wheeze and eczema in infants. Eur Respir J 2010;35: Holick MF. Vitamin D: evolutionary, physiological and health perspectives. Curr Drug Targets 2011;12: Brehm JM, Celedon JC, Soto-Quiros ME, Avila L, Hunninghake GM, Forno E, et al. Serum vitamin D levels and markers of severity of childhood asthma in Costa Rica. Am J Respir Crit Care Med 2009;179: Hollams EM, Hart PH, Holt BJ, Serralha M, Parsons F, de Klerk NH, et al. Vitamin D and atopy and asthma phenotypes in children: a longitudi

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소아알레르기호흡기 : 제 22 권제 3 호, pp219~223, 2012 년 Pediatr Allergy Respir Dis(Korea) 2012;22: ) 비타민 D와천식

http://dx.doi.org/10.7581/pard.2012.22.3.219 소아알레르기호흡기 : 제 22 권제 3 호, pp219~223, 2012 년 Pediatr Allergy Respir Dis(Korea) 2012;22:219-223 1) D와천식 성균관대학교의과대학삼성창원병원소아청소년과 이주석 Vitamin D and Asthma Ju Suk