Persistent eczema leads to both impaired growth and food allergy: JECS birth cohort.

Skin inflammation leads to altered cytokine/chemokine production and causes systemic inflammation. The systemic mechanism of atopic dermatitis (AD) is recognized to affect systemic metabolism. This study aimed to examine the relationship between early-onset persistent eczema and body weight, height, and body mass index (BMI), in addition to food allergy in a birth cohort among infants. This study design was a nationwide, multicenter, prospective birth cohort study-the Japan Environment and Children's Study (JECS). Generalized linear models were fitted for z scores of weight, height, BMI, and food allergy to evaluate the relationship between eczema and these outcomes for infants at age1, 2, and 3 years. Persistent eczema was negatively associated with height at the age of 2 years (estimated coefficient, -0.127; 95% confidence interval [CI], -0.16 to -0.095) and 3 years (-0.177; 95% CI, -0.214 to -0.139). The same tendency was also observed with weight and BMI. Early disease onset at younger than 1 year and persistent eczema had the strongest association with development of food allergy at age 3 years (OR, 11.794; 95% CI, 10.721-12.975). One phenotype of eczema with early-onset and persistent disease creates a risk of both physical growth impairment and development of food allergy. Infants who present with the early-onset and persistent type of eczema should be carefully evaluated daily for impaired physical growth and development of food allergy.

Introduction

Atopic dermatitis (AD) is characterized by chronic skin inflammation and heterogeneous disease [1]. Several studies reported several phenotypes of AD in children [2, 3]. In Japan, 7.3% young children were diagnosed as AD from a national birth cohort [4]. AD is associated with various comorbidities such as anxiety, depression, and attention deficit hyperactivity disorder [5, 6]. Skin inflammation leads to altered cytokine/chemokine production and causes systemic inflammation [7]. Thereby, the systemic mechanism of AD is recognized to affect systemic metabolism. Nomura et al. [8] reported that infants hospitalized with severe AD had impaired mental and physical growth, protein loss through skin inflammation, and elevated serum interleukin (IL), including IL5, IL6, and IL12. Furthermore, early-onset and/or persistent AD is a known risk factor for food allergy based on a birth cohort study [3, 9]. We hypothesized that early-onset and persistent AD in infants may lead not only to impaired physical growth but food allergy as well because of long-term skin inflammation. This study aimed to examine the relationship between early-onset persistent AD and body weight, height, and body mass index (BMI), in addition to food allergy in a birth cohort.

Materials and methods

This study design was a nationwide, multicenter, prospective birth cohort study—the Japan Environment and Children’s Study (JECS), funded by the Ministry of the Environment, Japan [10-12]. The JECS enrolled a general population of 103,060 pregnant women in 15 Study Areas covering a wide region across Japan from the north (Hokkaido) to south (Okinawa) from January 2011 to March 2014. Eligibility criteria were as follows: 1) currently pregnant; 2) living in the Study Area for the foreseeable future; 3) expected delivery between August 1, 2011, and mid-2014; and 4) ability to understand the Japanese language. In total, 104,062 fetuses were enrolled in the JECS. The registry of the JECS is the University Hospital Medical Information Network (UMIN Clinical Trials Registry 000030786). The JECS protocols for the main study and the sub-cohort study are described on the websites of the Ministry of the Environment, Japan [13, 14]. The JECS protocol was reviewed and approved by the Ministry of Environment’s Institutional Review Board for Epidemiologic Studies (#100910001) and by the ethics committees of all participating institutions (#2019–070). Written informed consent was obtained from all participants. The JECS was conducted in accordance with the principles laid out in the Helsinki Declaration and other national regulations and guidelines.

Questionnaire

Written questionnaires were provided to caregivers during pregnancy for child participants at age 6 months and 1, 1.5, 2, 2.5, and 3 years. Caregivers answered questions regarding the child and the family.

Outcomes

Information on each child’s background and lifestyle was assessed using questionnaires in Japanese. Eczema history and Caregiver-reported physician diagnoses food allergy were obtained from questionnaires at ages 1, 2, and 3 years.

This study extracted the children’s weight and height data from surveys conducted at age 1, 2, and 3 years. The LMS (lambda-mu-sigma) statistical method was used to calculate z scores for weight, height, and BMI (weight/height2) [15]. Age- and sex-specific values of L, M, and S were obtained from the Japanese growth curve criteria [16, 17].

Statistical analyses

After excluding preterm birth, twin birth, neonatal complications, and chronic disease other than eczema and food allergy, 59,847 mother–child pairs remained for analysis (S1 Fig). A fixed data set (jecs-ta-201901930-qsn, released in October 2019) was used for this study. Generalized linear models were fitted for z scores of weight, height, BMI, and food allergy. An identity link function was used to model continuous outcomes (z scores of weight, height, BMI), and a logit link was used for modeling the binary outcome (food allergy). The coefficients in the models provided measures for the strength of associations (compared with the reference group). Three models were fitted for each outcome (z scores of weight, height, BMI, and food allergy) for children at ages 1, 2, and 3 years. For the models evaluating the relationship between eczema and outcomes for children at age 2 years, the exposure variable eczema was classified into four groups: 1) no eczema at 1 and 2 years; 2) eczema at 1–2 years; 3) eczema only at 1 year; and 4) eczema only at 2 years. The group that had no eczema at age 1 and 2 years was designated as reference group. Similarly, on assessment at age 3 years, children with eczema during 1–3 years had eight patterns based on whether they had eczemaat age 1, 2, and 3 years or not. The status of no eczema at 1, 2, and 3 years was designated as reference group in the models. Eczema and food allergy are high multicollinearity so we did not input food allergy in the models. An assumption was made that data were missing at random. Missing data for independent variables were imputed using multiple imputation (MI) analysis with a chained equations (MICE) algorithm. The variables used for MI process included sex, siblings, maternal history of AD, paternal history of AD, and maternal highest level of education. To obtain pooled coefficients of models, 20 data sets with missing data were generated. Bonferroni correction was applied for correcting multiple testing, and the thresholds were set at 0.05/44 (0.001). For the sensitivity analysis, the same models were refitted using complete dataset.

All the analyses were performed using R software (version 4.0.3, Institute for Statistics and Mathematics, Vienna, Austria; www.r-project.org). The R packages “MICE” was used for the MI process.

Results

Table 1 shows the baseline characteristics. Maternal history of AD was found for 15.8% of participants. Income: <4,000,000 yen/annual income was reported from 38.8 participants.

Table 1

Baseline characteristics for participants.

Participant	n	N	%
Place at recruitment
Hokkaido	4570	59847	7.6
Miyagi	5196	59847	8.7
Fukushima	7929	59847	13.2
Chiba	3110	59847	5.2
Kanagawa	3916	59847	6.5
Koshin	4245	59847	7.1
Toyama	3377	59847	5.6
Aichi	3343	59847	5.6
Kyoto	2512	59847	4.2
Osaka	4791	59847	8
Hyogo	3147	59847	5.3
Tottori	1877	59847	3.1
Kochi	4075	59847	6.8
Fukuoka	4424	59847	7.4
South Kyushu/Okinawa	3335	59847	5.6
Mother
Age <35 years	44473	59577	74.6
Age > = 35 years	15104	59577	25.4
Education: Middle school and high school	20144	59319	34
Education: Technical, College, University and Graduate	39175	59319	66
Income: <4,000,000 yen/annual income	21640	55768	38.8
Income: > = 4,000,000 yen/annual income	34128	55768	61.2
Health: Maternal atopic dermatitis history (+)	9400	59580	15.8
Health: Maternal food allergy history (+)	2793	59580	4.7
Child
Sibling	33766	59580	56.7
Boys	30051	59847	50.2
Girls	29796	59847	49.8

n, yes, N, variables without missing data.

Table 2 presents the numbers of participants with AD and food allergy. At the age of 1 year, 19% infants had AD and food allergy. At the age of 3 years, 27.7% infants had persistent AD and food allergy. Most cases of AD at the age of 1 year were transient.

Table 2

Number of participants with AD and FA.

Child (age in years)	FA (–)		FA (+)
	n	(%)	n	(%)
1 year of age
eczema1Y (–)	46065	96.2	1809	3.8
eczema1Y(+)	8861	81	2082	19
Missing	246	–	15	–
ALL	55172	93.4	3906	6.6
2 years of age
eczema1Y(–) and eczema2Y(–)	41592	96.5	1518	3.5
eczema1Y(+) and eczema2Y(+)	3832	72.6	1448	27.4
eczema1Y(–) and eczema2Y(+)	4093	89.8	465	10.2
eczema1Y(+) and eczema2Y(–)	4860	87	729	13
Missing	1203	–	107	–
ALL	55580	92.9	4267	7.1
3 years of age
eczema1Y(–) and eczema2Y(–) and eczema3Y(–)	39143	97.2	1135	2.8
eczema1Y(+) and eczema2Y(+) and eczemaY(+)	2416	72.8	904	27.2
eczema1Y(+) and eczema2Y(+) and eczema3Y(–)	1504	80.7	360	19.3
eczema1Y(+) and eczema2Y(–) and eczema3Y(+)	834	82.5	177	17.5
eczema1Y(+) and eczema2Y(–) and eczema3Y(–)	4049	89.5	477	10.5
eczema1Y(–) and eczema2Y(+) and eczema3Y(+)	1592	87.9	220	12.1
eczema1Y(–) and eczema 2Y(+) and eczema3Y(–)	2509	93.2	182	6.8
eczema1Y(–) and eczema2Y(–) and eczema3Y(+)	2481	93.2	181	6.8
Missing	1523	–	160	–
ALL	56051	93.7	3796	6.3

ALL, participants including; FA, food allergy; 1Y, age 1 year; 2Y, age 2 years; 3Y, age 3 years.

Table 3 presents the eczema associations with z scores of body weight, height, and BMI at ages 1, 2, and 3 years. Early disease onset at younger than 1 year and persistent eczema were evaluated for association with the child’s status at ages 2 and 3 years as follows. Body weight was negatively associated with persistent eczema at the age of 2 years (estimated coefficient, −0.146; 95% confidence interval [CI], −0.174 to −0.117) and 3 years (−0.148; 95% CI, −0.181 to −0.114). Height was negatively associated with persistent eczema at the age of 2 years (estimated coefficient, −0.127; 95% CI, −0.16 to −0.095) and 3 years (−0.177; 95% CI, −0.0214 to −0.139). Also, BMI was negatively associated with height at the age 2 years (estimated coefficient, −0.081; 95% CI, −0.113 to −0.05) and 3 years (−0.058; 95% CI, −0.094 to −0.022).

Table 3

Caregiver-reported physician diagnoses of atopic dermatitis and physical growth.

Age (years)	Outcomes (z scores)		Eczema	Eczema	Eczema	Coefficienta	SE	95% CI		p valueb
			1 year	2 years	3 years			Lower	Upper
1	Weight	Eczema1Y (–)	–			1
		Eczema1Y(+)	+			–0.093	0.011	–0.114	–0.072	<0.0001
2	Weight	Eczema 1Y(–) Eczema 2Y(–)	–	–		1
		Eczema1Y(+) Eczema2Y(+)	+	+		–0.146	0.015	–0.174	–0.117	<0.0001
		Eczema 1Y(–) Eczema 2Y(+)	–	+		0.012	0.016	–0.018	0.042	0.4404
		Eczema1Y(+) Eczema2Y(–)	+	–		–0.079	0.014	–0.107	–0.051	<0.0001
3	Weight	Eczema 1Y(–) Eczema 2Y(–) Eczema 3Y(–)	–	–	–	1
		Eczema1Y(+) Eczema2Y(+) Eczema3Y(+)	+	+	+	–0.148	0.017	–0.181	–0.114	<0.0001
		Eczema1Y(+) Eczema 2Y(+) Eczema3Y(–)	+	+	–	–0.067	0.022	–0.111	–0.023	0.0029
		Eczema1Y(+) Eczema 2Y(–) Eczema 3Y(+)	+	–	+	–0.019	0.03	–0.079	0.04	0.5230
		Eczema1Y(+) Eczema2Y(–) Eczema3Y(–)	+	–	–	–0.058	0.015	–0.087	–0.029	0.000108
		Eczema 1Y(–) Eczema 2Y(+) Eczema 3Y(+)	–	+	+	–0.037	0.023	–0.082	0.008	0.1068
		Eczema 1Y(–) Eczema 2Y(+) Eczema 3Y(–)	–	+		–0.011	0.019	–0.048	0.026	0.5487
		Eczema 1Y(–) Eczema 2Y(–) Eczema 3Y(+)	–	–	+	–0.005	0.019	–0.043	0.032	0.7718
1	Height	Eczema1Y (–)	–			1
		Eczema1Y(+)	+			–0.047	0.011	–0.068	–0.025	<0.0001
2	Height	Eczema 1Y(–) Eczema 2Y(–)	–	–		1
		Eczema1Y(+) Eczema2Y(+)	+	+		–0.127	0.017	–0.16	–0.095	<0.0001
		Eczema 1Y(–) Eczema 2Y(+)	–	+		–0.029	0.018	–0.064	0.005	0.0982591
		Eczema1Y(+) Eczema2Y(–)	+	–		–0.042	0.016	–0.074	–0.011	0.0088
3	Height	Eczema 1Y(–) Eczema 2Y(–) Eczema 3Y(–)	–	–	–	1
		Eczema1Y(+) Eczema2Y(+) Eczema3Y(+)	+	+	+	–0.177	0.019	–0.214	–0.139	<0.0001
		Eczema1Y(+) Eczema 2Y(+) Eczema3Y(–)	+	+	–	–0.065	0.025	–0.114	–0.016	0.0098
		Eczema1Y(+) Eczema 2Y(–) Eczema 3Y(+)	+	–	+	–0.098	0.034	–0.165	–0.032	0.0038
		Eczema1Y(+) Eczema2Y(–) Eczema3Y(–)	+	–	–	–0.055	0.017	–0.088	–0.022	0.0010
		Eczema 1Y(–) Eczema 2Y(+) Eczema 3Y(+)	–	+	+	–0.095	0.025	–0.145	–0.045	0.0002
		Eczema 1Y(–) Eczema 2Y(+) AD3Y(–)	–	+		–0.027	0.021	–0.068	0.014	0.2007
		Eczema 1Y(–) Eczema 2Y(–) Eczema 3Y(+)	–	–	+	–0.048	0.021	–0.09	–0.006	0.0246
1	BMI	Eczema1Y (–)	–			1
		Eczema1Y(+)	+			–0.069	0.011	–0.09	–0.048	<0.0001
2	BMI	Eczema 1Y(–) Eczema 2Y(–)	–	–		1
		Eczema1Y(+) Eczema2Y(+)	+	+		–0.081	0.016	–0.113	–0.05	<0.0001
		Eczema 1Y(–) Eczema 2Y(+)	–	+		0.049	0.017	0.015	0.082	0.0046
		Eczema1Y(+) Eczema2Y(–)	+	–		–0.064	0.016	–0.094	–0.033	<0.0001
3	BMI	Eczema 1Y(–) Eczema 2Y(–) Eczema 3Y(–)	–	–	–	1
		Eczema1Y(+) Eczema2Y(+) Eczema3Y(+)	+	+	+	–0.058	0.018	–0.094	–0.022	0.001483
		Eczema1Y(+) Eczema 2Y(+) Eczema3Y(–)	+	+	–	–0.051	0.024	–0.098	–0.003	0.0367
		Eczema1Y(+) Eczema 2Y(–) Eczema 3Y(+)	+	–	+	0.053	0.033	–0.011	0.117	0.1064
		Eczema1Y(+) Eczema2Y(–) Eczema3Y(–)	+	–	–	–0.041	0.016	–0.072	–0.009	0.0118
		Eczema 1Y(–) Eczema 2Y(+) Eczema 3Y(+)	–	+	+	0.041	0.025	–0.008	0.089	0.1011
		Eczema 1Y(–) Eczema 2Y(+) Eczema 3Y(–)	–	+		0.007	0.02	–0.033	0.047	0.7271
		Eczema 1Y(–) Eczema 2Y(–) Eczema 3Y(+)	–	–	+	0.046	0.02	0.006	0.086	0.0253

AD, atopic dermatitis; CI, confidence interval; 1 Y, age 1 year; 2 Y, age 2 years; 3 Y, age 3 years.

aGeneralized linear models with identity link function.

bBonferroni correction was applied for correcting multiple testing, and the thresholds were set at 0.05/44 (0.001).

Table 4 shows the associations of eczema with food allergy. Early disease onset at younger than 1 year and persistent eczema had the strongest association with development of food allergy at age 2 years (odds ratio [OR], 9.861; 95% CI, 9.115–10.668) and 3 years (OR, 11.794; 95% CI, 10.721–12.975). Late onset of eczema (diagnosis at three years of age) was less associated with food allergy development (OR, 2.373; 95%CI, 2.02–2.789) compared to the early-onset and persistent eczema.

Table 4

Caregiver-reported physician diagnoses of atopic dermatitis and food allergy.

Age (years)	Outcomes		Odds ratio	95% CI		p valueb
				Lower	Upper
1	Food allergy	Eczema1Y (–)	1
		Eczema1Y(+)	5.943	5.558	6.354	<0.0001
2	Food allergy	Eczema 1Y(–) Eczema 2Y(–)	1
		Eczema1Y(+) Eczema2Y(+)	9.861	9.115	10.668	<0.0001
		Eczema 1Y(–) Eczema 2Y(+)	3.012	2.703	3.356	<0.0001
		Eczema1Y(+) Eczema2Y(–)	3.962	3.61	4.348	<0.0001
3	Food allergy	Eczema 1Y(–) Eczema 2Y(–) Eczema 3Y(–)	1
		Eczema1Y(+) Eczema2Y(+) Eczema3Y(+)	11.794	10.721	12.975	<0.0001
		Eczema1Y(+) Eczema 2Y(+) Eczema3Y(–)	7.603	6.687	8.646	<0.0001
		Eczema1Y(+) Eczema 2Y(–) Eczema 3Y(+)	6.767	5.698	8.037	<0.0001
		Eczema1Y(+) Eczema2Y(–) Eczema3Y(–)	3.791	3.392	4.236	<0.0001
		Eczema 1Y(–) Eczema 2Y(+) AD3Y(+)	4.428	3.797	5.163	<0.0001
		Eczema 1Y(–) Eczema 2Y(+) AD3Y(–)	2.366	2.013	2.782	<0.0001
		Eczema 1Y(–) Eczema 2Y(–) Eczema 3Y(+)	2.373	2.02	2.789	<0.0001

CI, confidence interval; 1 Y, age 1 year; 2 Y, age 2 years; 3 Y, age 3 years.

aGeneralized linear models with Logit link function (logistic regression model).

bBonferroni correction was applied for correcting multiple testing, and the thresholds were set at 0.05/44 (0.001).

Discussion

Based on these data from a large-scale, national, birth cohort study in Japan, early-onset and persistent eczema negatively affected physical growth and created a risk of low body weight, short height, low BMI, and development of food allergy. To the best of our knowledge, this is the first report on the relationship between infant eczema and physical growth among the Japanese general population. We demonstrated that early-onset and persistent eczema phenotype was the strongest risk factor for both physical growth retardation and food allergy. This is also the first report regarding the mechanism by which eczema phenotypes are linked to body weight, height, and BMI. A systematic review and meta-analysis [18] of AD and weight status in children observed that AD overall was associated with overweight (random effects OR, 1.24; 95% CI, 1.08–1.43), obesity (random effects OR, 1.44; 95% CI, 1.12–1.86), or overweight/obesity (random effects OR, 1.32; 95% CI, 1.15–1.51). This systematic review included all phenotypes of AD, which is a heterogeneous disease with several phenotypes [2, 3]. The associations of comorbidity, such as allergic diseases—food allergy, asthma, and immunoglobulin E sensitization—differed among AD phenotypes. Adult populations with severe AD may gain weight after treatment with dupilumab [19]. Early-onset AD tended to be more severe disease [20]. A systematic review of 66 studies concluded that AD appeared to precede the development of food allergy. Therefore, we considered that AD occurs before food allergy. It is also known that AD can be a risk factor for developing IgE sensitization to allergens. We considered that eczema occurred first, sensitization second, and food allergy third based on the systematic review. The present study speculates that severe and persistent eczema may lead to persistent skin inflammation, producing various cytokines/chemokines from the skin that may in turn affect systemic metabolism. A previous study reported that severe childhood AD led to hypoprotenemia, hyperkaremia, and hyponatremia as leaking through the skin [8]. Homeostasis of the body could be damaged by skin inflammation. Early-onset and persistent eczema may create a risk of not only “allergic march” but also slowed physical growth. Multiple comorbidities related to eczema should be considered for this eczema phenotype [21].

In general, epidemiologic studies have limitations. Reporting biases inevitably arise. Outcome assessments were not made directly by clinicians but through a questionnaire given to caregivers. The prevalence and incidence of the disease may have been overestimated or underestimated. However, we could apply physician-diagnosis outcomes. Various past studies have used same definitions. Second, information regarding medical interventions, including medications, was not obtained, thus it was not possible to evaluate how medical interventions and disease activities may affect physical growth and food allergy. In terms of for the elimination status, we did not evaluate the details of the elimination diet. However, we believe that the Japanese guidelines on food allergy recommend minimum causal food elimination; thus, we considered that most children underwent only minimum food elimination that did not affect physical growth.

Conclusions

This study highlighted that one phenotype of eczema with early-onset and persistent disease creates a risk of both physical growth impairment and development of food allergy. Infants who present with the early-onset and persistent type of eczema should be carefully evaluated daily for impaired physical growth and development of food allergy.

Flow chart of the study participants.

(DOCX)

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21 Oct 2021

PONE-D-21-29612Persistent atopic dermatitis leads to both impaired growth and food allergy: JECS Birth CohortPLOS ONE

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The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: General Comments:

This paper used a large prospective cohort study to investigate atopic dermatitis and food allergy and body size. The weakness of this paper is that the diagnosis of food allergy is not clear. It is likely that most children did not receive appropriate oral food challenge tests during the follow-up period because the number of children with food allergies changed little between the ages of one, two, and three years. Therefore, I frankly felt that children with persistent atopic dermatitis are more likely to be misdiagnosed with food allergy. In the future, studies with a definitive diagnosis of food allergy will be more valuable than ones with large numbers of subjects. On the other hand, as far as I know, there are no studies of this size or larger, so this study is of great value. Hence, I believe that this study is worthy of publication.

Specific recommendations for revision minor:

1. Reference 18 shows that patients with obesity are more likely to have complications of atopic dermatitis. This does not seem to be relevant to the discussion of this study. For example, I propose to discuss reference "Zhang A, et al. Association of atopic dermatitis with being overweight and obese: a systematic review and metaanalysis. J Am Acad Dermatol. 2015; 72: 606-16.e4." as a foundation. Excluding severe cases, such as those involving sleep disorders, atopic dermatitis was not thought to affect the physique. It is interesting that your study found that growth retardation was present at age 3 years.

Reviewer #2: The strength of this study are impressive numbers. It’s also interesting and definite.

We know that chronic conditions could impair the growth and development of children, it is anything new here. What’s interesting, as authors have mentioned in the discussion – in other studies no such impairment was observed in AD – it will be highly welcomed to discuss this in more detailed way - why the differences between current study and previous reports are present – whether it is the age of children, comorbidities or other factors.

The coexistence of atopic dermatitis and food allergy – we don’t know what comes first in infants. The most possible course is that food allergy if the first phenomenon with the presentation of symptoms from the skin – that’s why many infants improve on elimination diet. Another aspect not discussed in the manuscript is how elimination diet could impair the growth.

For better understanding I suggest to add the deceptive characteristics – BMI, height and weight for different ages and diagnoses in the table together with the information how the food allergy was diagnosed and what symptoms children presented – e.g. diagnosis based on the elimination and provocation diet, based on sIgE results, diagnosed by physician. We could have 10 times higher frequencies of food allergy based only on self-reported data.

The conclusion of the study should be rather that the early onset of persistent atopic dermatitis is more likely related to food allergy, while late onset is less likely. Put in that way it doesn’t suggest causal relationship. It is known that AD could be the risk factor for developing sensitisation to other allergens – because of the damage of the skin barrier, but still at the beginning we could have food allergy as the main initiating trigger for skin lesions – it is difficult to establish if food allergy is a risk or outcome of AD.

Another observation, worthy mention is that majority of AD present in the 1 y of life in transient (8861 in 1y. and 2416 in 3y.) and it is also true for FA+AD (2082 in the 1y. and 904 in the 3y.), after exclusion of possibilities that those are the missing cases.

Authors speculate that chronic inflammation affect the metabolism. Please explain the possible mechanism. More detailed discussion is needed here.

In the abstract and in the discussion there is information about the association of BMI with height – but I can’t see that in the data given. Anyway, is it always true based on the equation?

It will be helpful to add the questionnaire to the manuscript.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: Yes: Mitsuhiro Okamoto

Reviewer #2: No

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8 Nov 2021

PONE-D-21-29612

Persistent atopic dermatitis leads to both impaired growth and food allergy: JECS Birth Cohort

PLOS ONE

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Response: Noted.

________________________________________

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Response: Noted.

________________________________________

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

Response: We have already mentioned the data-sharing policy of our study in our first submission.

Data are unsuitable for public deposition because of ethical restrictions and the legal framework of Japan. The Act on the Protection of Personal Information (Act No.57 of May 30, 2003, amendment on September 9, 2015) prohibits the public deposition of data containing personal information. The Ethical Guidelines for Medical and Health Research Involving Human Subjects enforced by the Japan Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labour and Welfare also restricts the open sharing of epidemiologic data. All inquiries about access to data should be sent to jecs-en@nies.go.jp. The person responsible for handling inquiries sent to this e-mail address is Dr Shoji F. Nakayama, JECS Programme Office, National Institute for Environmental Studies. URL: https://www.env.go.jp/chemi/ceh/en/index.html. The authors had no special access privileges to data others would not have.

________________________________________

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Response: Noted.

________________________________________

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Response: Noted.

Reviewer #1: General Comments:

This paper used a large prospective cohort study to investigate atopic dermatitis and food allergy and body size. The weakness of this paper is that the diagnosis of food allergy is not clear. It is likely that most children did not receive appropriate oral food challenge tests during the follow-up period because the number of children with food allergies changed little between the ages of one, two, and three years. Therefore, I frankly felt that children with persistent atopic dermatitis are more likely to be misdiagnosed with food allergy. In the future, studies with a definitive diagnosis of food allergy will be more valuable than ones with large numbers of subjects. On the other hand, as far as I know, there are no studies of this size or larger, so this study is of great value. Hence, I believe that this study is worthy of publication.

Response: Thank you for your kind comments. The discrepancy in the diagnosis of food allergy has been described in the Discussion section. Our study was not performed in hospitals or clinics, as we evaluated the entire general population with and without food allergy. Furthermore, an oral food challenge test was performed only at a certified allergy department. Therefore, it was not feasible to conduct the oral food challenge test for all general children in our study. Regarding the outcome assessment, various studies in high-impact journals have reported the use of the physician’s diagnosis of food challenge via the caregiver’s report. We believe that our study outcome assessment is acceptable. A systematic review of 66 studies concluded that atopic dermatitis appeared to precede the development of food allergy (Tsakok T, Marrs T, Mohsin M, Baron S, du Toit G, Till S, Flohr C. Does atopic dermatitis cause food allergy? A systematic review. J Allergy Clin Immunol. 2016 Apr;137(4):1071-1078). Therefore, we consider that atopic dermatitis occurs before food allergy.

Specific recommendations for revision minor:1. Reference 18 shows that patients with obesity are more likely to have complications of atopic dermatitis. This does not seem to be relevant to the discussion of this study. For example, I propose to discuss reference "Zhang A, et al. Association of atopic dermatitis with being overweight and obese: a systematic review and metaanalysis. J Am Acad Dermatol. 2015; 72: 606-16.e4." as a foundation. Excluding severe cases, such as those involving sleep disorders, atopic dermatitis was not thought to affect the physique. It is interesting that your study found that growth retardation was present at age 3 years.

Response: Thank you for this informative comment. We have referred to a different reference. We were supposed to discuss the same study (Zhang A, et al. Association of atopic dermatitis with being overweight and obese: a systematic review and metaanalysis. J Am Acad Dermatol. 2015; 72: 606-16.e4) that the reviewer has proposed here. We have updated reference 18; however, we have not revised the description of the discussion.

Reviewer #2: The strength of this study are impressive numbers. It’s also interesting and definite.

We know that chronic conditions could impair the growth and development of children, it is anything new here. What’s interesting, as authors have mentioned in the discussion – in other studies no such impairment was observed in AD – it will be highly welcomed to discuss this in more detailed way - why the differences between current study and previous reports are present – whether it is the age of children, comorbidities or other factors.

The coexistence of atopic dermatitis and food allergy – we don’t know what comes first in infants. The most possible course is that food allergy if the first phenomenon with the presentation of symptoms from the skin – that’s why many infants improve on elimination diet. Another aspect not discussed in the manuscript is how elimination diet could impair the growth.

Response: Thank you for these important comments. Accordingly, we have added an explanation to the Discussion section. To the best of our knowledge, this is the first report on the relationship between infant AD and physical growth among the general Japanese population of preschool children. In addition, we reported the difference between AD phenotypes and physical growth, although prior studies evaluated only the relationship among all ADs, including all phenotypes and physical growth. We believe that these are the interesting points of our study. Although we mentioned “the present study speculates that severe and persistent AD may lead to persistent skin inflammation, producing various cytokines/chemokines from the skin that may, in turn, affect systemic metabolism” in the Discussion section, a search of past studies did not reveal any reports on the detailed mechanism of infant AD and physical growth, including comorbidities and other factors. Unfortunately, we could not add many references to the Discussion section. However, a systematic review of 66 studies has already concluded that atopic dermatitis appears to precede the development of food allergy (Tsakok T, Marrs T, Mohsin M, Baron S, du Toit G, Till S, Flohr C. Does atopic dermatitis cause food allergy? A systematic review. J Allergy Clin Immunol. 2016 Apr;137(4):1071-1078). Therefore, we consider that atopic dermatitis occurs before food allergy. We have added the explanation following the comments on Line 188-192. As for the elimination status, we did not evaluate the details of the elimination diet. However, we believe that food allergy guidelines recommend minimum causal food elimination; thus, we consider that most children underwent only minimum causal food elimination that did not affect physical growth. We have added this information within the discussion of the study limitations on 206-210.

For better understanding I suggest to add the deceptive characteristics – BMI, height and weight for different ages and diagnoses in the table together with the information how the food allergy was diagnosed and what symptoms children presented – e.g. diagnosis based on the elimination and provocation diet, based on sIgE results, diagnosed by physician. We could have 10 times higher frequencies of food allergy based only on self-reported data.

The conclusion of the study should be rather that the early onset of persistent atopic dermatitis is more likely related to food allergy, while late onset is less likely. Put in that way it doesn’t suggest causal relationship. It is known that AD could be the risk factor for developing sensitisation to other allergens – because of the damage of the skin barrier, but still at the beginning we could have food allergy as the main initiating trigger for skin lesions – it is difficult to establish if food allergy is a risk or outcome of AD.

Response: Thank you for the comments. We added information regarding how we defined the outcomes to the table legends. We have also added an explanation in the Discussion section following the comments.

Line 188-192: “A systematic review of 66 studies concluded that atopic dermatitis appeared to precede the development of food allergy ((Tsakok T, Marrs T, Mohsin M, Baron S, du Toit G, Till S, Flohr C. Does atopic dermatitis cause food allergy? A systematic review. J Allergy Clin Immunol. 2016 Apr;137(4):1071-1078). Therefore, we considered that atopic dermatitis occurs before food allergy. It is also known that AD can be a risk factor for developing IgE sensitization to allergens. We considered that eczema occurred first, sensitization second, and food allergy third based on the systematic review.”

Another observation, worthy mention is that majority of AD present in the 1 y of life in transient (8861 in 1y. and 2416 in 3y.) and it is also true for FA+AD (2082 in the 1y. and 904 in the 3y.), after exclusion of possibilities that those are the missing cases.

Response: Thank you for this comment. We agree with it. Most cases of AD at the age of 1 year were transient. We have added an explanation to the Results section on Line 137-138.

Authors speculate that chronic inflammation affect the metabolism. Please explain the possible mechanism. More detailed discussion is needed here.

Response: Thank you for this comment. We agree with it. Accordingly, we have added an explanation to the Discussion section.

Lines 195-197: A previous study reported that severe childhood AD led to hypoprotenemia, hyperkaremia, and hyponatremia as leaking through the skin. [22] Homeostasis of the body could be damaged by skin inflammation.

Nomura I, Katsunuma T, Tomikawa M, Shibata A, Kawahara H, Ohya Y, et al. Hypoproteinemia in severe childhood atopic dermatitis: a serious complication. Pediatr Allergy Immunol. 2002;13(4):287-94. Epub 2002/10/23. doi: 10.1034/j.1399-3038.2002.01041.x. PubMed PMID: 12390445.

In the abstract and in the discussion there is information about the association of BMI with height – but I can’t see that in the data given. Anyway, is it always true based on the equation?

Response: We have made mistakes on these points. However, the results presented in the table are correct. We revised the explanation in the abstract along with the table. Also, we have revised the explanation in the Discussion section.

In the abstract: Persistent AD was negatively associated with height at the age of 2 years (estimated coefficient, −0.127; 95% CI, −0.16 to −0.095) and 3 years (−0.177; 95% CI, −0.214 to −0.139)). The same tendency was also observed with weight and BMI.

Lines 175-177: Data obtained from a large-scale, national, birth cohort study in Japan revealed that early-onset and persistent AD negatively affected physical growth and created a risk of low body weight, short height, low BMI, and development of food allergy.

It will be helpful to add the questionnaire to the manuscript.

Response: We understand this point. However, the JECS study group has not completed the preparation of the questionnaire for the public. However, the Ministry of the Environment, Japan is preparing to share the questionnaire via the study website. All can access the questionnaire via the study website.

________________________________________

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Mitsuhiro Okamoto

Reviewer #2: No

Response: Noted.

Submitted filename: renamed_a7c05.docx

Click here for additional data file.

10 Nov 2021

Persistent atopic dermatitis leads to both impaired growth and food allergy: JECS Birth Cohort

PONE-D-21-29612R1

Dear Dr. Yamamoto-Hanada,

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19 Nov 2021

PONE-D-21-29612R1

Persistent eczema leads to both impaired growth and food allergy: JECS Birth Cohort

Dear Dr. Yamamoto-Hanada:

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