Clin. Lab. 2013;59:XXX-XXX ©Copyright
ORIGINAL ARTICLE
Low Birth Weight is Associated with Lower Respiratory Tract Infections in Children with Hand, Foot, and Mouth Disease YONG-PING LU 1*, DE-YING ZENG 2*, YOU-PENG CHEN 1, XU-JING LIANG 1, JIE-PING XU 3, SI-MIN HUANG 1, ZHI-WEI LAI 4, WANG-RONG WEN 5, KAROLINE VON WEBSKY 6, BERTHOLD HOCHER 1,6 * both authors contributed equally Department of Infectious Diseases, The first Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong province, China 2 Department of Pediatrics, Beijiang Hospital of Southern Medical University, Qingyuan 511800, Guangdong province, China 3 Department of Clinical Laboratory, Beijiang Hospital of Southern Medical University, Qingyuan 511800, Guangdong province, China 4 Department of Infectious Diseases, The Fifth Affiliated Hospital of Medical College, Jinan University, Qingyuan 511500, Guangdong province, China 5 Center for Clinical Laboratory, The First Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong province, China 6 Institute of Nutritional Science, University of Potsdam, D-14558 Nuthetal, Potsdam, Germany 1
SUMMARY Background: Low birth weight (LBW) might be a risk factor for acquiring lower respiratory tract infections (LRTIs) associated with disease related complications in early childhood. HFMD, a frequent viral infection in southern China, is a leading cause of lower respiratory tract infections in children. We analyzed whether LBW is a risk factor for children with HFMD to develop lower respiratory tract infections. Methods: A total of 298 children with HFMD, admitted to a hospital in Qingyuan city, Guangdong province, were recruited. Demographic data and clinical parameters such as serum glucose level and inflammatory markers including peripheral white blood cell count, serum C-reactive protein, and erythrocyte sedimentation rate were routinely collected on admission. Birth weight data were derived from birth records. Results: Mean birth weight (BW) was 167 g lower in patients with HFMD and LRTIs as compared to patients with solely HFMD (p = 0.022) and the frequency of birth weight below the tenth percentile was significantly higher in patients with HFMD and LRTIs (p = 0.002). Conclusions: The results of the study show that low birth weight is associated with a higher incidence of lower respiratory tract infections in young children with HFMD. (Clin. Lab. 2013;59:xx-xx. DOI: 10.7754/Clin.Lab.2012.120725) LRTIs - lower respiratory tract infections PLT - platelet WBC - white blood cell CRP - C-reactive protein ESR - erythrocyte sedimentation rate ELISA - enzyme-linked immunosorbent assay SFDA - state food and drug administration IgM - immunoglobulin M OR - odds ratio
KEY WORDS hand, foot and mouth disease (HFMD), low birth weight (LBW), lower respiratory tract infections (LRTIs), pneumonia, children LIST OF ABBREVATIONS HFMD - hand, foot, and mouth disease EV71 - enterovirus 71 CA16 - coxsackievirus A16 RSV - respiratory syncytial virus LBW - low birth weight MLBW - moderately low birth weight Clin. Lab. 9+10/2013
_____________________________________________ Manuscript accepted November 12, 2012
1
YONG-PING LU et al.
INTRODUCTION
MATERIALS AND METHODS
In recent years, large-scale outbreaks of hand, foot and mouth disease (HFMD) have increased and more severe cases have appeared in China, causing health economic as well as health care problems [1]. In mainland China in 2010, the reported numbers were 1,795,336 cases diagnosed with 905 deaths and in 2011 1,619,706 cases with 509 deaths [2]. Guangdong province was the most endemic region of HFMD. In this province the morbidity increased by about twelve percent from 226,620 cases in 2010 to 273,902 cases in 2011, whereas the number of deaths decreased from 63 cases in 2010 to 34 cases in 2011 [3]. HFMD is a common disease which is caused mainly by enterovirus 71 (EV71) and coxsackievirus A16 (CA16) and which generally affects children under the age of five years. Most children typically present with papulovesicular rash on the palms of their hands, soles of their feet, knees and/or buttocks, and multiple oral ulcers. Both viruses belong to the enterovirus genus of the picornaviridae family and can also cause other diseases, such as herpangina or flu-like symptoms [4]. A small proportion of younger children develop severe complications including pneumonia, myocarditis, encephalitis, brain-stem encephalitis, and acute flaccid paralysis. Other complications are neurogenic pulmonary edema. The pathogenesis is not completely understood but can lead to a rapid disease progression and a higher mortality rate especially in EV71-infected children [5-7]. Specific biomarkers were identified to estimate the severity of HFMD cases [8-10]. Hyperglycemia and leukocytosis are two important characteristics in severe patients, and blood glucose and peripheral white blood cell (WBC) count seem to change with the severity of the disease [8,9]. Although results of different studies were not always consistent, a recent meta-analysis indicated that the prevalence of hyperglycemia and WBC count increases with the severity of HFMD [10]. Infants with LBW are more likely to be admitted to the newborn intensive care unit and they have a higher risk to acquire infections. In a study, LBW was associated with a higher risk of acquiring respiratory syncytial virus (RSV)-induced lower respiratory tract infection (LRTI) severe enough to lead to hospital admission [11]. A population-based case-control study in the US showed that adults aged 18 through 27 years, with a history of very low birth weight (VLBW) or moderately low birth weight (MLBW), were at increased risk of hospitalization for respiratory illness [12]. However, it is unclear if LBW is associated with a higher incidence of HFMD complicated by LRTIs such as pneumonia. This study investigated whether LBW is associated with higher incidence of LRTIs in children with HFMD in the Guangdong province.
Patients and data collection A total of 298 singleton infants and children with HFMD were admitted to the Department of Pediatrics in the Beijiang hospital of Southern Medical University in 2011. Most children were admitted between May and August (figure 1) and patients were between 1 and 142 months old, median 23 months. Demographic data such as age, gender, case history, and hospitalization time were collected. Clinical findings including fever, peak body temperatures, cough, rhinorrhea, and consciousness change were recorded. Clinical signs including oral ulcers, skin rashes, heartbeat, and respiratory rate, laboratory data such as hemoglobin level, peripheral red blood cell (RBC), white blood cell (WBC) and platelet count, hepatic and renal functional markers, serum glucose, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were routinely collected on admission. Birth weight records were obtained from the parents and later cross-checked with data sets obtained from the hospitals where the children were born. Very low birth weight (VLBW) is defined as a birth weight lower than 1500 g and moderately low birth weight (MLBW) is defined as a birth weight of 1500 to 2499 g. Diagnostic definitions All hospitalized cases included in this study were confirmed cases of HFMD based on the clinical criteria according to the standard China guidelines for HFMD diagnostic procedures of 2010 [13]. The patients with the following symptoms were defined as having HFMD: acute onset with fever, oral ulcers on the tongue or the buccal mucosa which produces obvious pain, vesicular rashes on the palms, soles, knees, and/or buttocks. Fever was defined as axillary temperature more than 37.3°C. Secondary bacterial and viral infections such as influenza A virus, RSV, adenovirus, and chlamydia/mycoplasma pneumoniae infections were excluded. The clinical diagnosis of lower respiratory tract infections (LRTIs), such as pneumonia and acute bronchitis, was based on the diagnosis given by pediatricians in charge, attributed to a combination of clinical, laboratory, and radiological findings from a chest X-ray and/ or a thoracic computed tomographic scan [14]. If the patient was more than one year old, leukocytosis was defined as WBC count > 10×109/L. HFMD patients were divided into two groups, patients with LRTIs and patients without LRTIs as control group. We collected serum samples from all patients on the second day of admission. Serological tests for EV71 IgM and CA16 IgM were carried out as described previously [15-17]. The EV71 IgM ELISA kits (no. 3400526) and CA16 IgM ELISA kits (no. 3400427) were provided by Beijing Wantai Biological Pharmacy, approved by the State Food and Drug Authority (SFDA) of China in 2010 and 2011, respectively [17].
2
Clin. Lab. 9+10/2013
INFECTIOUS DISEASE AND FETAL PROGRAMMING Table 1. Demographic characteristics of 298 patients with HFMD in this study.
Type of delivery
Characteristics
Number (%) or mean ± SD
Male
183 (61.41)
Age, months
26.82 ± 18.10
The admission day
2.47 ± 1.67(1 to 9)
Preterm birth
35 (11.74)
Caesarean section
27 (9.06)
Natural delivery
197 (66.11)
Other
74 (24.83)
Supplementation of vitamin A in children under one year
23 (7.72)
Full-course national-planned vaccination
236 (79.19)
Polio vaccination
296 (99.33)
BCG vaccination
296 (99.33)
Multivalent pneumococcal vaccination
13 (4.36)
Chickenpox
4 (1.30)
Low serum potassium
1 (0.33)
Oral candidiasis
1 (0.33)
G-6-PD deficiency
18 (6.04)
Thalassemia
7 (2.35)
Pneumonia
47 (15.77)
Acute bronchitis
10 (3.36)
Data are presented as mean ± SD and number (%).
All of the infants and children generally recovered within seven to twelve days after hospitalization. They were admitted at 2.47 ± 1.68 days, range 1 day to 9 days, median 2 days after the onset of HFMD. The admission days made no statistical difference between the LRTIs group and control group. Intravenous immunoglobulin was given routinely for the treatment of severe cases according to the standard China guideline of treatment 2010.
Data analysis Data was analyzed with SPSS version 17.0. Results are presented as mean ± standard deviation. When examining frequencies, Chi-square and Fisher’s exact tests were applied. T-Test was used to detect significant differences between the two groups of interest. A p-value of less than 0.05 was considered significant. RESULTS
Birth weight Birth weight data reported by the parents were cross checked, and only those cases were included into the study where birth weight data reported by the parents could be confirmed by hospital reports. Mean birth weight was 3100.23 ± 423.87 grams (range 1300 to 4500 grams, median 3100 grams). For details, see table 1.
HFMD infants and children All the hospitalized infants and children with HFMD were included retrospectively in the study. We identified 298 cases, predominantly male infants (183 cases (61.41%) with a male-to-female ratio of 1.59:1). The mean age was 26.82 ± 18.10 months. The incidence of preterm birth was 11.74%. Forty-seven cases (15.77%) were complicated by pneumonia and ten cases (3.36%) by acute bronchitis in patients with HFMD. One threeyear-old female infant had low serum potassium. Four patients also had chickenpox. The history data such as delivery type, supplementation of vitamin A in children younger than one year, full-course national vaccination, and multivalent pneumococcal vaccination are shown in table 1. Clin. Lab. 9+10/2013
Association of LBW with the occurrence of LRTIs in infants and children with HMFD Mean birth weight was 167 grams lower in the LRTIs group than in the control group, p = 0.022. Compared to the control group, the percentages of both LBW and BW below the tenth percentile were significantly higher in patients with LRTIs, p = 0.002 and p = 0.043, respec3
YONG-PING LU et al. Table 2. Comparison of the variables in HFMD patients between LRTIs and control. Variables Male, n (%) Age, months < 12 months, (%) < 36 months, (%) < 60 months, (%) The day on admission Birth weight, g < 1500g, (%) 1500 ~ 2499g, (%) ≥ 2500g, (%) LBW, (%) Below the tenth percentile, (%) Fever, (%) peak Temp. ≥ 38°C peak Temp. ≥ 39°C Cough, (%) Rhinorrhea, (%) Oral ulcer, (%) Skin rashes no rash, (%) one site, (%) two sites, (%) three sites, (%) Heartbeat, beats/min Respiratory rate, beats/min Hb, g/L RBC, ×1012/L WBC, ×109/L Neutrophils Lymphocytes Glucose, mmol/L TP, g/L ALB, g/L A/G ratio Total bililrubin, umol/L Creatinine, mmol/L ALT, U/L AST, U/L ALP, U/L GGT, U/L LDH, U/L LDH1, U/L CK, U/L CK-MB, U/L HBDH, U/L CrP, mg/L ESR, mm/h
5.733 (1.659 - 19.812) 0.145 (0.044 - 0.484) 6.880 (2.064 - 22.930)
ⅹ2 or t-value 0.091 3.423 0.059 2.889 0.355 1.011 8.725 Fisher’s Fisher’s Fisher’s Fisher’s
7.34
3.942 (1.591 - 9.767)
Fisher’s
0.043
54.38 38.60 14.04 89.47 1.75 87.72
51.87 40.83 11.62 5.39 2.07 94.61
1.106 (0.620 - 1.975) 0.911 (0.504 - 1.647) 1.242 (0.534 - 2.891) 149.077 (54.087 - 410.889) 0.843 (0.097 - 7.358) 0.407 (0.155 - 1.073)
0.117 0.096 0.254 193.24 Fisher’s Fisher’s
0.732 0.757 0.615 0.000 1.000 0.076
5.26 0 82.46 10.52 112.88 ± 8.00 27.49 ± 3.02 116.82 ± 11.29 4.76 ± 0.63 12.47 ± 4.44 6.29 ± 3.83 4.79 ± 2.45 4.86 ± 1.26 68.07 ± 4.99 43.64 ± 4.42 1.83 ± 0.39 6.32 ± 3.79 23.99 ± 8.01 18.53 ± 12.78 33.88 ± 12.08 207.50 ± 41.03 13.18 ± 3.06 271.30 ± 62.60 85.45 ± 18.80 150.02 ± 135.20 29.30 ± 11.42 219.32 ± 55.30 12.06 ± 25.28 14.93 ± 11.63
2.07 1 (0.41) 83.82 13.69 111.05 ± 8.71 26.59 ± 2.12 117.56 ± 11.19 4.80 ± 0.55 11.00 ± 4.01 5.61 ± 3.02 4.64 ± 6.70 5.08 ± 1.28 68.27 ± 4.97 43.41 ± 3.81 1.79 ± 0.34 5.76 ± 3.73 26.64 ± 9.84 19.30 ± 12.91 32.28 ± 8.23 208.06 ± 65.50 15.45 ± 28.28 267.61 ± 58.93 84.49 ± 18.32 121.24 ± 92.78 26.50 ± 9.00 222.24 ± 189.85 9.02 ± 22.34 13.01 ± 9.19
2.622 (0.608 - 11.309) 0.907 (0.423 - 1.948) 0.742 (0.295 - 1.865)
Fisher’s Fisher’s 0.062 0.406 0.110 2.605 0.004 1.608 1.460 4.510 0.145 0.104 0.093 1.288 2.560 0.948 1.598 0.087 1.902 2.067 0.783 1.627 0.030 6.702 3.859 0.030 1.891 0.004
0.182 1.000 0.803 0.524 0.148 0.009 0.656 0.657 0.015 0.145 0.861 0.237 0.786 0.699 0.422 0.314 0.064 0.684 0.657 0.800 0.673 0.675 0.809 0.132 0.046 0.908 0.369 0.308
LRTI group N = 57 63.16 22.96 ± 13.47 15.79 84.21 98.25 2.73 ± 1.92 2965.48 ± 559.13 2.38 14.29 83.33 16.67
Control group N = 241 60.99 27.73 ± 18.94 14.52 73.44 95.44 2.42 ± 1.62 3132.20 ± 379.94 0 2.82 97.18 2.82
23.81
OR （95% CI） 1.096 (0.603 - 1.992) 1.104 (0.497 - 2.449) 1.928 (0.895 - 4.153) 2.768 (0.339 - 21.179)
p-value 0.763 0.074 0.808 0.089 0.551 0.317 0.022 0.192 0.008 0.002 0.002
Data are presented as mean ± SD (number) and number (%).
4
Clin. Lab. 9+10/2013
INFECTIOUS DISEASE AND FETAL PROGRAMMING
120
108
Case number
100 80 60
52 55
51
40 14
20 1
1
2
1
2
3
6
4
4
0 4
5
6 7 Month
8
9
10 11
0 12
Figure 1. Monthly distribution of hospitalized cases with HFMD in Qingxin county People’s Hospital, 2011.
tively. 14.29% had MLBW in the LRTIs group and 2.82% in the control group. MLBW counted for a high risk of acquiring LRTIs in children with HFMD, the odds ratio was 5.733 with 95% confidence interval of 1.659 to 19.812, p = 0.008. Concerning clinical manifestations, the incidence of cough and mean respiratory rate was significantly higher in patients with HFMD and LRTIs than in patients with solely HFMD, p < 0.001 and p = 0.009, respectively. In the laboratory tests, WBC count and CK-MB level were higher in HFMD patients with LRTIs than in the control group, p = 0.015 and p = 0.046, respectively. Other markers, such as platelet counts, serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum glucose at admission time, creatinine and liver transferase levels were not significantly different between the two groups (table 2). The gathered data were analyzed again excluding infants aged younger than twelve months. The results were similar. Mean birth weight was 164 g lower in the LRTIs group than in the control group, p = 0.043 and the respiratory rate showed significant differences between the LRTIs group and the control group in HFMD patients, p = 0.021 (data not shown).
Clin. Lab. 9+10/2013
DISCUSSION Our study, performed in southern China, demonstrated for the first time that low birth weight is associated with poorer outcome in young children with HFMD in terms of higher rates of lower respiratory tract infections. In mainland China, nationwide HFMD outbreaks have recently become a significant public health concern [1]. Over 3.4 million cases of HFMD including over 1,000 deaths have been reported in China since the epidemic in Fuyang city, Anhui province, 2008. Following this event, HFMD has been a disease that must be reported by physicians to the health authorities in China [18]. Guangdong province is one of the highly endemic regions, which is located in the south of China [19,20]. In our study, the male-to-female ratio was 1.59:1, similar to the ratio 1.5:1 from Taiwan [21], but somewhat lower than the ratio 1.9:1 from a one-year report of 2009 in Guangdong province by De et al. [20]. Thus, our study is within the range of other reports showing that more males are affected. The reason why the infection is predominantly seen in male infants is unknown so far. The higher overall male to female newborn rate and also better medical care of Chinese parents to male offspring might explain this. Other studies trying to identify risk factors for poor outcome of HFMD could demonstrate that high fever, fatigue, respiratory distress, mucocutaneous papulovesicular rashes, cyanosis, and laboratory markers, such as 5
YONG-PING LU et al.
out complications was only 165 g does not support a major role of gestational age as confounding. So far, lower birth weight was just recognized as an important risk factor for type 2 diabetes mellitus and cardiovascular diseases, such as myocardial infarction, hypertension, and stroke in later life [32,33]. Concerning lung diseases, current studies suggest that both environmental and genetic factors in various periods of life, and their epigenetic mechanisms, may underlie the complex associations of low birth weight with respiratory diseases such as asthma and respiratory tract infections in later life [34,35]. The ‘fetal origin’ hypothesis proposes that adulthood lung, cardiovascular, and metabolic diseases originate through adaptation of the fetus in relationship to environmental conditions in early life [36]. It was proposed that an event in a critical early period of life permanently alters organ structure and function in response to environmental factors. Such events may lead to lung/cardiovascular/metabolic diseases in later life. The classical event causal for fetal programming is maternal undernutrition during pregnancy. This was first recognized in epidemiological studies and later confirmed in animal experiments [37-39]. Meanwhile several other mechanisms caused by environmental conditions in early life leading to lifelong functional and structural alterations have been described, among them glucocorticoid exposure of the fetus due to 11 beta-hydroxysteroid dehydrogenase deficiency of the placenta [40,41] or even a high protein diet during pregnancy [42]. Another mechanism responsible for programming events during intrauterine life might be related to maternal genes affecting the fetal phenotype independent of the fetal genome (43,44). In conclusion, our study demonstrated for the first time that LBW in children with HFMD might be a risk factor for developing complications with poorer outcome such as lower respiratory tract infections including pneumonia and acute bronchitis.
higher peripheral WBC counts and elevated levels of serum glucose, are indicators of serious complications and progressive pulmonary edema and/or haemorrhage [810]. In two retrospective studies of severe HFMD cases in Fuyang city, Anhui province from 2008, all patients who died were under the age of three years. The cases with poor outcome are often complicated by central nervous system manifestations of the disease such as encephalitis and myelomeningitis. Levels of serum aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), and serum glucose were also elevated in those studies [22,23]. In our cohort, serum CK-MB levels were increased in patients with HFMD and LRTIs as compared to the control group (p = 0.046). An elevation of this cardiac specific creatine kinase in patients with HFMD indicates cardiac involvement (myocarditis) [24]. This is of particular interest, since CNS involvement of HFMD and cardiomyopathy are major prognostic factors for severe EV71 meningoencephalitis, a fatal complication of HFMD [25]. Lower birth weight in general is a known risk factor for poor outcome of any major disease in the first months of life. This was, however, never analyzed for HFMD. Hence, we set up a study to analyze whether low birth weight is indeed another risk factor for poorer outcome of HFMD infections in young children. A major complication of HFMD is the development of lower respiratory tract infections. Our data clearly show that low birth weight is also an independent prognostic factor for the outcome of HFMD in young children. So far lower birth weight was associated with poorer pulmonary outcome for other viral diseases. Premature infants are particularly susceptible to RSV infections and their severe complications [11] due to an immaturity of the lung and the immune system [26]. It was shown that premature birth is associated with reductions in functional residual capacity, compliance, flow and gas exchange capacity [27-29]. LBW children might have disturbed cell immunity and an increased vulnerability to infectious diseases in later life [30]. In this context, it is also of note that in a study of 298 healthy term newborns in the Netherlands, children with a birth weight below 4 kg had a much higher risk of acquiring RSV-LRTIs in the first year of their life [31]. A population-based case-control study was conducted from 1998 to 2007 in Washington State, USA. In this study, it was shown that adults aged 18 to 27 years, with a history of low birth weight (VLBW or MLBW), were at increased risk for hospitalization for respiratory illnesses [12]. Those studies show that the association of birth weight or preterm birth with the susceptibility for viral infections in later life and poorer outcome persists into later life. This, for sure, needs to be confirmed in future larger epidemiological studies. A limitation of our study is the fact that we had no data on gestational age and thus could not exclude that our findings might be driven by preterm birth cases. However, the finding that the differences between the HFMD with and with-
Acknowledgment and Funding: We thank the Medical Scientific Research Foundation of Guangdong Province, China (no A2011348) for the support. The authors gratefully acknowledge the contributions of the general practitioners, the children which took part in the study, and their parents for their cooperation. Declaration of Interest: None. Contributors: Yong-Ping Lu was responsible for data collection, data analysis, and writing of the manuscript. De-Ying Zeng was the coordinator and she designed the study. Xu-Jing Liang, Si-Min Huang, and Zhi-Wei Lai contributed to planning and data collection. Jie-Ping Xu and Wang-
6
Clin. Lab. 9+10/2013
INFECTIOUS DISEASE AND FETAL PROGRAMMING 14. Chen X, Zhang ZY, Zhao Y, Liu EM, Zhao XD. Acute lower respiratory tract infections by human metapneumovirus in children in Southwest China: a 2-year study. Pediatr Pulmonol 2010;45(8): 824-31.
Rong Wen are technicians at the clinical laboratory contributing to the laboratory findings. Karoline von Websky and Berthold Hocher analyzed the data and critically reviewed the paper. You-Peng Chen contributed to planning, data analysis, and wrote the manuscript.
15. Wang SY, Lin TL, Chen HY, Lin TS. Early and rapid detection of enterovirus 71 infection by an IgM-capture ELISA. J Virol Methods 2004;119(1):37-43.
References: 1.
2.
3.
4.
World Health Organization Regional Office for the Western Pacific and the Regional Emerging Diseases Intervention (REDI) Centre. A Guide to Clinical Management and Public Health Response for Hand, Foot and Mouth Disease (HFMD), 2011.
17. EV71. Manufacturer of Infectious Diseases Diagnostics in Beijing Wantai. http://www.ystwt.com/WANTAI_English/ev71.html Accessed June 11, 2012.
Ministry of Health of the People’s Republic of China. The mortality and morbidility of nationally notifiable infectious diseases in 2011 (in document). http://www.moh.gov.cn/publicfiles/business/htmlfiles/mohjbyfkzj/s3578/201202/54106.htm Accessed April 26, 2012.
18. Gan ZH, Zhuo JT. Advances of Research on Hand, Foot and Mouth Disease. China Tropical Medicine, 2009; 9: 373-5. 19. Zhu Q, Hao YT, Ma JQ, Yu SC, Wang Y. Surveillance of Hand, Foot, and Mouth Disease in Mainland China (2008-2009). Biomed Environ Sci 2011;24(4):349-56.
Department of Health of Guangdong Province. The mortality and morbidility of nationally notifiable infectious diseases in Guangdong Province in 2011. http://www.gdwst.gov.cn/a/ yiqingxx/201202159566.html Accessed April 26, 2012.
20. De W, Changwen K, Wei L, Monagin C, Jin Y, Cong M, Hanri Z, Jun S. A large outbreak of hand, foot, and mouth disease caused by EV71 and CAV16 in Guangdong, China, 2009. Arch Virol 2011;156(6):945-53.
Harvala H, McLeish N, Kondracka J, et al. Comparison of human parechovirus and enterovirus detection frequencies in cerebrospinal fluid samples collected over a 5-year period in Edinburgh: HPeV type 3 identified as the most common picornavirus type. J Med Virol 2011;83:889-96.
5.
Wang SM, Liu CC. Enterovirus 71: epidemiology, pathogenesis and management. Expert Rev Anti Infect Ther 2009;7:735-42.
6.
Chen SC, Chang HL, Yan TR, Cheng YT, Chen KT. An eightyear study of epidemiologic features of enterovirus 71 infection in Taiwan. Am J Trop Med Hyg 2007;77:188-91.
7.
Solomon T, Lewthwaite P, Perera D, Cardosa MJ, McMinn P, Ooi MH. Virology, epidemiology, pathogenesis, and control of enterovirus 71. Lancet Infect Dis 2010;10(11):778-90.
8.
Mao GS, Luo L, Liu XL, et al. The comparison between mild cases and severe cases of hand-foot-mouth disease. Chin J Infect Dis 2008;26(7):387-90.
9.
16. Zhao J, Xu J, Chen WW, et al. The early diagnosis value of EV7l IgM class antibodies in the hand, foot and mouth disease. Chin J Exp Clin Virol 2011;25(2):140-2. [in Chinese, Abstract in English]
21. Chen TC, Chen GW, Hsiung CA, et al. Combining multiplex reverse transcription-PCR and a diagnostic microarray to detect and differentiate enterovirus 71 and coxsackievirus A16. J Clin Microbiol 2006;44(6):2212-9. 22. Han MF, Chen XF, Ran XG, et al. Analysis of death causes and preventive measures for severe cases with hand, foot, and mouth diseases. ANHUI YIXUE 2008;29(4):350-1. [in Chinese] 23. Du J, Ding ZT, Wang JF, Zhu LY. The epidemiological analysis of death cases with hand, foot, and mouth disease in Fuyang city. ANHUI YIXUE 2009;30(3):256-7. [in Chinese] 24. Fu YC, Chi CS, Chiu YT, et al. Cardiac complications of enterovirus rhombencephalitis. Arch Dis Child 2004;89:368-73. 25. Huang YF, Chiu PC, Chen CC, et al. Cardiac troponin I: a reliable marker and early myocardial involvement with meningoencephalitis after fatal enterovirus-71 infection. J Infect 2003;46: 238-43.
Yu LX, Zhe LL, Liu WD. The pre-albumin and blood glucose in serum of severe cases of hand foot and mouth disease and its significance. Chin Pediatr Emerg Med 2011;18(1):57-8.
26. Aujard Y, Faroux B. Risk factors for severe respiratory syncytial virus infection in infants. Respir Med 2002;96 (Suppl B):S9-S14.
10. Li Y, Zhu R, Qian Y, Deng J. The characteristics of blood glucose and WBC Counts in peripheral blood of cases of hand foot and mouth disease in China: A systematic review. PloS ONE 2012;7(1): e29003.
27. Langston C, Kida K, Reed M, Thurlbeck WM. Human lung growth in late gestation and in the neonate. Am Rev Respir Dis 1984;129:607-13.
11. Rossi GA, Medici MC, et al. Osservatorio RSV Study Group. Risk factors for severe RSV-induced lower respiratory tract infection over four consecutive epidemics. Eur J Pediatr 2007;166: 1267-72.
28. Hjalmarson O, Sandberg K. Abnormal lung function in healthy preterm infants. Am J Respir Crit Care Med 2002;165:83-7. 29. Friedrich L, Stein RT, Pitrez PM, Corso AL, Jones MH. Reduced lung function in healthy preterm infants in the first months of life. Am J Respir Crit Care Med 2006;173:442-7.
12. Walter EC, Ehlenbach WJ, Hotchkin DL, Chien JW, Koepsell TD. Low birth weight and respiratory disease in adulthood: A population-based case-control study. Am J Respir Crit Care Med 2009;180:176-80.
30. Raqib R, Alam DS, Sarker P, et al. Low birth weight is associated with altered immune function in rural Bangladeshi children: a birth cohort study. Am J Clin Nutr 2007;85(3):845-52.
13. Ministry of Health of the People’s Republic of China. Hand, foot and mouth disease clinic guide (2010 edition). Available at: http://www.moh.gov.cn/publicfiles/business/htmlfiles/mohyzs/s3 586/ 201004/46884.htm (in Chinese) Accessed January 19, 2012.
Clin. Lab. 9+10/2013
31. Houben ML, Bont L, Wilbrink B, et al. Clinical Prediction Rule for RSV Bronchiolitis in Healthy Newborns: Prognostic Birth Cohort Study. Pediatrics 2011;127(1):35-41.
7
YONG-PING LU et al. 32. Hocher B. Fetal programming of cardiovascular diseases in later life - mechanisms beyond maternal undernutrition. J Physiol 2007;579(Pt 2):287-8.
41. Aufdenblatten M, Baumann M, Raio L, et al. Prematurity is related to high placental cortisol in preeclampsia. Pediatr Res 2009; 65:198-202.
33. Hocher B. Neonatal handling: a potential new underlying reason for programming of renal diseases in later life. Kidney Blood Press Res 2009;32(4):284-5.
42. Thone-Reineke C, Kalk P, Dorn M, et al. High-protein nutrition during pregnancy and lactation programs blood pressure, food efficiency, and body weight of the offspring in a sex-dependent manner. Am J Physiol Regul Integr Comp Physiol 2006;291: R1025-30.
34. Duijts L. Fetal and infant origins of asthma. Eur J Epidemiol 2012 Jan;27(1):5-14. doi: 10.1007/s10654-012-9657-y. Epub 2012 Feb 18.
43. Hocher B, Slowinski T, Stolze T, Pleschka A, Neumayer HH, Halle H. Association of maternal G protein ß3 subunit 825T allele with low birthweight. Lancet 2000;355;1241-2.
35. Wang WH, Chen PC, Hsieh WS, Lee YL. Joint effects of birth outcomes and childhood body mass index on respiratory symptoms. Eur Respir J 2012 May;39(5):1213-9. Epub 2012 Mar 22.
44. Hocher B, Slowinski T, Bauer C, Halle H. The advanced fetal programming hypothesis. Nephrol Dial Transpl 2001;16:1298-9.
36. Barker DJ. The developmental origins of adult disease. J Am Coll Nutr 2004;23(6 suppl):588S-95S.
Correspondence: Dr. You-Peng Chen Department of Infectious Diseases The First Affiliated Hospital of Jinan University Tianhe Zone, Guangzhou 510630 Guangdong province, China Tel.: +86 20 38688104 Fax: +86 20 38688205 Email:
[email protected]
37. Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ. Weight in infancy and death from ischaemic heart disease. Lancet 1989;ii:577-80. 38. Ravelli AC, van der Meulen JH, Michels RP, et al. Glucose tolerance in adults after prenatal exposure to famine. Lancet 1998; 351:173-7. 39. Vehaskari VM, Aviles DH, Manning J. Prenatal programming of adult hypertension in the rat. Kidney Int 2001;59:238-45. 40. Seckl JR, Cleasby M, Nyirenda MJ. Glucocorticoids, 11beta-hydroxysteroid dehydrogenase, and fetal programming. Kidney Int 2000;57:1412-7.
Prof. Dr. Berthold Hocher Institute of Nutritional Science University of Potsdam D-14558 Nuthetal Potsdam, Germany Email:
[email protected] Homepage: http://www.uni-potsdam.de/eem
8
Clin. Lab. 9+10/2013
