Ten years of prevalence and clinical laboratory features of HCMV infected children in a hospital of Jiangsu Province

Background: Human cytomegalovirus (HCMV) is prevalent worldwide and causing lifelong infection. We conducted a retrospective study to determine the epidemiology and clinical laboratory characteristics of CMV infection in children in a hospital of Jiangsu Province. Methods: Totally 2600 urine specimens of infants and children hospitalized in general pediatric from 2009 to 2018 were collected followed by CMV-DNA loads detection. Among them, clinical records and laboratory results of 971 infants aged 3-12 months were focused for further statistics analysis. Results: Urine CMV-DNA load test was intensively ordered in 2011 (17.76%; 532/2996) for infants under 1 month but the rate continuously dropped ever since. In fact, infants under 1 month had the lowest detection sensitivity and children aged between 3 to 24 months had the highest positive rate. On the contrary, analysis of blood routine test showed that the absolute counts of peripheral leukocytes (P=0.008), monocytes (P=0.039), neutrophils (P<0.001) and platelets (P=0.006) were significantly decreased in CMV+ group compared with CMV- group. The percentages of neutrophils (NEUT%) were decreased (P<0.001) while the percentages of lymphocytes (LYM%) were increased (P<0.001) by CMV infection. Moreover, NLR (neutrophil to lymphocyte ratio) (P<0.01), MLR (monocyte to lymphocyte ratio) (P=0.017) and SII (systemic immune index) (P=0.002) were also decreased in CMV+ group. The hospitalization of cases in CMV+ group was significantly longer than that of the CMV- group (P=0.039), and the proportion of children with hospitalization stay longer than 2 weeks in CMV+ group was higher, with significant difference (P=0.006). Conclusion: CMV survey has not drawn much attention in hospitalized infants and children, and the combined application of urine CMV detection and blood routine test should be benefit when assessing CMV infections.

Moreover, NLR (neutrophil to lymphocyte ratio) (P<0.01), MLR (monocyte to lymphocyte ratio) (P=0.017) and SII (systemic immune index) (P=0.002) were also decreased in CMV+ group. The hospitalization of cases in CMV+ group was significantly longer than that of the CMV-group (P=0.039), and the proportion of children with hospitalization stay longer than 2 weeks in CMV+ group was higher, with significant difference (P=0.006). Conclusion: CMV survey has not drawn much attention in hospitalized infants and children, and the combined application of urine CMV detection and blood routine test should be benefit when assessing CMV infections. Background HCMV is a latent herpes virus and is highly prevalent in 30% to 100% populations throughout the world [ 1,2]. CMV replicates silently in immune system and tissue cells after a series of immune responses and establishes lifelong persistence within the host [ 3], highly CMV viral loads were considered for lacking of control by the immune system and accounts for a considerable high frequency of reactivation [ 4]. Shedding CMV in urine and saliva appear to be the leading cause of CMV in primary infection, which is the major cause of severe congenital infection [ 5,6]. Thus, representative epidemiological data on the CMV infection of the infants and children may contribute useful information to infection prevention measures. In this study, we retrospectively summarized CMV test order and positive rate according to both year and age. We also comprehensively investigate the laboratory features of peripheral immune system in hospitalized infants and children to evaluate last 10 year's clinic situation. Based on these representative epidemiological data in one general hospital of Jiangsu Province, we hope to arise public concern on CMV early intervention and control. Statistical analysis SPSS 20.0 software (IBM Corp, Armonk, NY, USA) was used to analyze all data. An independent samples t-test was used for analyzing the differences between two groups. Data were presented as means ± SEM, P value less than 0.05 was considered significant.

Ten years survey of hospitalized children CMV epidemiology
The number of children tested for CMV and the numbers of positive cases were showed in Fig.1  is to say, the rates of CMV tests were getting lower and lower from 2011 to 2018, and were lowest in 2018. By contrast, the rates of CMV positive weren't decreased but increased slightly, with more than 30% in 8 out of 10 years. We further analyzed the epidemic of age distribution in 2600 children tested for CMV as shown in Fig.2, and found that the rates of CMV tests were 28.50% (741/2600) in infants aged under 1 months, 24.08% (626/2600) in infants aged 1-2 months, 11.50% (299/2600) in infants

Extended hospitalization duration of CMV-infected infants
As follow-up extended, we calculated their days of hospitalization respectively and found that CMV+ group had prolonged hospitalization cycle (9.12±2.88 vs. 8.28±1.79, P=0.039), and the proportion of children with hospitalization stay longer than 2 weeks in CMV+ group was higher than that of CMVgroup, with significant difference (14.44% vs. 1.56%, P=0.006). These results indicated that CMV infected infants required superior nursing and longer recovery.

Discussion
CMV becomes a public health event in developing countries. The seroprevalence of CMV in Chinese pregnant women is over 90% and 0.03%-2.0% in newborns leading to high morbidity and mortality in newborns. Nevertheless, awareness and surveillance of CMV in infants and children have remained unsubstantial in most Chinese hospitals although CMV test is one of the laboratory routine test after initial admission [15][16][17]. In this study, we present data from a large cohort of infants and children with CMV infection in the past 10 years. To our knowledge, this is the first prospective investigation about CMV-DNA loads in infants and children in Jiangsu Province. The data revealed that CMV tests were being ignored for the rates of CMV test were 17.75% to 3.15% from 2011 to 2018, but the positive rates were more than 30%. And the age distribution characteristics showed that attention has been paid to congenital CMV infection with the most CMV-DNA test rate of infants under 1 months, however, the positive rate was far beyond 50% in infants aged 3-24 months. In view of the low detection rate and high incidence of CMV in China, routine laboratory monitor and effective treatment strategies should be emphasized and improved.
CMV reactivates and spreads to organs as well as immune cells including lymphocytes, monocytes and neutrophils to accomplish dissemination [18][19][20], when blood routine test result can reflect the systemic inflammatory and immune responses [21][22][23]. In this study, we collected blood routine test results of 971 hospitalized infants aged from 3 to 12 months and found that the absolute counts of peripheral leukocytes, monocytes, neutrophils and platelets were significantly decreased in CMV+ group. As previously reported, CMV is associated with pancytopenia: 1) it downregulates granulocyte colony stimulating factor (G-CSF) or induces production of inhibitory cytokines as Interleukin-6 (IL-6) [   Author contributions WS, HZ and GR contributed equally to this work. WS collected the data, analyzed the data and wrote the paper; HZ and GR collected the data; TX and LW wrote the paper; PH and FW supported the clinical data of these patients; JZ designed and supervised the study. All authors have read and approved the final manuscript.