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Risk factors for and expression of immune and inflammatory factors in atopic dermatitis in Chinese population: A birth cohort study
Molecular and Cellular Probes xxx (2016) 1e6
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Original research article
Risk factors for and expression of immune and inflammatory factors in atopic dermatitis in Chinese population: A birth cohort study Jing-ji Jin a, 1, Ying-xue Zou b, 1, San-wu Zeng a, * a b
Department of Dermatology, Tianjin First Center Hospital, Tianjin, 300192, China Department of Respiration, Tianjin Children Hospital, Tianjin, 300074, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 December 2015 Received in revised form 28 March 2016 Accepted 28 March 2016 Available online xxx
Objective: To explore the risk factors for atopic dermatitis (AD) and disclose the relationship between immune inflammatory factors (Immunoglobulin E (IgE), interleukin (IL)-4, IL-18) and the prevalence of AD in a Chinese population. Methods: To evaluate the risk factors for infant AD, a total of 921 mother-newborn pairs were recruited through a questionnaire survey conducted during 2009e2011. Venous blood was collected from the mothers during birth hospitalization and umbilical cord blood was collected during delivery. Thirty-five infants with AD paired with their mothers served as the patient group. Thirty-five non-AD pairs were selected randomly and were used as the control group. Enzyme-linked immunosorbent assay (ELISA) was performed to detect the levels of IgE, IL-4, and IL-18. The relationship between the prevalence of AD and the levels of IgE, IL-4, and IL-18 was analyzed. The risk factors for allergy were assessed in IgE positive cases. Results: Family income, parental history of atopy, age of menarche, performing housing renovation before pregnancy, instance of a virus infection during pregnancy, and calcium supplementation during pregnancy were potential factors determining the incidence rate of infant AD. Compared with the control group, the AD patient group showed higher levels of IgE and IL-4 in both the maternal serum and umbilical cord blood (P < 0.01). In the cases with AD, IL-8 was increased only in the maternal serum (P < 0.01). In addition, the allergens dust mite, mugwort pollen, and mycete spores were risk factors for the incidence of IgE-positive AD. Conclusion: IgE and IL-4 levels in the maternal serum and umbilical cord blood as well as IL-18 level in the maternal serum are related to the occurrence of childhood AD. Potential factors for infant AD include family income, parental history of atopy, age of menarche, housing renovation before pregnancy, virus infection, and calcium supplementation during pregnancy. © 2016 Elsevier Ltd. All rights reserved.
Keywords: Atopic dermatitis Immunoglobulin E Interleukin-4 Interleukin-18
1. Introduction Atopic dermatitis (AD), also known as atopic eczema, is a type of skin inflammation, characterized by itchy, red, swollen, and cracked skin. Typically, AD initiates in childhood and progresses with varying degrees of severity over the years [1,2]. In children under one year of age, much of the body may be affected. Scratching worsens symptoms, and the patients have an increased risk of skin infections. AD patients also have complications, such as asthma,
* Corresponding author. Department of Dermatology, Tianjin First Center Hospital, No. 24, Fukang Road, Nankai District, Tianjin, 300192, China. E-mail address: [email protected] (S.-w. Zeng). 1 Equal contribution.
allergic rhinitis, and hay fever. The causes of AD are not completely clear but are believed to involve genetic factors, immune system dysfunction, environmental exposures, and difficulties with the permeability of the skin [1,2]. From a genetic point of view, when one twin is reported to have AD, the other twin has a high chance of developing AD [3]. Environmental factors also affect the development of AD [4]. Persons who live in cities and dry climates are more commonly affected by the disease [5]. The contact with allergens, such as pollen, dust, etc., is also related to AD incidence [6]. Additionally, emotional stress may also exert an impact on the development of AD [7]. Therefore, a systematic analysis of risk factors for AD occurrence is urgently required. The diagnosis of AD is commonly based on the signs and
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Please cite this article in press as: J.-j. Jin, et al., Risk factors for and expression of immune and inflammatory factors in atopic dermatitis in Chinese population: A birth cohort study, Molecular and Cellular Probes (2016), http://dx.doi.org/10.1016/j.mcp.2016.03.006
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symptoms manifested. Other diseases that need to be excluded before making a diagnosis are contact dermatitis, psoriasis, and seborrheic dermatitis [2]. Reportedly, the levels of immune and inflammatory factors are considerably altered in the serum of AD patients. The results of a study showed that the concentration of IgE in neonatal umbilical cord blood can be used to predict the occurrence of AD [3]. Furthermore, the levels of IgE, IL- 4, and IL- 18 were identified as risk factors for AD [8]. However, there are no publications elucidating whether those immune inflammatory factors are associated with AD incidence in a Chinese population. Herein, a birth cohort study is reported that was carried out in a Chinese population to evaluate the risk factors for AD and establish the association between AD and the levels of IgE, IL- 4, and IL- 18 in both maternal serum and neonatal umbilical cord blood serum. 2. Materials and methods 2.1. Patients Pregnant women who had their antenatal examinations and deliveries in Tianjin First Central Hospital (Nankai, Tianjin, China) and Tianjin Center of Obstetrics and Gynecology Hospital between January 2009 and January 2011 were recruited to establish a birth cohort. Questionnaires were distributed to those pregnant women. All participants in this study signed informed consent, and all experiments were conducted after the approval of the Ethics Committee of the Tianjin First Central Hospital and Tianjin Center of Obstetrics and Gynecology Hospital.
mothers served as the patient group, while 35 infants without AD paired with the mothers were selected randomly and served as the control group. All patients and matched controls were from the Han Chinese population. 2.4. Measurement of total IgE level Total IgE was detected by ELISA following the instruction of the kit manufacturer (Diaclone Research Company, French). A wavelength of 450 nm was used for determination of IgE level. Values higher than 165 IU/mL were considered IgE-positive. 2.5. Measurement of specific IgE level We used Western blot to detect serum IgE levels. Ingested and inhaled allergens were analyzed. The inhaled allergens included dust mites, house dust, ragweed pollen, Artemisia pollen, mold, poplar pollen, willow, elm, cat hair, dog dander, cockroaches, and Humulus scandens. Crab, shrimp, marine and freshwater fish, egg, peanut, soybean, beef, and mutton constituted the ingested allergens. The measurement of IgE was based on the instructions detailed on the assay kit. A sample was regarded as allergenpositive at an IgE concentration higher than 0.35 IU/mL. 2.6. Determination of IL-4 and IL-18 levels The levels of IL-4 and IL-18 were detected via ELISA at a wavelength of 450 nm following the instructions of the kit manufacturer (DiacloneReserch Company, French).
2.2. Questionnaires 2.7. Statistical analysis Questionnaire content included children's gender, family information of the children, family income, etc. The analyzed data of the questionnaires are presented in Table 1. Housing renovation was defined by referring to the literature [9]. Venous blood (2 mL) was collected from the pregnant women, and umbilical cord blood (2 mL) was collected during the infant delivery. Telephone followups to the parents were made at the two time points: 12 and 24 months after the baby's birth. The children who had itches or a skin rash in an itchy area were invited to the clinic and examined by dermatologists. The levels of IgE, IL-4, and IL-18 in the maternal serum and neonatal umbilical cord blood were determined by ELISA method. Non-AD mothernewborn pairs served as the control group. 2.3. AD diagnostic criteria During the follow-up at the 12th and 24th months, AD was confirmed by the Williams diagnostic criteria [10] with a minor modification. The child was diagnosed with AD when both the first item and any one item within the range 2e5 were fitted (Table 1). The revised diagnostic criteria were more suitable to the population in China [11]. Venous blood was collected from the mothers during birth hospitalization, and umbilical cord blood was collected from the newborns at birth. Thirty-five infants with AD paired with their
Statistical analyses were performed using SPSS version 19. The prevalence of AD was calculated using the chi-square test. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic analysis. Data are presented as the mean ± standard deviation. The t-test was utilized to analyze the difference between the two groups. A P value less than 0.05 was considered statistically significant. 3. Results 3.1. Risk factors for atopic dermatitis A total of 1215 questionnaires were distributed to the pregnant women, and 1208 effective questionnaires were collected, accounting for a response rate of 99.42%. A small number of the cases (n ¼ 287) were excluded due to delivery in other hospitals, delivery after less than 32 completed weeks of gestation, and loss of followup. Finally, a total of 921 cases completed the study. According to Williams's diagnostic criteria of AD, 35 children were diagnosed with AD 24 months after birth. Among them, 19 cases were male and 16 cases were female. The prevalence of AD was 3.80%. Five of the 35 AD mothers had AD history, three had asthma history, and five had allergic rhinitis history. Among them, AD prevalence rate
Table 1 Questions for the diagnosis of AD. Questions for the follow-up: 1. 2. 3. 4. 5.
Whether pruritus often appears on child skin? Whether itchy skin disease often occurs in the back of neck, bilateral elbow, and knee? Whether children and parents have any other history of allergic disease? Is there a rash in your child's back of neck, bilateral elbow, and knee? Has the child's skin been dry ever?
Please cite this article in press as: J.-j. Jin, et al., Risk factors for and expression of immune and inflammatory factors in atopic dermatitis in Chinese population: A birth cohort study, Molecular and Cellular Probes (2016), http://dx.doi.org/10.1016/j.mcp.2016.03.006
J.-j. Jin et al. / Molecular and Cellular Probes xxx (2016) 1e6
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was distributed as follows: 3.88% were living in a city, 5.88% were inhabitants of rural areas, and 1.89% resided suburbs. Details of the AD prevalence rates determined are listed in Table 2. Family income, parental history of atopy, age of menarche, accommodation, housing renovation before pregnancy, virus infection during pregnancy, supplementation with folic acid and calcium during pregnancy were potential risk factors for AD (P < 0.05) (Table 3). No statistically significant differences were found (P > 0.05) in AD prevalence in groups with different gender of the babies, family children, dying the hair of the mother three months before pregnancy, alcoholic beverages and smoking by the mother, and smoking of the spouse during pregnancy. The results the examination of the influence of various factors as independent variables by logistic regression analysis are presented in Supplementary Table 1.
maternal and umbilical cord blood. In the AD group, IL-4 levels were elevated in both the maternal serum (Control: 425.34 ± 278.38 IU/mL; Patients: 87.12 ± 47.48 IU/mL, P < 0.01) and umbilical cord blood. IL-18 levels were augmented in only the maternal venous serum in the AD group, but not in the umbilical cord blood.
3.2. The expression levels of IgE, IL-14, and IL-18 were elevated in AD cases
4. Discussion
The serum IgE, IL-14, and IL-18 levels were determined in venous sera from both maternal and umbilical cord blood (Fig. 1). Compared with control group, the patient group showed higher IgE levels in the maternal serum (Control: 425.34 ± 278.38 IU/mL; Patients: 87.12 ± 47.48 IU/mL, P < 0.01) and umbilical cord blood (Control: 418.23 ± 256.76, Patients: 81.77 ± 45.26) IU/mL, P < 0.01). The IgE-positive rates of the maternal serum and umbilical cord blood in the AD group were significantly more increased than those in the control group (P < 0.05). The serum IL-4 and IL-18 levels were also detected in the
3.3. Association between allergens and IgE-positive rates In the maternal venous serum, dust mite, house dust, ragweed pollen, mugwort pollen, mycetes, willow, elm pollen, shrimp, and marine fishes were significant factors inducing positive expression of IgE (P < 0.05). In the umbilical cord blood, only ragweed pollen and mugwort pollen were significant factors causing positive expression of IgE (P < 0.05) (Table 4).
The incidence of AD is increasing worldwide. According to the results of a birth cohort study in Taiwan, the prevalence of AD in 2011 was 5.90% in Taiwan [12]. The findings of an international study of asthma and allergies in childhood (ISAAC) revealed that in 1998 the prevalence of AD in was within the approximate range of 0e2.50% [13]. Gu et al. [14] summarized that the prevalence of AD in 11 areas in China was 0.69% in 2000. In our investigation, there were 35 children who were diagnosed with AD, and the prevalence rate in two-year-old infants was 3.80%. The parents with atopic disease history seriously affected the incidence of AD in infants. Statistically, 43%e83% children have AD
Table 2 Prevalence rates of AD in 1e2-year-old children. Characteristic Gender Male Female Number of children 1 2 3 Family income <1000Yuan 1000Yuan ~ 3000Yuan ~ 5000 Parental history of atopy No Yes The age of menarche <11 year 11 year ~ 13 year ~ 15 year Before 3 months of pregnancy hair No Yes Use perfume before pregnancy No Yes Drinking water situation Drinking water situation Mineral water Smoking during pregnancy No 832 31 (3.73) Yes 832 31 (3.73)
Prevalence rate, N/M (%)
P
Characteristic 0.583
19/458 (4.15) 16/463 (3.46) 0.545 29/778 (3.73) 5/129 (3.88) 1/14 (7.14) <0.001 3/27 32/416 0/430 0/48
(11.11) (7.69) (0.00) (0.00) <0.001
10/654 (1.53) 25/267 (9.36) 0.004 11/104 (10.58) 17/427 (3.98) 7/256 (2.73) 0/134 (0.00) coloring 31/836 (3.71) 4/85 (4.71)
0.872
0.016 16/597 (2.68) 19/324 (4.71) 0.643 20/491 (4.07) 15/430 (3.49) 0.945 31/832 (3.73) 4/89 (4.49)
Prevalence rate, N/M (%)
Spouse smoking during pregnancy No 19/468 (4.06) Yes 16/453 (3.53) Accommodation Bungalow 14/71 (19.72) Multi-storey buildings 17/713 (2.38) Villa 4/137 (2.92) Housing renovation before pregnancy No renovation 6/6 (100) <3 months 8/96 (8.33) 3 months 11/58 (18.97) 6 months 7/588 (1.19) 12 months 3/173 (1.73) Virus infection during pregnancy No 29/524 (5.53) Yes 6/397 (1.51) Pregnancy folic acid No 14/541 Yes 21/380
Taking calcium during pregnancy No 10/94 (10.99) Yes 25/830 (3.01) Living conditions Urban 851 33 ( 3.88) 33/851 (3.88) Suburb 53 1 (1.89) 1/53 (1.89) Rural 17 1 (5.88) 1/17 (5.88) The family pet No 24/754 (3.18) Yes 11/167(6.59) Feeding mode Breast milk 14/574 (2.44) Breast milk 14/75 (18.67) Mixed feeding 7/272 (2.57)
P 0.675
<0.001
<0.001
0.002
0.022
<0.001
0.519
0.037
<0.001
N, frequency of AD in each subgroup; M, frequency of respondents in each subgroup.
Please cite this article in press as: J.-j. Jin, et al., Risk factors for and expression of immune and inflammatory factors in atopic dermatitis in Chinese population: A birth cohort study, Molecular and Cellular Probes (2016), http://dx.doi.org/10.1016/j.mcp.2016.03.006
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Table 3 Potential risk factors estimation of AD for 1e2 years children (n ¼ 921). Factors
Constant Family income Parental history of atopy The age of menarche Housing renovation before pregnancy Virus infection during pregnancy Taking calcium during pregnancy a
Coefficienta
12.98 3.14 1.70 1.52 2.39 5.33 2.34
SE
3.00 0.99 0.72 0.47 0.44 0.89 0.89
P
<0.001 <0.001 0.020 <0.001 0.004 <0.001 0.010
OR
e 0.04 5.50 0.22 0.09 0.01 0.10
95% CI for OR Lower
Upper
e 0.01 1.34 0.09 0.04 0.00 0.02
e 0.30 22.53 0.55 0.214 0.03 0.552
Stepwise logistic regression analysis was performed.
Fig. 1. Comparison of total Ig4, IL-4, and IL-18 levels in maternal serum and umbilical cord blood between the AD group and the control group. *P < 0.05, AD group compared with control group for maternal serum; #P < 0.05, AD group compared with control group for umbilical cord blood.
when one of the parents has atopic history, and 50%e75% children are diagnosed with AD when both parents have history of atopic disease [15]. Besides the genetic factor, in this survey, the risk factors for occurrence of AD in the Han Chinese population were reevaluated. Using the single-factor logistic regression analysis, we discovered that family income, parental history of atopy, age of menarche, housing renovation before pregnancy, virus infection during pregnancy, and calcium supplementation during pregnancy were supposedly the potential risk factors for AD. In a birth cohort study of infants in southeast Turkey, positive family history of atopic diseases, prenatal infections, and presence of food allergy were identified as risk factors for early occurrence of AD [16], which is consistent with the findings of our study. Theoretically, maternal
sex hormones during pregnancy affect the development of the fetal immune system and modulate the subsequent development of atopic disorders. Early onset of menarche performs important roles in determining the level of estrogen in adult women. There are reports suggesting that menarche precipitates the onset of atopic dermatitis [17,18]. However, these presumptions are inconsistent with other results indicating that maternal age at menarche was not related to atopic diseases [19]. These discrepancies might have been caused by the different races of the subjects studied. Associations between AD incidence and home environmental factors, including non-electric heating system without a ventilation duct to the outside (compared to the use of an electric heating system), having visible mold in the house, having a mouldy odor in the house, and condensation on the windowpanes in the house, were established [20]. Direct correlation between calcium supplementation before pregnancy and AD occurrence has been rarely reported. However, the uptake of Vitamin D, which is beneficial for calcium absorption, was associated with AD [21]. In our study, we found that the age of menarche, housing renovation before pregnancy, and calcium supplementation during pregnancy were important factors for AD incidence. Besides, we suggested that virus infections during pregnancy were also related to AD occurrence. IgE is an important target in the interventions with the pathological processes of allergy, asthma, and other IgE-mediated diseases. AD also displays a higher level of IgE in umbilical cord blood. Therefore, the IgE level in umbilical cord blood is a critical biomarker for the diagnosis of AD in infants. Our study showed consistent data regarding the association between IgE concentrations in both of maternal serum and umbilical cord blood and AD incidence. In AD animal models, IgE level was also elevated [22,23]. However, in the Turkey cohort study mentioned earlier, IgE level was not supposed to be a risk factor for AD development [16]. This discrepancy might be explained by the different races of the participants. In our examination, the level of IgE in both the maternal and the umbilical cord sera was elevated in AD cases. That finding suggests a consistent elevation of IgE concentrations in the maternal and umbilical cord sera and its potential application as a diagnostic marker for AD. Qian et al. [24] suggested that children under three years of age are sensitive to food allergens, especially those in the milk, egg white, whereas children above the age of three years are susceptible to inhaled allergens, especially mites. Allergen-specific IgE levels are altered due to the influence exerted by different factors, such as geographic location, time, age, environmental factors. In this study, we found that during pregnancy, women were allergic to dust mites, house dust, pollens from plants, mold, shrimp, marine fish, whereas the babies were allergic to pollens and mold. Although different types of allergens exerted predominant influence in mothers and children, inhaled allergens were of critical importance to disease development. Moreover, these inconsistent results might have been caused by the smaller sample size and the
Please cite this article in press as: J.-j. Jin, et al., Risk factors for and expression of immune and inflammatory factors in atopic dermatitis in Chinese population: A birth cohort study, Molecular and Cellular Probes (2016), http://dx.doi.org/10.1016/j.mcp.2016.03.006
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Table 4 Positive frequency of specific IgE for various allergens in maternal serum and umbilical cord blood. Allergen
Dust mite House dust Ragweed pollen Mugwort pollen Mycete Willow and elm pollen Cat dander Dog dander Cockroach Humulus Crab Shrimp Marine fishes Freshwater fishes Egg white Peanut Soybean Beef Mutton
Maternal serum
P
AD group, n ¼ 35
Control group, n ¼ 35
15 13 11 11 9 8 6 5 4 3 11 10 9 9 7 6 6 4 3
7 5 4 4 2 2 1 2 1 1 5 2 2 3 1 2 1 0 0
(42.86) (37.14) (31.43) (31.43) (25.71) (22.86) (17.14) (14.29) (11.43) (8.57) (31.43) (28.57) (25.71) (25.71) (20.00) (17.14) (17.14) (11.43) (8.57)
(20.00) (14.29) (11.43) (11.43) (5.71) (5.71) (2.86) (5.71) (2.86) (2.86) (14.29) (5.71) (5.71) (8.57) (2.86) (5.71) (2.86) (0.00) (0.00)
imbalanced immune system of the children. The findings of our investigation reveal that in addition to the action of genetic factors, nurture or the contact with allergens are also important causes for AD occurrence. Hence, in the process of its immune reconstruction, specific allergic desensitization therapy and effective protection could reduce the incidence of AD in genetically predisposed allergic children [25]. However, there were also IgE-positive cases in the control group, which indicates that the occurrence and development of AD are not only related to allergen contact in the environment, the causative agent, the immune status, and mental factors. AD occurrence and development are a result of the interaction among a great number of factors, suggesting that mothers and children should avoid contact allergens, and early prevention could reduce the incidence and progression of atopic dermatitis. Nevertheless, a larger cohort study is still required for further confirmation in the future. AD is an inflammatory skin disease caused by various cell types, especially T lymphocytes, mast cells, and eosinophils. Herberth [26] found that elevated IL-4 levels in umbilical cord blood can increase the risk of AD. Our research results show that the levels of serum IL4 in AD children and mothers are significantly higher than those in the control group. These data suggest that IL-4 has a predictive effect for AD occurrence. In the process of AD pathogenesis, IL-18 plays a two-way role. On one hand, it can activate the Thl-related immune response and trigger the Th2 immune response; on the other hand, it can stimulate the synthesis of IL-4 and IL-13 in mast cells and basophils, and cause elevated IgE concentrations. Higher serum levels of IL-18 in atopic disease patients also increase the expression of IL-4 and IL-13 [8]. Our data are consistent with earlier findings revealing that the serum IL-18 level was increased in AD patients [27]. However, in the present investigation, IL-18 concentration in cord blood was not significantly altered in the AD group. Therefore, IL-4 but not IL-18 is a better predictor for infant AD. 5. Conclusion In this study, we found that maternal disease history is critically important for the incidence of infant AD. Additionally, to reduce the risk of disease onset, more considerations should be paid to limiting housing renovation, occurrence of infections, and carefully choice of nutrition during pregnancy. In addition, IgE and IL-4 levels in maternal serum and umbilical cord blood as well as the IL-18 level
0.039 0.029 0.041 0.041 0.022 0.040 0.106 0.428 0.357 0.614 0.088 0.011 0.022 0.057 0.055 0.230 0.106 0.114 0.239
Umbilical cord blood
P
AD group, n ¼ 35
Control group, n ¼ 35
11 10 9 8 8 7 5 4 3 2 8 7 6 5 5 3 2 1 1
5 4 3 2 2 1 1 1 1 0 4 2 1 3 1 1 2 0 0
(31.43) (28.57) (25.71) (22.86) (22.86) (20.00) (14.29) (11.43) (8.57) (5.71) (22.86) (20.00) (17.14) (14.29) (14.29) (8.57) (5.71) (2.86) (2.86)
(14.29) (11.43) (8.57) (5.71) (5.71) (2.86) (2.86) (2.86) (2.86) (0.00) (11.43) (5.71) (2.86) (8.57) (2.86) (2.86) (5.71) (0.00) (0.00)
0.088 0.073 0.057 0.040 0.040 0.055 0.198 0.357 0.614 0.493 0.342 0.151 0.106 0.710 0.198 0.614 1.000 1.000 1.000
in maternal serum could be used to diagnose infant AD. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.mcp.2016.03.006. References [1] K.M. Donohue, et al., Anti-cockroach and anti-mouse IgE are associated with early wheeze and atopy in an inner-city birth cohort, J. Allergy Clin. Immunol. 122 (5) (2008) 914e920. [2] W.J. Choi, et al., Prevalence and risk factors for atopic dermatitis: a crosssectional study of 6,453 Korean preschool children, Acta Derm. Venereol. 92 (5) (2012) 467e471. [3] N. Kawamoto, et al., Total IgE at 6 months predicts remittance or persistence of atopic dermatitis at 14 months, Allergy Asthma Proc. 34 (4) (2013) 362e369. [4] I.J. Wang, J.Y. Wang, K.W. Yeh, Childhood atopic dermatitis in Taiwan, Pediatr. Neonatol. 57 (2) (2016 Apr) 89e96. [5] M. Herrant, et al., Risk factors associated with asthma, atopic dermatitis and rhinoconjunctivitis in a rural Senegalese cohort, Allergy Asthma Clin. Immunol. 11 (1) (2015) 24. [6] S. Weidinger, N. Novak, Atopic dermatitis, Lancet 387 (10023) (2016 Mar 12) 1109e1122. [7] C. Schut, et al., Coping as mediator of the relationship between stress and itch in patients with atopic dermatitis: a regression and mediation analysis, Exp. Dermatol. 24 (2) (2015) 148e150. [8] K. Kou, et al., Association of serum interleukin-18 and other biomarkers with disease severity in adults with atopic dermatitis, Arch. Dermatol Res. 304 (4) (2012) 305e312. [9] Z. Liu, et al., Association between maternal exposure to housing renovation and offspring with congenital heart disease: a multi-hospital case-control study, Environ. Health 12 (2013) 25. [10] H.C. Williams, et al., Validation of the U.K. diagnostic criteria for atopic dermatitis in a population setting. U.K. Diagnostic Criteria for Atopic Dermatitis Working Party, Br. J. Dermatol. 135 (1) (1996) 12e17. [11] H. Gu, Y. Yan, K. Chen, Epidemiological survey of atopic dermatitis in Chinese population, Chin. J. Dermatol. 33 (6) (2000) 379e382. [12] H.J. Wen, et al., Prediction of atopic dermatitis in 2-yr-old children by cord blood IgE, genetic polymorphisms in cytokine genes, and maternal mentality during pregnancy, Pediatr. Allergy Immunol. 22 (7) (2011) 695e703. [13] Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC, Int. Study Asthma Allerg. Child. (ISAAC) Steer. Comm. Lancet 351 (9111) (1998) 1225e1232. [14] H. Gu, Y. Yan, K. chen, Epidemiological survey in atopic dermatitis, Chin. Dermatol. J. 33 (6) (2000) 379e382. [15] S.J. Uekert, et al., Sex-related differences in immune development and the expression of atopy in early childhood, J. Allergy Clin. Immunol. 118 (6) (2006) 1375e1381. [16] D. Dogruel, et al., Prevalence of and risk factors for atopic dermatitis: a birth cohort study of infants in southeast Turkey, Allergol. Immunopathol. Madr. (2015 Nov 14) pii: S0301-0546(15)00122-00126.
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Please cite this article in press as: J.-j. Jin, et al., Risk factors for and expression of immune and inflammatory factors in atopic dermatitis in Chinese population: A birth cohort study, Molecular and Cellular Probes (2016), http://dx.doi.org/10.1016/j.mcp.2016.03.006
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Original research article
Risk factors for and expression of immune and inflammatory factors in atopic dermatitis in Chinese population: A birth cohort study Jing-ji Jin a, 1, Ying-xue Zou b, 1, San-wu Zeng a, * a b
Department of Dermatology, Tianjin First Center Hospital, Tianjin, 300192, China Department of Respiration, Tianjin Children Hospital, Tianjin, 300074, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 December 2015 Received in revised form 28 March 2016 Accepted 28 March 2016 Available online xxx
Objective: To explore the risk factors for atopic dermatitis (AD) and disclose the relationship between immune inflammatory factors (Immunoglobulin E (IgE), interleukin (IL)-4, IL-18) and the prevalence of AD in a Chinese population. Methods: To evaluate the risk factors for infant AD, a total of 921 mother-newborn pairs were recruited through a questionnaire survey conducted during 2009e2011. Venous blood was collected from the mothers during birth hospitalization and umbilical cord blood was collected during delivery. Thirty-five infants with AD paired with their mothers served as the patient group. Thirty-five non-AD pairs were selected randomly and were used as the control group. Enzyme-linked immunosorbent assay (ELISA) was performed to detect the levels of IgE, IL-4, and IL-18. The relationship between the prevalence of AD and the levels of IgE, IL-4, and IL-18 was analyzed. The risk factors for allergy were assessed in IgE positive cases. Results: Family income, parental history of atopy, age of menarche, performing housing renovation before pregnancy, instance of a virus infection during pregnancy, and calcium supplementation during pregnancy were potential factors determining the incidence rate of infant AD. Compared with the control group, the AD patient group showed higher levels of IgE and IL-4 in both the maternal serum and umbilical cord blood (P < 0.01). In the cases with AD, IL-8 was increased only in the maternal serum (P < 0.01). In addition, the allergens dust mite, mugwort pollen, and mycete spores were risk factors for the incidence of IgE-positive AD. Conclusion: IgE and IL-4 levels in the maternal serum and umbilical cord blood as well as IL-18 level in the maternal serum are related to the occurrence of childhood AD. Potential factors for infant AD include family income, parental history of atopy, age of menarche, housing renovation before pregnancy, virus infection, and calcium supplementation during pregnancy. © 2016 Elsevier Ltd. All rights reserved.
Keywords: Atopic dermatitis Immunoglobulin E Interleukin-4 Interleukin-18
1. Introduction Atopic dermatitis (AD), also known as atopic eczema, is a type of skin inflammation, characterized by itchy, red, swollen, and cracked skin. Typically, AD initiates in childhood and progresses with varying degrees of severity over the years [1,2]. In children under one year of age, much of the body may be affected. Scratching worsens symptoms, and the patients have an increased risk of skin infections. AD patients also have complications, such as asthma,
* Corresponding author. Department of Dermatology, Tianjin First Center Hospital, No. 24, Fukang Road, Nankai District, Tianjin, 300192, China. E-mail address: [email protected] (S.-w. Zeng). 1 Equal contribution.
allergic rhinitis, and hay fever. The causes of AD are not completely clear but are believed to involve genetic factors, immune system dysfunction, environmental exposures, and difficulties with the permeability of the skin [1,2]. From a genetic point of view, when one twin is reported to have AD, the other twin has a high chance of developing AD [3]. Environmental factors also affect the development of AD [4]. Persons who live in cities and dry climates are more commonly affected by the disease [5]. The contact with allergens, such as pollen, dust, etc., is also related to AD incidence [6]. Additionally, emotional stress may also exert an impact on the development of AD [7]. Therefore, a systematic analysis of risk factors for AD occurrence is urgently required. The diagnosis of AD is commonly based on the signs and
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Please cite this article in press as: J.-j. Jin, et al., Risk factors for and expression of immune and inflammatory factors in atopic dermatitis in Chinese population: A birth cohort study, Molecular and Cellular Probes (2016), http://dx.doi.org/10.1016/j.mcp.2016.03.006
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symptoms manifested. Other diseases that need to be excluded before making a diagnosis are contact dermatitis, psoriasis, and seborrheic dermatitis [2]. Reportedly, the levels of immune and inflammatory factors are considerably altered in the serum of AD patients. The results of a study showed that the concentration of IgE in neonatal umbilical cord blood can be used to predict the occurrence of AD [3]. Furthermore, the levels of IgE, IL- 4, and IL- 18 were identified as risk factors for AD [8]. However, there are no publications elucidating whether those immune inflammatory factors are associated with AD incidence in a Chinese population. Herein, a birth cohort study is reported that was carried out in a Chinese population to evaluate the risk factors for AD and establish the association between AD and the levels of IgE, IL- 4, and IL- 18 in both maternal serum and neonatal umbilical cord blood serum. 2. Materials and methods 2.1. Patients Pregnant women who had their antenatal examinations and deliveries in Tianjin First Central Hospital (Nankai, Tianjin, China) and Tianjin Center of Obstetrics and Gynecology Hospital between January 2009 and January 2011 were recruited to establish a birth cohort. Questionnaires were distributed to those pregnant women. All participants in this study signed informed consent, and all experiments were conducted after the approval of the Ethics Committee of the Tianjin First Central Hospital and Tianjin Center of Obstetrics and Gynecology Hospital.
mothers served as the patient group, while 35 infants without AD paired with the mothers were selected randomly and served as the control group. All patients and matched controls were from the Han Chinese population. 2.4. Measurement of total IgE level Total IgE was detected by ELISA following the instruction of the kit manufacturer (Diaclone Research Company, French). A wavelength of 450 nm was used for determination of IgE level. Values higher than 165 IU/mL were considered IgE-positive. 2.5. Measurement of specific IgE level We used Western blot to detect serum IgE levels. Ingested and inhaled allergens were analyzed. The inhaled allergens included dust mites, house dust, ragweed pollen, Artemisia pollen, mold, poplar pollen, willow, elm, cat hair, dog dander, cockroaches, and Humulus scandens. Crab, shrimp, marine and freshwater fish, egg, peanut, soybean, beef, and mutton constituted the ingested allergens. The measurement of IgE was based on the instructions detailed on the assay kit. A sample was regarded as allergenpositive at an IgE concentration higher than 0.35 IU/mL. 2.6. Determination of IL-4 and IL-18 levels The levels of IL-4 and IL-18 were detected via ELISA at a wavelength of 450 nm following the instructions of the kit manufacturer (DiacloneReserch Company, French).
2.2. Questionnaires 2.7. Statistical analysis Questionnaire content included children's gender, family information of the children, family income, etc. The analyzed data of the questionnaires are presented in Table 1. Housing renovation was defined by referring to the literature [9]. Venous blood (2 mL) was collected from the pregnant women, and umbilical cord blood (2 mL) was collected during the infant delivery. Telephone followups to the parents were made at the two time points: 12 and 24 months after the baby's birth. The children who had itches or a skin rash in an itchy area were invited to the clinic and examined by dermatologists. The levels of IgE, IL-4, and IL-18 in the maternal serum and neonatal umbilical cord blood were determined by ELISA method. Non-AD mothernewborn pairs served as the control group. 2.3. AD diagnostic criteria During the follow-up at the 12th and 24th months, AD was confirmed by the Williams diagnostic criteria [10] with a minor modification. The child was diagnosed with AD when both the first item and any one item within the range 2e5 were fitted (Table 1). The revised diagnostic criteria were more suitable to the population in China [11]. Venous blood was collected from the mothers during birth hospitalization, and umbilical cord blood was collected from the newborns at birth. Thirty-five infants with AD paired with their
Statistical analyses were performed using SPSS version 19. The prevalence of AD was calculated using the chi-square test. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic analysis. Data are presented as the mean ± standard deviation. The t-test was utilized to analyze the difference between the two groups. A P value less than 0.05 was considered statistically significant. 3. Results 3.1. Risk factors for atopic dermatitis A total of 1215 questionnaires were distributed to the pregnant women, and 1208 effective questionnaires were collected, accounting for a response rate of 99.42%. A small number of the cases (n ¼ 287) were excluded due to delivery in other hospitals, delivery after less than 32 completed weeks of gestation, and loss of followup. Finally, a total of 921 cases completed the study. According to Williams's diagnostic criteria of AD, 35 children were diagnosed with AD 24 months after birth. Among them, 19 cases were male and 16 cases were female. The prevalence of AD was 3.80%. Five of the 35 AD mothers had AD history, three had asthma history, and five had allergic rhinitis history. Among them, AD prevalence rate
Table 1 Questions for the diagnosis of AD. Questions for the follow-up: 1. 2. 3. 4. 5.
Whether pruritus often appears on child skin? Whether itchy skin disease often occurs in the back of neck, bilateral elbow, and knee? Whether children and parents have any other history of allergic disease? Is there a rash in your child's back of neck, bilateral elbow, and knee? Has the child's skin been dry ever?
Please cite this article in press as: J.-j. Jin, et al., Risk factors for and expression of immune and inflammatory factors in atopic dermatitis in Chinese population: A birth cohort study, Molecular and Cellular Probes (2016), http://dx.doi.org/10.1016/j.mcp.2016.03.006
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was distributed as follows: 3.88% were living in a city, 5.88% were inhabitants of rural areas, and 1.89% resided suburbs. Details of the AD prevalence rates determined are listed in Table 2. Family income, parental history of atopy, age of menarche, accommodation, housing renovation before pregnancy, virus infection during pregnancy, supplementation with folic acid and calcium during pregnancy were potential risk factors for AD (P < 0.05) (Table 3). No statistically significant differences were found (P > 0.05) in AD prevalence in groups with different gender of the babies, family children, dying the hair of the mother three months before pregnancy, alcoholic beverages and smoking by the mother, and smoking of the spouse during pregnancy. The results the examination of the influence of various factors as independent variables by logistic regression analysis are presented in Supplementary Table 1.
maternal and umbilical cord blood. In the AD group, IL-4 levels were elevated in both the maternal serum (Control: 425.34 ± 278.38 IU/mL; Patients: 87.12 ± 47.48 IU/mL, P < 0.01) and umbilical cord blood. IL-18 levels were augmented in only the maternal venous serum in the AD group, but not in the umbilical cord blood.
3.2. The expression levels of IgE, IL-14, and IL-18 were elevated in AD cases
4. Discussion
The serum IgE, IL-14, and IL-18 levels were determined in venous sera from both maternal and umbilical cord blood (Fig. 1). Compared with control group, the patient group showed higher IgE levels in the maternal serum (Control: 425.34 ± 278.38 IU/mL; Patients: 87.12 ± 47.48 IU/mL, P < 0.01) and umbilical cord blood (Control: 418.23 ± 256.76, Patients: 81.77 ± 45.26) IU/mL, P < 0.01). The IgE-positive rates of the maternal serum and umbilical cord blood in the AD group were significantly more increased than those in the control group (P < 0.05). The serum IL-4 and IL-18 levels were also detected in the
3.3. Association between allergens and IgE-positive rates In the maternal venous serum, dust mite, house dust, ragweed pollen, mugwort pollen, mycetes, willow, elm pollen, shrimp, and marine fishes were significant factors inducing positive expression of IgE (P < 0.05). In the umbilical cord blood, only ragweed pollen and mugwort pollen were significant factors causing positive expression of IgE (P < 0.05) (Table 4).
The incidence of AD is increasing worldwide. According to the results of a birth cohort study in Taiwan, the prevalence of AD in 2011 was 5.90% in Taiwan [12]. The findings of an international study of asthma and allergies in childhood (ISAAC) revealed that in 1998 the prevalence of AD in was within the approximate range of 0e2.50% [13]. Gu et al. [14] summarized that the prevalence of AD in 11 areas in China was 0.69% in 2000. In our investigation, there were 35 children who were diagnosed with AD, and the prevalence rate in two-year-old infants was 3.80%. The parents with atopic disease history seriously affected the incidence of AD in infants. Statistically, 43%e83% children have AD
Table 2 Prevalence rates of AD in 1e2-year-old children. Characteristic Gender Male Female Number of children 1 2 3 Family income <1000Yuan 1000Yuan ~ 3000Yuan ~ 5000 Parental history of atopy No Yes The age of menarche <11 year 11 year ~ 13 year ~ 15 year Before 3 months of pregnancy hair No Yes Use perfume before pregnancy No Yes Drinking water situation Drinking water situation Mineral water Smoking during pregnancy No 832 31 (3.73) Yes 832 31 (3.73)
Prevalence rate, N/M (%)
P
Characteristic 0.583
19/458 (4.15) 16/463 (3.46) 0.545 29/778 (3.73) 5/129 (3.88) 1/14 (7.14) <0.001 3/27 32/416 0/430 0/48
(11.11) (7.69) (0.00) (0.00) <0.001
10/654 (1.53) 25/267 (9.36) 0.004 11/104 (10.58) 17/427 (3.98) 7/256 (2.73) 0/134 (0.00) coloring 31/836 (3.71) 4/85 (4.71)
0.872
0.016 16/597 (2.68) 19/324 (4.71) 0.643 20/491 (4.07) 15/430 (3.49) 0.945 31/832 (3.73) 4/89 (4.49)
Prevalence rate, N/M (%)
Spouse smoking during pregnancy No 19/468 (4.06) Yes 16/453 (3.53) Accommodation Bungalow 14/71 (19.72) Multi-storey buildings 17/713 (2.38) Villa 4/137 (2.92) Housing renovation before pregnancy No renovation 6/6 (100) <3 months 8/96 (8.33) 3 months 11/58 (18.97) 6 months 7/588 (1.19) 12 months 3/173 (1.73) Virus infection during pregnancy No 29/524 (5.53) Yes 6/397 (1.51) Pregnancy folic acid No 14/541 Yes 21/380
Taking calcium during pregnancy No 10/94 (10.99) Yes 25/830 (3.01) Living conditions Urban 851 33 ( 3.88) 33/851 (3.88) Suburb 53 1 (1.89) 1/53 (1.89) Rural 17 1 (5.88) 1/17 (5.88) The family pet No 24/754 (3.18) Yes 11/167(6.59) Feeding mode Breast milk 14/574 (2.44) Breast milk 14/75 (18.67) Mixed feeding 7/272 (2.57)
P 0.675
<0.001
<0.001
0.002
0.022
<0.001
0.519
0.037
<0.001
N, frequency of AD in each subgroup; M, frequency of respondents in each subgroup.
Please cite this article in press as: J.-j. Jin, et al., Risk factors for and expression of immune and inflammatory factors in atopic dermatitis in Chinese population: A birth cohort study, Molecular and Cellular Probes (2016), http://dx.doi.org/10.1016/j.mcp.2016.03.006
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Table 3 Potential risk factors estimation of AD for 1e2 years children (n ¼ 921). Factors
Constant Family income Parental history of atopy The age of menarche Housing renovation before pregnancy Virus infection during pregnancy Taking calcium during pregnancy a
Coefficienta
12.98 3.14 1.70 1.52 2.39 5.33 2.34
SE
3.00 0.99 0.72 0.47 0.44 0.89 0.89
P
<0.001 <0.001 0.020 <0.001 0.004 <0.001 0.010
OR
e 0.04 5.50 0.22 0.09 0.01 0.10
95% CI for OR Lower
Upper
e 0.01 1.34 0.09 0.04 0.00 0.02
e 0.30 22.53 0.55 0.214 0.03 0.552
Stepwise logistic regression analysis was performed.
Fig. 1. Comparison of total Ig4, IL-4, and IL-18 levels in maternal serum and umbilical cord blood between the AD group and the control group. *P < 0.05, AD group compared with control group for maternal serum; #P < 0.05, AD group compared with control group for umbilical cord blood.
when one of the parents has atopic history, and 50%e75% children are diagnosed with AD when both parents have history of atopic disease [15]. Besides the genetic factor, in this survey, the risk factors for occurrence of AD in the Han Chinese population were reevaluated. Using the single-factor logistic regression analysis, we discovered that family income, parental history of atopy, age of menarche, housing renovation before pregnancy, virus infection during pregnancy, and calcium supplementation during pregnancy were supposedly the potential risk factors for AD. In a birth cohort study of infants in southeast Turkey, positive family history of atopic diseases, prenatal infections, and presence of food allergy were identified as risk factors for early occurrence of AD [16], which is consistent with the findings of our study. Theoretically, maternal
sex hormones during pregnancy affect the development of the fetal immune system and modulate the subsequent development of atopic disorders. Early onset of menarche performs important roles in determining the level of estrogen in adult women. There are reports suggesting that menarche precipitates the onset of atopic dermatitis [17,18]. However, these presumptions are inconsistent with other results indicating that maternal age at menarche was not related to atopic diseases [19]. These discrepancies might have been caused by the different races of the subjects studied. Associations between AD incidence and home environmental factors, including non-electric heating system without a ventilation duct to the outside (compared to the use of an electric heating system), having visible mold in the house, having a mouldy odor in the house, and condensation on the windowpanes in the house, were established [20]. Direct correlation between calcium supplementation before pregnancy and AD occurrence has been rarely reported. However, the uptake of Vitamin D, which is beneficial for calcium absorption, was associated with AD [21]. In our study, we found that the age of menarche, housing renovation before pregnancy, and calcium supplementation during pregnancy were important factors for AD incidence. Besides, we suggested that virus infections during pregnancy were also related to AD occurrence. IgE is an important target in the interventions with the pathological processes of allergy, asthma, and other IgE-mediated diseases. AD also displays a higher level of IgE in umbilical cord blood. Therefore, the IgE level in umbilical cord blood is a critical biomarker for the diagnosis of AD in infants. Our study showed consistent data regarding the association between IgE concentrations in both of maternal serum and umbilical cord blood and AD incidence. In AD animal models, IgE level was also elevated [22,23]. However, in the Turkey cohort study mentioned earlier, IgE level was not supposed to be a risk factor for AD development [16]. This discrepancy might be explained by the different races of the participants. In our examination, the level of IgE in both the maternal and the umbilical cord sera was elevated in AD cases. That finding suggests a consistent elevation of IgE concentrations in the maternal and umbilical cord sera and its potential application as a diagnostic marker for AD. Qian et al. [24] suggested that children under three years of age are sensitive to food allergens, especially those in the milk, egg white, whereas children above the age of three years are susceptible to inhaled allergens, especially mites. Allergen-specific IgE levels are altered due to the influence exerted by different factors, such as geographic location, time, age, environmental factors. In this study, we found that during pregnancy, women were allergic to dust mites, house dust, pollens from plants, mold, shrimp, marine fish, whereas the babies were allergic to pollens and mold. Although different types of allergens exerted predominant influence in mothers and children, inhaled allergens were of critical importance to disease development. Moreover, these inconsistent results might have been caused by the smaller sample size and the
Please cite this article in press as: J.-j. Jin, et al., Risk factors for and expression of immune and inflammatory factors in atopic dermatitis in Chinese population: A birth cohort study, Molecular and Cellular Probes (2016), http://dx.doi.org/10.1016/j.mcp.2016.03.006
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Table 4 Positive frequency of specific IgE for various allergens in maternal serum and umbilical cord blood. Allergen
Dust mite House dust Ragweed pollen Mugwort pollen Mycete Willow and elm pollen Cat dander Dog dander Cockroach Humulus Crab Shrimp Marine fishes Freshwater fishes Egg white Peanut Soybean Beef Mutton
Maternal serum
P
AD group, n ¼ 35
Control group, n ¼ 35
15 13 11 11 9 8 6 5 4 3 11 10 9 9 7 6 6 4 3
7 5 4 4 2 2 1 2 1 1 5 2 2 3 1 2 1 0 0
(42.86) (37.14) (31.43) (31.43) (25.71) (22.86) (17.14) (14.29) (11.43) (8.57) (31.43) (28.57) (25.71) (25.71) (20.00) (17.14) (17.14) (11.43) (8.57)
(20.00) (14.29) (11.43) (11.43) (5.71) (5.71) (2.86) (5.71) (2.86) (2.86) (14.29) (5.71) (5.71) (8.57) (2.86) (5.71) (2.86) (0.00) (0.00)
imbalanced immune system of the children. The findings of our investigation reveal that in addition to the action of genetic factors, nurture or the contact with allergens are also important causes for AD occurrence. Hence, in the process of its immune reconstruction, specific allergic desensitization therapy and effective protection could reduce the incidence of AD in genetically predisposed allergic children [25]. However, there were also IgE-positive cases in the control group, which indicates that the occurrence and development of AD are not only related to allergen contact in the environment, the causative agent, the immune status, and mental factors. AD occurrence and development are a result of the interaction among a great number of factors, suggesting that mothers and children should avoid contact allergens, and early prevention could reduce the incidence and progression of atopic dermatitis. Nevertheless, a larger cohort study is still required for further confirmation in the future. AD is an inflammatory skin disease caused by various cell types, especially T lymphocytes, mast cells, and eosinophils. Herberth [26] found that elevated IL-4 levels in umbilical cord blood can increase the risk of AD. Our research results show that the levels of serum IL4 in AD children and mothers are significantly higher than those in the control group. These data suggest that IL-4 has a predictive effect for AD occurrence. In the process of AD pathogenesis, IL-18 plays a two-way role. On one hand, it can activate the Thl-related immune response and trigger the Th2 immune response; on the other hand, it can stimulate the synthesis of IL-4 and IL-13 in mast cells and basophils, and cause elevated IgE concentrations. Higher serum levels of IL-18 in atopic disease patients also increase the expression of IL-4 and IL-13 [8]. Our data are consistent with earlier findings revealing that the serum IL-18 level was increased in AD patients [27]. However, in the present investigation, IL-18 concentration in cord blood was not significantly altered in the AD group. Therefore, IL-4 but not IL-18 is a better predictor for infant AD. 5. Conclusion In this study, we found that maternal disease history is critically important for the incidence of infant AD. Additionally, to reduce the risk of disease onset, more considerations should be paid to limiting housing renovation, occurrence of infections, and carefully choice of nutrition during pregnancy. In addition, IgE and IL-4 levels in maternal serum and umbilical cord blood as well as the IL-18 level
0.039 0.029 0.041 0.041 0.022 0.040 0.106 0.428 0.357 0.614 0.088 0.011 0.022 0.057 0.055 0.230 0.106 0.114 0.239
Umbilical cord blood
P
AD group, n ¼ 35
Control group, n ¼ 35
11 10 9 8 8 7 5 4 3 2 8 7 6 5 5 3 2 1 1
5 4 3 2 2 1 1 1 1 0 4 2 1 3 1 1 2 0 0
(31.43) (28.57) (25.71) (22.86) (22.86) (20.00) (14.29) (11.43) (8.57) (5.71) (22.86) (20.00) (17.14) (14.29) (14.29) (8.57) (5.71) (2.86) (2.86)
(14.29) (11.43) (8.57) (5.71) (5.71) (2.86) (2.86) (2.86) (2.86) (0.00) (11.43) (5.71) (2.86) (8.57) (2.86) (2.86) (5.71) (0.00) (0.00)
0.088 0.073 0.057 0.040 0.040 0.055 0.198 0.357 0.614 0.493 0.342 0.151 0.106 0.710 0.198 0.614 1.000 1.000 1.000
in maternal serum could be used to diagnose infant AD. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.mcp.2016.03.006. References [1] K.M. Donohue, et al., Anti-cockroach and anti-mouse IgE are associated with early wheeze and atopy in an inner-city birth cohort, J. Allergy Clin. Immunol. 122 (5) (2008) 914e920. [2] W.J. Choi, et al., Prevalence and risk factors for atopic dermatitis: a crosssectional study of 6,453 Korean preschool children, Acta Derm. Venereol. 92 (5) (2012) 467e471. [3] N. Kawamoto, et al., Total IgE at 6 months predicts remittance or persistence of atopic dermatitis at 14 months, Allergy Asthma Proc. 34 (4) (2013) 362e369. [4] I.J. Wang, J.Y. Wang, K.W. Yeh, Childhood atopic dermatitis in Taiwan, Pediatr. Neonatol. 57 (2) (2016 Apr) 89e96. [5] M. Herrant, et al., Risk factors associated with asthma, atopic dermatitis and rhinoconjunctivitis in a rural Senegalese cohort, Allergy Asthma Clin. Immunol. 11 (1) (2015) 24. [6] S. Weidinger, N. Novak, Atopic dermatitis, Lancet 387 (10023) (2016 Mar 12) 1109e1122. [7] C. Schut, et al., Coping as mediator of the relationship between stress and itch in patients with atopic dermatitis: a regression and mediation analysis, Exp. Dermatol. 24 (2) (2015) 148e150. [8] K. Kou, et al., Association of serum interleukin-18 and other biomarkers with disease severity in adults with atopic dermatitis, Arch. Dermatol Res. 304 (4) (2012) 305e312. [9] Z. Liu, et al., Association between maternal exposure to housing renovation and offspring with congenital heart disease: a multi-hospital case-control study, Environ. Health 12 (2013) 25. [10] H.C. Williams, et al., Validation of the U.K. diagnostic criteria for atopic dermatitis in a population setting. U.K. Diagnostic Criteria for Atopic Dermatitis Working Party, Br. J. Dermatol. 135 (1) (1996) 12e17. [11] H. Gu, Y. Yan, K. Chen, Epidemiological survey of atopic dermatitis in Chinese population, Chin. J. Dermatol. 33 (6) (2000) 379e382. [12] H.J. Wen, et al., Prediction of atopic dermatitis in 2-yr-old children by cord blood IgE, genetic polymorphisms in cytokine genes, and maternal mentality during pregnancy, Pediatr. Allergy Immunol. 22 (7) (2011) 695e703. [13] Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC, Int. Study Asthma Allerg. Child. (ISAAC) Steer. Comm. Lancet 351 (9111) (1998) 1225e1232. [14] H. Gu, Y. Yan, K. chen, Epidemiological survey in atopic dermatitis, Chin. Dermatol. J. 33 (6) (2000) 379e382. [15] S.J. Uekert, et al., Sex-related differences in immune development and the expression of atopy in early childhood, J. Allergy Clin. Immunol. 118 (6) (2006) 1375e1381. [16] D. Dogruel, et al., Prevalence of and risk factors for atopic dermatitis: a birth cohort study of infants in southeast Turkey, Allergol. Immunopathol. Madr. (2015 Nov 14) pii: S0301-0546(15)00122-00126.
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Please cite this article in press as: J.-j. Jin, et al., Risk factors for and expression of immune and inflammatory factors in atopic dermatitis in Chinese population: A birth cohort study, Molecular and Cellular Probes (2016), http://dx.doi.org/10.1016/j.mcp.2016.03.006