Hypothesis Proposal about Predictive Factors and Optimal Age for Response to Herbal Medicine Treatment for Height Gain in Children: a Retrospective Review

Jungtae Leem, Jeeyeun Kim, Kyeungsuk Suh, Youngkwern Lim, Junhee Lee Department of Internal Medicine of Korean Medicine, Dongshin Korean Medicine Hospital, 351, Omok-ro, Yangcheon-gu, Seoul, 07999, Republic of Korea Chung-Yeon Medical Institute, 64, Sangmujungang-ro, Seo-gu, Gwangju, 61949, Republic of Korea Korean Medicine Clinical Trial Center, Kyung Hee University Korean Medicine Hospital, 23 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, South Korea Aijoafamily Korean Medical Clinic Network, 1587 Bongyeong-ro, Yeongtong-gu, Suwon-si Gyeonggi-do, 16703, South Korea Department of Sasang Constitutional Medicine, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, South Korea Original Article


Introduction
Idiopathic short stature (ISS) is defined by a height less than 2.0 standard deviation (SD) of the average height of the corresponding population in the absence of any other disease that could explain the short stature 1) .
The fact that 80% of short children who visit pediatric clinics are diagnosed with ISS indicates that most children of short stature exhibit no pathological findings or history of low birth weight and/or height 1) . The Food and Drug Administration approved growth hormone (GH) therapy for patients with ISS with height less than 2.25 SD (1.2 percentile) of the corresponding population 2) . Although GH therapy has been known to increase height in adults by up to 4 cm 2) , several side effects of treatment have been reported, including intracranial hypertension, edema, worsening of scoliosis, and hyperglycemia 3),4) .
Herbal medicine is a widely used intervention for height gain in children in Korea. According to a previous study, 4.4-7.3% of school-children attempt treatment for height gain, and herbal medicine is the most commonly administered treatment modality 5) . Several clinical studies have reported the positive effects of herbal medicine on height gain [6][7][8][9] . In addition, the side effects of herbal medicine in children are relatively few and not serious. In a previous study, only 4.2% of the children exhibited side effects, most of which disappeared spontaneously 10) . Another study reported that most parents (89%) expected that Korean medicine (KM) therapy would increase the rate of height gain and believed herbal medicine to be the most important treatment modality for the same 11) . Satisfaction with the outcome of herbal medicine treatment was also reported to be high (62%), and 52% of parents were reported as believing KM treatment to be better than western medicine 12) .
Several factors, including the initiation of GH therapy in the prepubescent period, delay in bone aging, and dosage of GH, can predict the outcome of GH therapy 2), 13) . Patient age, weight, midparental height (MPH), GH dosage, and response to GH treatment in standard provocation tests were reported as being important determinants for treatment outcome in a statistical model study 14) . However, most patients who present at KM clinics for treatment for height gain do not satisfy the criteria for ISS diagnosis. In a previous report, only 12.1% of the patients were reported as being shorter than the 3 rd percentile 15) , which indicates that patients who prefer herbal medicine treatment do not often satisfy the indication criteria for GH therapy.
Therefore, application of predictive factors for treatment response in western medicine therapy to KM without evaluation is not reasonable. The determinants for treatment response have not yet been established in herbal medicine treatment. Therefore, in this study, we attempted to determine the factors that could predict treatment response with herbal medicine for height gain in children by multiple linear regression analysis with adjustment for confounding factors. Additionally, we also attempted to determine the optimum cutoff value of the continuous variable by receiver operating characteristic (ROC) curve analysis.

Methods
We conducted a retrospective chart review of children  Individualized herbal medicine in the form of water-extract decoction (60 mL; twice a day) was prescribed to each patient on the basis of pattern identification. The composition of the prescribed herbal medicine and treatment duration were also recorded.
Treatment duration was defined as the number of prescribed herbal medicine packages divided by two, since every patient was instructed to ingest two packages of herbal medicine per day. Since treatment for rhinitis or obesity is often performed in conjunction with treatment for height gain, the usage of major medicinal herbs that treat obesity, such as Ephedra sinica, and rhinitis, such as Forsythiae fructus and Schizonepeta tenuifolia, was recorded in order to investigate the effects of these additional medicinal herbs on treatment response.
Herbal formula prescribed to each child was defined as the formula prescribed for more than 30% of the total treatment duration. The names of the herbal formulas have been presented in Table 5, along with the 'methods of treatment (治法)' according to traditional Chinese medicine theory. Description of the 'methods of treatment' followed the World Health Organization  Table 1.
In order to avoid multicollinearity, the representative variables were included in regression analysis. For example, height and weight were integrated into the BMI index. In simple linear regression, the p-values for sex, age, expression of secondary sex characteristics, MPH, BMI, CA minus BA, and administration of Forsythiae fructus and Schizonepeta tenuifolia were less than 0.2 (Table 2). Therefore, these eight variables were further analyzed by multiple regression analysis.   The differences in height percentile before and after treatment ranged from 3 to 14 in the responder group  Figure 2). This indicated that treatment response in children below 9.75 years of age was better compared to that in children older than 9.75 years.
Based on the cutoff value of age, we performed  to that in the older group (p < 0.001; Table 4).
The dryness-moistening (潤燥劑) and tonifying and replenishing (補益劑) formulas are the most frequently used treatment methods for height gain in children.
The most frequently prescribed herbal formula in the present study was modified Jaeumyangyeongtang (滋陰 養榮湯加減方), which was administered to 26 children.
Detailed method of treatment and herbal formula for height gain in each child are shown in Table 5

Discussion
The results of the present study showed that the age of initiation of herbal medicine treatment and administration of Forsythiae fructus are predictive factors for treatment response for height gain in children.
The optimal cutoff value of age for the prediction of treatment response with herbal medicine was 9.75 years, which indicated that the children of the younger age group exhibited better treatment response than the  [29][30][31] . In our study, although the occurrence of secondary sex characteristics was not found to affect treatment response, patient age was an important predictive factor. In previous studies, the effect of age on treatment response with herbal medicine was a matter of controversy 7), 9) . However, since neither study adjusted for confounding factors, the results of the present study might be more reliable in comparison.
Additionally, patient age was reported as an important predictor of GH therapy response 2),30), 31) . In Korea, the ages of onset of puberty in boys and girls were reported to be 12.1 ± 1.5 years and 11.3 ± 1.3 years, respectively 32) .
The results of subgroup analysis in the present study revealed a significant increase in height percentile in the younger age group, but not in the older age group.
Additionally, herbal medicine treatment for height gain was more effective in children below 9.75 years than in those older than 9.75 years, according to our results of ANCOVA. Therefore, we recommend the initiation  Gwiinansimtang (歸仁安心湯; n = 2) Gwibiondamtang (歸脾溫膽湯; n = 2) Herbal formula prescribed to each child was defined as the formula prescribed for more than 30% of the total treatment duration. Therefore, the total number of herbal formulas exceeds 61. The results of multiple regression analysis revealed no associations between several independent variables and treatment response. However, because of the lack of statistical power, the negative results of the present study should be interpreted with caution. Heredity are important predictors of growth and GH treatment response 13),21) . However, MPH was not found to be a predictor of response to herbal medicine treatment in the present study; this is in agreement with the results of previous studies on herbal medicine, which reported no influence of heredity on treatment response 6),7) . The baseline height percentile was also not found to be a predictor of treatment response in the present study.
However, whether baseline percentile is a determinant of treatment response with herbal medicine is a matter of controversy [6][7][8][9] . In a previous study, GH therapy was reported as being effective in children of the lower percentile group 30) . Therefore, further investigation regarding the influence of baseline height percentile on treatment response with herbal medicine is required.
The administration of Ephedra sinica, which is frequently prescribed for the treatment of obesity 39), 40) , was not found to influence treatment response.
Additionally, because of the small proportion of children with a history of previous therapy, we were unable to evaluate the influence of previous KM or GH therapy on treatment response in the present study. The tonifying and replenishing formula (補益劑) is used to nourish blood or replenish qi 22) . Both these treatment methods target the deficiency syndrome, which is an important factor in growth treatment in children 15) . The phlegm-dispelling formula (祛痰劑) is used for dissipating or expelling phlegm. Phlegm is defined as a pathological product accumulated in the body, which causes several diseases 22) . Several medicinal herbs are used to remove phlegm accumulated in the body. In the present study, Ephedra sinica was administered for weight loss, especially in obese children. Although the influence of herbal formulas for obesity treatment on height growth in children is not well established, it is an interesting subject for further research. The digestant formula (消食劑) is used to enhance digestion and disperse stagnant food 22) . Herbal medicine treatment for digestive problems is known to aid height growth in children 8) . Sleep disorders due to chronic rhinitis interferes with growth in children 37) . The tranquillizing formula (安神劑) is used to relieve mental stress and stabilize the mind to improve sleep quality 22) . The exterior-releasing formula (解表劑) is used to discharge pathogenic factors from superficial parts of the body such as the nose or skin. 22) . In our study, several exterior-releasing formulas were used to treat rhinitis. to construct a prediction model for herbal medicine (355) treatment that could help determine the optimal treatment regimen and goals based on realistic expectations 14) . Prospective long-term follow-up studies with large sample sizes are required to conclusively confirm the findings of our study. Finally, the criteria for inclusion in our study were relatively broad. We did not target specified herbal prescription or medicinal herbs. We could not identify effect of specific prescription or medicinal herbs. However, this study was the first report regarding the determinants of response to various herbal medicine treatment for height gain in children. We recommend further analysis involving a broad spectrum of patients in order to achieve a greater generalization of results. We also recommend study design about effect of specific herbal prescription or medicinal herbs on height growth.
The present study has several strengths. Ours is the first study involving the use of multiple regression analysis for the prediction of treatment response with various herbal medicine for height gain. Consequently, the results of our study are more robust compared to those of previous studies that performed univariate analysis 6),7),9),15),37), 44) . Determination of the cutoff value of treatment age can be helpful in the assessment of the best course of treatment in clinical practice. The relatively wide ranges of inclusion criteria and herbal medicine prescriptions allow the generalization of results of the present study. A prospective cohort study is required to conclusively confirm the feasibility of the determinants of treatment response. However, in consideration of the time and money that a prospective study would entail, retrospective chart reviews should be given precedence. The results of our study will form the basis for further studies in this area.

Conclusion
According to the results of our retrospective review, patient age and administration of Forsythiae fructus were predictive of response to herbal medicine treatment for height gain in children. The optimal cutoff value of age for the prediction of treatment response was 9.75 years. Children below 9.75 years of age exhibited a significant increase in height percentile. The results of our study will help clinicians decide on the course of treatment. Future studies with prospective design, specific inclusion criteria and herbal medicine prescriptions, evaluation of a greater number of predictive variables, and larger sample size are required.
The findings of the present study will be fundamental for creating prediction models in future studies.

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