A risk factor for early wheezing in infants: rapid weight gain

Wheezing, as a common clinical symptom of pediatric respiratory disease, is characterized by a continuous and sonorous voice in the expiratory phase, and sometimes appears in the inspiratory phase which results in increased respiratory rate [1]. Approximately 50% of children suffered from wheezing in infancy and childhood [2], and roughly 26% of 6265 babies had wheezing at least once within 18 months after birth from a prospective study [3]. Furthermore, about 30–40% of patients with recurrent wheezing were eventually diagnosed as bronchial asthma [4]. Therefore, it is necessary to explore the potentially risk factors to improve the pediatric respiratory system disease.

Infancy, especially the first year after birth, is one of peak periods of growth and development of the whole life. The rapid growth of the body signifies the further maturation and functional perfection of various organs. The pathogenesis of wheezing may be special and complicated in this period. Studies have confirmed that obesity and bronchial asthma suffered in adulthood, are closely connected with this period [5]. The previous study has manifested that weight-gain acceleration in early infancy was related to the increased risk of asthma symptoms in preschool children [6]. However, wheezing in infants is a heterogeneous disease, and the current mechanism of non-allergic wheezing is still unclear [7]. Several studies have reported that weight gain in infants is a risk factor for wheezing in childhood and even puberty [8‐14]. To our best knowledge, however, there are few researches focusing on the relationship between the weight gain speed and wheezing in infants, especially early infantile.

Herein, we investigated the demographic and related clinical characteristics, weight growth speeds and serum lipid levels of infants with early wheezing after birth. The primary purpose of this study was, thus, to identify the rapid weight growth as a potential risk factor for the early wheezing.

Wheezing is a common chronic respiratory disease among children worldwide, and is also a worried event for parents and pediatricians because it may develop into asthma. The current study evaluated the potential predicting factors for infants with early wheezing. We retrospectively investigated 701 under 4 months infants hospitalized for lower respiratory tract infection. The findings suggested that the rapid weight gain could be a potential risk factor for infants with early wheezing.

Infancy, as a key stage, not only has profound effects on the physical growth and development, but also influences the occurrence and development of chronic diseases such as cardiovascular disease, hypertension and diabetes at various ages [5, 16, 17]. It is the fact that the first 6 months after birth is a high-risk period of overweight formation [18, 19]. Our study discovered the children in group III had lower birth weight and length, while those in group I had higher birth weight and length. When the infants were approximately at 4 months, the weight in group III was higher than other two groups, which had obvious catch-up growth trends. Theoretically, rapid weight gain may lead to different degrees of adipose tissue acquisition, and we observed the TC, LDL and TG in group III were distinctly higher than other two groups, in which TC was positively correlated with wheezing and wheezing days (P < 0.05), suggesting that lipid metabolism is enhanced with the increase of weight gain speed. Abnormal or disordered lipid metabolism is a common issue in adults and infants. However, to our best knowledge, there are lack of uniform standards for blood lipid detection in infants and normal standard value for the infants under 2 years old in China nowadays. In this study, no more than 20 cases of high blood lipids were found in all blood lipid indicators. The lipid disorder is temporary in infancy, and the level of lipid metabolism gradually decreases to the normal after one and a half years [20].

We discovered that the breastfeeding was a common feeding pattern, and no statistical differences were found among the three groups. Clinical observations displayed that the frequency of daily intake in group III was more than that other two groups. Nevertheless, it still needs further observation whether there exist differences in the growth speed of infants owing to lack of feeding knowledge. With the extension of breastfeeding time, the weight of mothers was on the decline, it may be self-fat catabolism of mothers leading to high breast milk fat content, which causes children to receive a high-fat diet from mothers. Imperfect synthetic function of HDL in small intestine and liver can result in enhancive cholesterol accumulation, elevated blood lipids containing the TC level, relatively increased LDL-carried cholesterol for the synthesis of cell membranes and steroid hormones, and accumulation of cell membranes and cholesterol of vital organs such as airway. Studies have reported that lipid metabolism has an impact on lung diseases. The data for animal experiments have observed that cholesterol transporters such as ABCG1, apoE and LXR are involved in immune defense of the respiratory tract, resulting in Th1/Th2 imbalance and elevated airway neutrophils and IL-17, which would lead to the susceptibility of respiratory tract infections [21, 22]. The clinical observation of this study discovered that neutrophils were mainly increased in bronchoalveoar lavage fluid (BALF) among wheezing infants, but not eosinophils. It is indicated that cholesterol transport promotes the neutrophil chemotaxis and upregulation of inflammatory cytokines which may participate in the development of wheezing [21].

Studies found that nearly half of children had wheezing within 1 year after birth, especially no more than 6 months [4]. To date scholars mostly had focused on investigating the effects of weight gain on wheezing or recurrent wheezing in different periods [12, 23‐26], meanwhile several researchers found that growth speed was a risk factor for respiratory disease among children [27]. Our results displayed the there was no statistical significance among the infants with normal weight, low weight and overweight. It is indicated that the occurrence of wheezing is not relevant to weight [27], but may be associated with growth speed, which is in accordance with previous reports [10, 28, 29]. Evidences demonstrated that the weight growth speed might serve as a potential influencing factor in obesity [19], pulmonary function decline [29], bronchial asthma [30], cardiovascular disease [16], and type 1 diabetes [17] during infancy. Although various assessment criteria for wheezing have been used in recent years, rapid weight gain may also be considered as a hazardous element in wheezing [30, 31]. The data from Table 4 we obtained that wheezing days were positively correlated with the weight gain (P < 0.05). However, the mechanism between rapid weight gain and wheezing among infants is currently unclear.

Differences between intrauterine environment and postnatal environment may lead to the development of postnatal diseases [32, 33], and the compensatory growth appeared due to the intrauterine growth in unfavorable intrauterine environment. While rapid compensatory growth may be detrimental to the future health [13], rapid weight gain can result in relatively poor lung development, and airway stenosis can increase the incidence and severity of wheezing [13, 29]. Studies showed that rapid weight gain, especially in the first year after birth, was significantly related to the frequency and degree of wheezing [26, 34]. Early reports demonstrated that allergy and eczema can enhance the risk of wheezing or asthma [35, 36]. The data of our research revealed the proportions of the individual history of hypersensitivity and eczema were higher in group III. Furthermore, the viral infection as a suspicious factor was considered in several researches. RSV is the most common pathogen for infantile wheezing, with 46.5% of infection rate, but no statistical differences were discovered among the three groups. It is indicated that RSV infection was involved in the occurrence and development of wheezing, while it may be not a major factor in infants with early wheezing. In addition, excessively rapid weight gain may cause changes in lung development, including alveolar number, lung weight and immune system, especially adverse changes in immune function can increase the occurrence of asthma in children. In this study, we found an obvious family characteristic among infants in group III. The infants had a positive family history of wheezing, particularly first-degree relatives, suggesting family genetic predisposition in these individuals. The previous protocol mentioned that wheezing may be associated with the mitochondrial gene variation, especially the father’s genes [17]. These still need further in-depth researches and discussions in the future.

The superiority of this study was that few previous researches had investigated the relationship between the weight gain speed and wheezing in infants, especially early infantile wheezing in Chinese population. It was the fact that rapid weight gain may be a risk factor in infants with early wheezing, which is beneficial for pediatricians to effectively identify wheezing children. There were some limitations that should be warranted caution for interpreting the data in this work. Firstly, our investigation was a retrospective study based on a single center, which is lack of parental serum lipid, antenatal and postnatal smoking, and intrauterine growth retardation (IUGR) or small for gestational age infant (SGA) collection. Secondly, there were no clear biologic targets as observation indicators to indicate the association between weight growth speed and infants with early wheezing. Thus, multicenter studies with larger samples should be needed for further verification of the role of weight growth speed in early wheezing infants in clinic.

The current study accessed the potential risk factors for early wheezing infants aged no more than 4 months. We analyzed the demographic and related clinical characteristics, weight growth speeds and serum lipid levels of infants with early wheezing after birth. Besides male, family wheezing, age, eczema, RSV infection, birth weight and TC, the rapid weight growth as a risk factor should be concerned in the early wheezing infants.