Endocrine changes in children with dengue virus infection

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1 Asian Biomedicine Vol. 3 No. 5 October 2009; Brief communication (Original) Endocrine changes in children with dengue virus infection Suttipong Wacharasindhu, Yupayong Bunjobpudsa, Somlak Tongmeesee, Suphab Aroonparkmongkol, Thaninee Sahakitrungrueng, Vichit Supornsilchai Division of Endocrinology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand Background: Dengue is a common infectious disease in Southeast Asia. The hormonal changes of dengue have rarely been studied. Objective: To demonstrate the endocrine changes in children with dengue viral infection, and to compare these changes with the severity of dengue virus infection. Materials and method: Twenty-three children (11 males and 12 females) presented with clinical features and serological confirmation of dengue fever (DF) were measured for thyroid function test (freet4, T3 and TSH), serum cortisol and serum insulin-like growth factor-i (IGF-I) and IGF-binding protein 3 (IGFBP-3) during febrile and convalescent periods. Sixteen children (8 males and 8 females) presented with clinical features and serological confirmation of dengue hemorrhagic fever (DHF) were measured for these parameters but during shock and convalescent periods. Results: In shock period of DHF, serum T3 was lower than that in febrile period of DF (90.5 ±34.0 and ±39.0 ng/dl) but not significantly different. Serum freet4 had positive correlation with serum T3 during febrile period (r=0.74, p < 0.001) in DF and during shock period (r=0.48, p=0.02) in DHF. During convalescent period, serum T3 had a positive correlation with serum TSH in DF but not in DHF. The increment of IGF-I was higher in DF than that in DHF in convalescent period. The changes represented a slower recovery of thyroid and GH-IGF axes in DHF. In addition, serum cortisol level trended to be insufficient. (<18 μg/dl) during febrile period in DF and shock period in DHF. Conclusion: Thyroid axis was influenced by the illness similar to changes in euthyroid sick syndrome. Insufficiency of adrenal reserve and changes of GH-IGF axis need to be further studied. Keywords: Cortisol, dengue virus, growth factors, thyroid. Dengue is an acute illness due to the dengue virus. It can present as an uncomplicated febrile illness called dengue fever (DF) or a severe form with shock and bleeding tendency called dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). In DHF, the increased vascular permeability and abnormal hemostasis are essential feature that can cause fatal outcomes. The mechanism of such Correspondence to: Suttipong Wacharasindhu, MRCP(UK), Division of Endocrinology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand. Wacharasindhu@Yahoo.com pathophysiological changes is still well understood. Certainly, inflammatory mediators, such as interleukin-6 (IL-6) and secretory phospholipase A2 (spla2), may have a role in these changes [1]. Endocrine changes have been widely studied in critical illnesses such as septic or cardiogenic shock, trauma and extensive burns, but they have rarely been studied in dengue. A better understanding of hormonal changes in this condition may help managing patients. This study is aimed to demonstrate changes in the hormonal status in children with dengue infection, and to compare these changes to the severity of dengue infection.

2 558 S. Wacharasindhu, et al. Materials and method This study has been approved by Ethics Committee of the Faculty of Medicine, Chulalongkorn University. Twenty-three children (11 males and 12 females) presenting with clinical features and serological confirmation of dengue fever (DF) were measured for thyroid function tests (freet4, T3 and TSH), serum cortisol and serum insulin-like growth factor-i (IGF-I) and IGF-binding protein 3 (IGFBP-3) during the febrile and convalescent periods. Sixteen children (8 males and 8 females) with clinical features and serological confirmation of DHF were also measured for these parameters during shock and convalescent periods. Serum freet4, T3, TSH, and cortisol were measured using Chemiluminescent immunoassay (Central lab, King Chulalongkorn Memorial Hospital). Serum IGF-I and IGFBP-3 were measured using commercial kits (DSL) (Diagnostic Systems Laboratories, Inc, Texas, USA). Serology of dengue was confirmed by the method of hemagglutination inhibition test (Division of Virology, Department of Microbiology, Faculty of Medicine, Chulalongkorn University). Statistical analysis All results were compared between the DF group and DHF group. They were expressed as mean ± SD. SPSS version 10 was used in data analysis. The statistical significance was considered at p-value <0.05. Results Thirty-nine children (23 DF and 16 DHF) with mean age of 10.2±2.4 years had a duration of fever (before seeking medical advice) of 4.2 ± 1.0 day (3.8±0.8 day for DF and 4.8 ± 1.1 day for DHF). All children with DHF first presented to our institute with evidence of vascular leakage or shock. Therefore, we did not collect blood samples during the febrile period. Baseline clinical data of 23 children with DF and 16 children with DHF are showed in Table 1. We found that the chronological age, sex distribution and clinical manifestations were not different between these two groups. However, the duration of fever before seeking medical advice was longer and the hematocrit (Hct) at presentation was higher in the DHF group. Serum freet4, T3, TSH, cortisol, IGF-I, and IGFBP-3 in DF and DHF children were demonstrated in Table 2. Figure 1 shows correlation between serum freet4 and serum T3 during febrile phase in DF (a) and during shock phase in DHF (b). Apparently, the serum freet4 had a positive correlation with serum T3 during the febrile period (r=0.74, p <0.001) in DF and during shock period (r=0.65, p=0.007) in DHF. Figure 2 shows correlation between serum T3 and serum TSH during convalescent phase in DF. Apparently, during the convalescent period, serum T3 had a positive correlation with serum TSH in DF but not with DHF. During the febrile period in DF and shock period in DHF, the serum cortisol level trended to be insufficient (<18 μg/dl). However, serum ACTH was not measured. Table 1. Baseline clinical data of children with DF and DHF. DF (n=23) DHF (n=16) Age (year) ± ± 2.4 Sex (Male/Female) 11/12 8/8 Fever (day) 3.8 ± ± 1.1 Hct (%) 39.3 ± ± 4.0 Headache 100% 90.1 % Nausea/vomiting 25% 55% Abdominal pain 37% 27% Hepatomegaly 63% 55%

3 Vol. 3 No. 5 October 2009 Endocrine changes in children with dengue virus infection 559 Table 2. Hormone changes in children with DF and DHF. DF DHF Febrile period Convalescent Shock period Convalescent P-value period period freet4 (ng/dl) 1.2 ± ± ± ± T3 (ng/dl) ± ± ± ± TSH (mu/l) 1.7 ± ± 0.8 ns 2.4 ± ± 1.1 ns Cortisol (ug/dl) 16.5 ± ± ± ± IGF-I (ng/dl) 95.8 ± ±194 ns 66.7± ± 59.3 ns IGFBP-3 (mg/l) 2.7 ± ± 1.1 ns 2.5 ± ± IGF-I/IGFBP ± ±0.033 ns 0.025± ±0.011 ns molar ratio ns= not significant. Fig. 1 Correlation between serum freet4 and serum T3 during febrile phase in DF (r= 0. 74, p=<0.001) (a) and during shock phase in DHF (r= 0. 65, p=0.007) (b).

4 560 S. Wacharasindhu, et al. Fig. 2 Correlation between serum T3 and serum TSH during convalescent phase in DF (r= 0.44, p=0.03). Discussion Dengue is a common infectious disease in Southeast Asia. However, endocrine changes in the disease have been rarely studied. Tuchinda C et al. reported that serum cortisol levels were elevated in dengue hemorrhagic fever, but this was not related to the degree of dehydration and hematocrit levels [2]. The plasma renin activity rose during the shock stage in DHF [3]. Min M et al. showed a decreased mortality in DHF with hydrocortisone treatment [4, 5]. There have been no further reports regarding endocrine changes in this common infection. We uncovered other aspects of endocrine changes in dengue virus infection. These aspects have never been reported before. IGF-I and IGFBP-3 Dysregulation of the hypothalamic-anterior pituitary axis is known to contribute to a higher risk for morbidity and mortality [6]. A previous study in children with acute illness showed nonsurvival in children with meningococcoal septic shock who had a very high level of GH and decreased IGF-I and IGFBP-3 levels suggesting a condition of GH resistance. However, GH profiles and growth factors did not differ between shock-survivors and sepsissurvivors. In addition, the intact/total IGFBP-3 ratio and IGFBP-1 level increased with disease severity and correlated inversely with free IGF-I levels, emphasizing its counter-regulatory role in critical illness [7]. Low IGF-I levels in critically ill patients reflect an adaptive change from the indirect to the direct effect of GH. We found that, after recovery from acute illness in DF and DHF, serum IGF-I and IGFBP-3 levels became elevated. The increment of IGF-I in DF was higher than that in DHF. The explanation for this is probably related to the severity of illness. In severe illness with DHF, the recovery phase of the GH-IGF axis may be longer. However, the IGF-I/IGFBP-3 ratio representing active IGF status did not change. Further studies on free IGF-I levels may confirm this. Serum IGF-I and IGFBP-3 levels had no correlation with serum cortisol, T3, free T4 or TSH levels. Thyroid axis In acute illness, serum T3 rapidly drops within 24 hours partly due to decreased conversion of T4 to T3 and/or increased turnover of thyroid hormone, which causes a low T3 syndrome. In contrast, serum TSH remains normal. Previous studies showed that cytokine TNF-α, interleukin-1 (IL-1) and IL-6 might play a role in the low T3 syndrome [8]. In prolonged illness, pulsatile TSH secretion was shown to be diminished and this is positively related to serum T3 levels [6]. We demonstrated similar changes. Serum T3 levels rose from the acute febrile period in DF and in the shock period of DHF to the convalescent phases in DF and DHF. Serum T3 in the shock period of DHF was lower than that in the febrile period of DF but did not reach statistically significant levels. This is probably due to a longer duration of fever and illness

5 Vol. 3 No. 5 October 2009 Endocrine changes in children with dengue virus infection 561 before the diagnosis was made. In the recovery or convalescent period, the rising of T3 did not correlate with the rising of TSH in DHF which is in contrast to that in DF patients. This suggests slow recovery of the pituitary-thyroidal axis in more severe illness. Changes of the thyroid axis in dengue are similar to those found in the low T3 or euthyroid sick syndrome. However, the serum rt3 level was not measured in this study. Adrenal axis Hypercortisolism and augmented ACTH are commonly found in acute illness as a natural mechanism to protect against excessive inflammation and to improve the hemodynamic state [6]. However, in prolonged illness, serum ACTH levels are low but serum cortisol levels remain high in order to exert its beneficial hemodynamic effects. During acute illness i.e. febrile period in DF and shock period in DHF, adrenal reserve function is insufficient as this level should be above18 μg/dl in response to acute stress [9]. This result disagrees with a previous study by Myo-khin et al., which showed no cortical insufficiency in DHF [10]. Measurement of serum ACTH or the ACTH stimulation test during acute stress, which was not performed in this study, may elucidate this issue. In conclusion, the thyroid axis was influenced by the illness similar to changes seen in the euthyroid sick syndrome. Insufficiency of adrenal reserves and changes of the GH-IGF axis need to be studied further. All patients in this study survived, and thus we could not demonstrate endocrine changes predicting mortality. Further detailed studies of each hormonal axis may elucidate physiological changes in dengue. Acknowledgement This work was supported by the Rachadapiseksompoch fund, Faculty of Medicine, Chulalongkorn University, Thailand. The authors have no conflict of interest to report. References 1. Juffrie M, Meer GM, Hack CE, Haasnoot K, Veerman AJ, Thijs LG. Inflammatory mediators in dengue virus infection in children: interleukin-6 and its relation to C-reactive protein and secretory phospholipase A2. Am J Trop Med Hyg. 2001; 65: Tuchinda C, Angsusingha K, Punnakanta L, Visutakul P, Tuchinda P. Serum cortisol level in Thai hemorrhagic fevers. J Med Assoc Thai. 1980; 63: Tuchinda C, Muarngmanee L. Plasma renin activity in children with dengue hemorrhagic fever. J Med Assoc Thai. 1983; 66: Min M, U T, Aye M, Shwe TN, Swe T. Hydrocortisone in management of dengue shock syndrome. Southeast Asian J Trop Med Public Health. 1975; 6: Panpanich R, Sornchai P, Kanjanaratanakorn K. Corticosteroids for treating dengue shock syndrome. Cochrane Database Syst Rev. 2006; 19:3(CD003488). 6. Langouche L, Van den Berghe G. The dynamic neuroendocrine response to critical illness. Endocrinol Metab Clin N Am. 2006; 35: Den Brinker M, Joosten KF, van Doorn J, Bannink EM, Janssen JA, Hop W, et al. Growth hormone-insulin like growth factor 1 axis in children with meningococcal sepsis: the spectrum from sepsis to fatal septic shock. In: den Brinker M, editor. Acute stress response in critically ill children: endocrine aspects. Amsterdam:Print Partners Ipskamp, Enschede p Reichlin S. Neuroendocrine-immune interaction. N Eng J Med. 1993; 329: Aneja R, Carcillo JA, What is the rationale for hydrocortisone treatment in children with infectionrelated adrenal insufficiency and septic shock? Arch Dis Child. 2007; 92: Myo-Khin, Soe-Thein, Thein-Thein-Myiet, Than-Nu- Swe, Muya-Than. Serum cortisol levels in children with dengue hemorrhagic fever. J Trop Pediatr. 1995; 41: