Analysis of the Thymus in 151 Healthy Infants From 0 to 2 Years of Age

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1 Article Analysis of the Thymus in 151 Healthy Infants From 0 to 2 Years of Age Ensar Yekeler, MD, Ahmet Tambag, MD, Atadan Tunaci, MD, Hakan Genchellac, MD, Memduh Dursun, MD, Gulbin Gokcay, MD, Gulden Acunas, MD Objective. A prospective sonographic study of the normal thymus was performed to determine the size changes with age and to compare the results according to some clinical conditions, such as sex, breast versus formula feeding, and term or preterm status. Methods. One hundred fifty-one healthy infants underwent thymic sonography. Maximal transverse and longitudinal dimensions and anteroposterior dimensions of the right and left lobes were measured, and thymic indices were calculated. Mean values of thymic measurements for each group (sex, age, breast or formula feeding, and term or preterm status) were determined. The results were statistically evaluated. Results. Thymic dimensions showed the maximal values at about 4 to 6 months and gradually decreased after 6 to 8 months. No significant differences were found between mean values of thymic dimensions according to the sex and formula- versus breast-fed groups. As expected, the term group had greater thymic size values than the preterm group, probably because of positive correlations between thymus size, birth weight, and height. Conclusions. The thymus is clearly and easily visualized on sonography in the 0- to 2-year age period. This may be useful for evaluating qualitative and quantitative properties of the thymus and determining size changes according to age in various clinical conditions. Key words: age and sex; breast versus formula feeding; prematurity; size changes; thymus. Abbreviations L.AP, left lobe anteroposterior dimension; LONG, longest craniocaudal dimension; MTD, maximal transverse diameter; R.AP, right lobe anteroposterior dimension; TI, thymic index Received February 26, 2004, from the Department of Radiology (E.Y., A.Ta., A.Tu., H.G., M.D., G.A.) and Institute of Child Health (G.G.), Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey. Revision requested March 25, Revised manuscript accepted for publication July 8, Address correspondence and reprint requests to Ensar Yekeler, MD, Department of Radiology, Istanbul University, Istanbul Faculty of Medicine, Capa, Istanbul, Turkey. ensaryekeler@hotmail.com. The thymus is a lymphoid organ that has many immunologic functions, primarily T-cell differentiation. In the diagnosis of many thymic conditions such as congenital thymic diseases and thymic hyperplasia, knowledge of thymus size changes with age is important for determining the effects of clinical and physiologic conditions on thymus size. 1 Although the sonographic features of the infantile thymus have been described, to our knowledge, there has been no combined study describing the changes of thymus size related to age, sex, birth weight and height, and clinical and physiologic variables such as breast versus formula feeding. 2 4 Therefore, a prospective sonographic study was performed to document the mean thymic size in infants up to 2 years of age and to compare the results between subgroups such as age, sex, birth weight and height, term or preterm condition, and breast versus formula feeding by the American Institute of Ultrasound in Medicine J Ultrasound Med 2004; 23: /04/$3.50

2 Analysis of the Thymus in Infants Materials and Methods After parental informed consent was obtained, mediastinal sonography was performed in 151 infants (79 boys [52%] and 72 girls [48%]) from 2 days (31 weeks premature) to 2 years of age (mean, 5.5 months). All infants enrolled in the study were admitted to the Institute of Child Health for routine care and had no stress factors to affect their thymic size. Premature infants with no medical problems, low-birth-weight infants, and formula-fed infants (Milumil 1; Milupa AG, Friedrichsdorf, Germany) were also included. Infants who had mixed breast and formula feeding were excluded. Infants with thymic disease, severe infection, and chronic illness and those receiving steroids or chemotherapy were also excluded. The premature group had no clinical or laboratory findings suggesting immune suppression or thymic disease. The median weight of the infants was 6225 g (range, g), and the median height was 62 cm (range, cm). Before sonographic examination, parameters such as age, sex, current weight and height, birth weight and height, gestational age of neonates, breast or formula feeding status, and feeding duration were recorded. Thymus sonography was performed with an Acuson 128XP/10 sonography system (Siemens Medical Solutions, Mountain View, CA) with 7- MHz linear and 5-MHz sector probes. The sector probe was used especially in older infants. Arrangement of the focus to both superficial and deep areas was made to measure the thymic dimensions accurately, to draw the thymic contours, and to delineate the deep extensions well. In all cases, the thymus was examined in longitudinal and transverse planes by transsternal, parasternal, and intercostal approaches. The suprasternal approach was also used to see whether suprasternal extension of the thymus was present. To obtain standardized thymic size values, the measurements were performed during expiration, when the thymus has the widest transverse diameter with well-defined contours. The measurements were performed by agreement of 2 examiners (E.Y. and A.Ta.) at the time of each examination. By transsternal and parasternal approaches, the maximal transverse diameter (MTD), right lobe anteroposterior dimension (R.AP), and left lobe anteroposterior dimension (L.AP) were measured. Then, perpendicular to this plane, the longest craniocaudal dimension (LONG) was measured by parasternal and suprasternal approaches. The LONG was defined as the distance between 2 parallel lines passing through the uppermost and lowest borders of the thymus (Figure 1, A and B). The thymic index (TI) was calculated by multiplying the largest transverse diameter (MTD) by the largest sagittal area. Variations in the appearance of the thymus in both transverse and longitudinal planes and its echo texture features were also recorded. The same measurement method described above was also adapted to the measurements of thymic variations (Figure 1, C F). The infants were grouped according to their ages: by month for the first 6 months, by 2 months for the second 6 months, and by 6 months between 12 and 24 months. Mean values and SDs of MTD, R.AP, L.AP, LONG, and TI measurements were calculated for each group and for overall. All statistical analyses were performed with SPSS statistical software (SPSS Inc, Chicago, IL). Normal Q-Q plots and Shapiro-Wilk test results of the measurements according to the different age groups did not reveal a normal distribution; hence, the Kruskal-Wallis test, a nonparametric test for several independent samples, was used to evaluate the size differences between the age groups. Comparison of R.AP and L.AP measurements was performed with a paired samples t test. Mean thymic size values of male and female populations irrespective of age, excluding premature neonates, were calculated and compared by the Student t test. The Pearson correlation test was used to determine the relationship of thymus size to birth weight and height in term neonates. In addition, 0- to 6- month-old infants were divided into 2 groups as breast-fed only and formula-fed only. Differences between the mean thymus size values of 20 premature neonates (35 37 weeks) and 18 term neonates were also evaluated with the Mann-Whitney U test. Results The thymus was easily identified in all 151 infants examined. The best images were obtained by the suprasternal approach with the 5-MHz probe. According to the shape on transverse scans; the thymus was rectangular or quadrilateral in 104 infants (69%), oval or round in 18 (12%), bilobate in 11 (7%), drumstick or L shaped in 9 (6%), and crescent shaped in 9 (6%) J Ultrasound Med 2004; 23:

3 Yekeler et al On longitudinal scans, the thymus was triangular in 100 infants (66%), teardrop shaped in 24 (16%), oval in 25 (17%), and sickle shaped in 2 (1%). The thymus was fairly symmetric in 82 infants (54%), had left predominance in 53 (35%), and had right predominance in 16 (11%). According to the echo texture, the thymus echogenicity was homogeneous and similar to that of the liver and spleen in most cases (129 [85%] of 151) and slightly coarse and granular in 22 (15%). The echogenicity of the thymus was less than that of the liver and spleen in 110 infants (73%), equal in 21 (14%), and greater in 6 (4%). In all subjects, the echogenicity of the thymus was less than that of the thyroid gland. Variations in the shape and location of the thymus were found in 48 (31%) of 151 infants. Superior pole variations were found in 30 (62.5%) Figure 1. A and B, Courses of measurement lines in both transverse and sagittal planes. Each dimension is measured on the longest diameter. C F, Measurement lines shown for thymic variations (C, oval or round; D, bilobate; E, drumstick or L shaped; F, crescent shaped). A B C D E F J Ultrasound Med 2004; 23:

4 Analysis of the Thymus in Infants of 48 (suprasternal extension, n = 22 [45.8%]; accessory thymic tissue adjacent to the superior pole, n = 8 [16.6%]); paracardiac extension was found in 15 (31.2%); and extension behind the brachiocephalic vein was found in 3 (6.2%). In a comparison of the mean values of thymic dimensions for each age group, statistically significant differences were found for all dimensions (P <.001). The difference between mean R.AP and L.AP values was also highly significant for all subjects (P <.001). The distribution and a graphic illustration of mean thymus dimensions according to age group are shown in Table 1 and Figure 2, respectively. Linear regression revealed no relationship between the age groups. The quadratic age effect was significant (multiple R = 0.480; r 2 = 0.230). The cubic age effect was more significant than the quadratic age effect (multiple R = 0.507; r 2 = 0.257). When the age-related changes of thymus size were examined, the thymus was found to be growing during the first 4 to 6 months and then shrinking gradually. When the mean values of the thymic size were calculated for both sexes, there was no significant difference between each sex group, although the boys had slightly greater means than those of the girls (P =.658,.402,.418,.666, and.337; Table 2). Statistically significant positive correlations were found between birth weight and TI and birth height and TI of term neonates (r = 0.538; P <.001; r = 0.485; P <.01, respectively). For the 0- to 6-month age group, when the mean values of thymic size in formulaand breast-fed infants were compared, there were no statistically significant differences (Table 3). When the thymus sizes between term and preterm neonates were compared, the thymus sizes of the term infants were significantly greater than those of the preterm neonates for 4 parameters, including MTD, R.AP, L.AP, and LONG (P =.002,.003,.003, and.002, respectively; Table 4). Discussion The thymus is an easily visible organ on sonography in the infantile period. Because sonography has some advantages, such as availability, expediency, and lack of ionizing radiation, contrast material injection, and sedation, it can be used to evaluate the thymus easily. Although variability in the size and radiographic appearance of the thymus has been well recognized, the normal variations in thymic size and shape may sometimes cause a diagnostic dilemma. 2,5,6 Sonography is often used for this purpose and gives valuable information about the morphometric parameters in addition to morphologic properties such as echogenicity, shape, extension, and gland contours. As in previous studies, we also encountered some location, contour, and echogenicity differences between individuals, which did not cause difficulties in interpretation. Thymic size measurement by sonography can have limitations. Some previous studies used the anteroposterior thickness and transverse diameter of the thymus for determining thymus size. However, in recent studies, the craniocaudal extent of the thymus could also be measured accurately 5 and was used in this study. In the older age groups, it can be difficult to see all the edges of the thymus and to measure the dimensions correctly. When linear probes with narrow dimension such as 38 mm are used, the whole Table 1. Distribution of Thymus Dimensions and Thymic Index With SDs According to the Age Groups Age Group, mo No. of Cases MTD, mm R.AP, mm L.AP, mm LONG, mm TI, cm 3 Premature ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 5.6 Values in Tables 1 4 are mean ± SD J Ultrasound Med 2004; 23:

5 Yekeler et al thymus cannot be seen in 1 image, especially in older infants. Because this study included infants at 1 and 2 years of age, it was easy to reveal all the thymic contours wholly. However, the sector probe was also used to reveal the thymic contours more clearly in the older infants. Some sonographic features of the infantile thymus have been described in previous studies. To our knowledge, there has been no combined study describing the changes of thymus size related to age, sex, birth weight and height, and clinical and physiologic variables such as breast versus formula feeding. In our study, all the parameters mentioned above were investigated. With regard to the age-related changes in thymic size, in our study, the thymus had grown until the sixth month and then started to involute. These findings were in accordance with findings from necropsy studies by Steinmann. 7 According to Liang and Huang, 2 the thymus has been found to be larger in boys than in girls during the first 2 years of life. In the necropsy studies including infants, it was found that, on average, girls had an approximately 20% smaller thymic volume than boys. 7 However, when the data were matched with body weight, no difference could be established between the sexes. 7 In our study, including a 0- to 2-year age group, no significant differences were found between both sexes, although the male population dimensions were slightly bigger than those of the female population. The presence of a positive correlation between birth weight and thymus size was also observed. Figure 2. Curves of the thymic dimensions according to the age groups. In our study, there was a positive correlation between dimensions of the thymus and birth height. These data show that thymus length is related to body height. Iscan et al 8 performed a sonographic study including 65 term neonates and found a significant positive correlation between birth weight and height, thymic size, and TI. Their thymic size measurements were similar to our study results. Hasselbalch et al 4 found that the breast-fed infants had a greater TI than formula-fed infants, which was statistically significant. They explained that this difference may have been due to some immune-modulating factors included in breast milk. Some different results were obtained in our study, including the 0- to 6-month age group, in which breast-fed infants had slightly greater thymus size than the formula-fed group, but the difference was not significant. Table 2. Mean Thymus Sizes and TI According to Both Sexes Sex No. of Cases MTD, mm R.AP, mm L.AP, mm LONG, mm TI, cm 3 Male ± ± ± ± ± 10.2 Female ± ± ± ± ± 8.5 Table 3. Thymus Sizes and TI of Breast- and Formula-Fed Infants Between the Ages of 0 and 6 Months No. of Age, mo Feeding Cases MTD, mm R.AP, mm L.AP, mm LONG, mm TI, cm Breast milk ± ± ± ± ± 8.3 Formula ± ± ± ± ± Breast milk ± ± ± ± ± 12.1 Formula ± ± ± ± ± Breast milk ± ± ± ± ± 10.1 Formula ± ± ± ± ± 9.5 J Ultrasound Med 2004; 23:

6 Analysis of the Thymus in Infants Table 4. Mean Thymus Sizes With SDs in Term and Preterm Infants Group No. of Cases MTD, mm R.AP, mm L.AP, mm LONG, mm TI, cm 3 Preterm ± ± ± ± ± 3.9 Term ± ± ± ± ± 6.9 In a comparison of the mean thymus size between term and preterm neonates, we found that the term group had significantly greater values than the preterm group. Previous studies had similar results and considered that they were related closely to parameters such as health status, intrauterine growth, and birth weight. 9,10 As in previous studies, in this study, the numbers in the subgroups divided by age, formula feeding, and premature birth were not adequate for us to draw far-reaching conclusions by confirmation of the statistical results mentioned above. In conclusion, the thymus can be easily evaluated by sonography in infancy for evaluation of the size, shape, echo texture, and variations. In addition to qualitative assessment, knowledge of thymus size according to age and parameters such as sex, term or preterm condition, and breast versus formula feeding is important for diagnosing or excluding diffuse thymic diseases. This study showed that involution of the thymus began before the end of the first year of life, and there were no significant thymus size differences between sexes and between formula- or breastfeeding status. Term infants have greater thymus size than preterm neonates, indicating a positive correlation between birth weight and height and thymus size. in formula-fed infants compared with breastfed infants. Acta Paediatr 1996; 85: Hasselbalch H, Jeppesen DL, Ersboll AK, Engelmann MD, Nielsen MB. Thymus size evaluated by sonography: a longitudinal study on infants during the first year of life. Acta Radiol 1997; 38: Chu WC, Metreweli C. Ectopic thymic tissue in the paediatric age group. Acta Radiol 2002; 43: Steinmann GG. Changes in the human thymus during aging. Curr Top Pathol 1986; 75: Iscan A, Tarhan S, Guven H, Bilgi Y, Yuncu M. Sonographic measurement of the thymus in newborns: close association between thymus size and birth weight. Eur J Pediatr 2000; 159: Jeppesen DL, Hasselbalch H, Nielsen SD, et al. Thymic size in preterm neonates: a sonographic study. Acta Paediatr 2003; 92: Hasselbalch H, Jeppesen DL, Ersboll AK, Nielsen MB. Thymus size in preterm infants evaluated by ultrasound: a preliminary report. Acta Radiol 1999; 40: References 1. Dominguez-Gerpe L, Rey-Mendez M. Evolution of the thymus size in response to physiological and random events throughout life. Microsc Res Tech 2003; 62: Liang CD, Huang SC. Sonographic study of the thymus in infants and children. J Formos Med Assoc 1997; 96: Hasselbalch H, Jeppesen DL, Ersboll AK, Lisse IM, Nielsen MB. Sonographic measurement of thymic size in healthy neonates: relation to clinical variables. Acta Radiol 1997; 38: Hasselbalch H, Jeppesen DL, Engelmann MD, Michaelsen KF, Nielsen MB. Decreased thymus size 1326 J Ultrasound Med 2004; 23: