Epidemiological survey of human cytomegalovirus antibody levels in children from Southeastern China

The β-herpesvirus, human cytomegalovirus (HCMV), is globally ubiquitous in the general population [1, 2]. Its prevalence varies from 60–80% to 80–100% in developed and developing countries, respectively, depending on geography, ethnicity, and socio-economic conditions [1, 3]. Prevalence tends to be high in South America, Africa, and Asia, but low in Western Europe and the United States [4].

HCMV can be transmitted to the fetus during the entire pregnancy period, and is the most frequent cause of congenital infections during pregnancy [5, 6]. More than 10–15% of congenitally infected newborns have symptoms at birth, and 5–15% of infected infants without symptoms will have adverse outcomes, including spontaneous abortion, neonatal death, or long-term neurologic sequelae (mental retardation, hearing loss, and visual impairment) [7‐10]. Up to 60% of children are infected with HCMV in the first year of life with a wide range of clinical manifestations, such as pneumonia, infant hepatitis syndrome, and infectious mononucleosis. In older children, HCMV usually causes asymptomatic infections, although it may also be responsible for symptomatic glandular fever and hepatitis [11]. Following primary infection, the virus may remain latent and later reactivate to cause recurrent infection under certain situations such as reinfection with other viral strains [12, 13].

However, data on HCMV infection prevalence in hospitalized children is scarce and most investigations have small sample sizes. Diagnosis of HCMV infection is mainly based on the HCMV specific IgG and IgM antibodies using enzyme-linked immunosorbent assay (ELISA) or chemiluminescence immunoassay in patient serum [14, 15]. However, HCMV IgG and IgM couldn’t be correctly quantified by ELISA because of the poor reproducibility of the ELISA tests [16]. This study determined HCMV infection prevalence in hospitalized children from the Wenzhou region by detecting anti-HCMV IgG and IgM accurately using the AxSYM CMV IgM and IgG chemiluminescence immunoassay in order to monitor early HCMV infection and diagnosis in hospitalized children.

In general, HCMV is acquired earlier in life among lower socioeconomic strata in developed countries and in developing countries [19]. In some African nations, HCMV seroprevalence is as high as 80–90% by 10 years of age; in contrast, seroprevalence is below 20% by 15 years of age among subgroups of children in the United States and Great Britain. Several studies have reported HCMV seropositivity rates in some parts of China. One study showed a more than 70% overall rate of HCMV infection among the children younger than 15 years old in the Shanghai area (Southeastern China) [20]. In Eastern China, several studies showed lower HCMV seroprevalence. Zhao et al. reported a 33.5% HCMV seroprevalence in Jinan (Eastern China) among people younger than 20 years of age [21] and Sun et al. showed a 42.5% HCMV seroprevalence in people younger than 6 years old in the Weifang area (Eastern China) [22]. Our data show a 83.7% HCMV infection rate among hospitalized children in Wenzhou, higher than the study by Fang et al. , significantly higher than in Eastern China, indicating that HCMV is an important pathogen in hospitalized children of Southeastern China. The reasons for this high infection rate may be related to geography, socio-economic conditions, or sensitivity differences between testing methodologies.

Our data show that children less than 28 days of age had the highest HCMV IgG⁺ and lowest HCMV IgM⁺ rates (Table 1). In addition, statistical analysis showed the 28 days group to have the highest HCMV IgM⁺ rate and the lowest HCMV IgG antibody concentrations. The reasons for these observations may include: (i) postnatal transmission of HCMV through breast milk [23‐25]. HCMV is reactivated in latently infected mothers during lactation and breast-fed infants are susceptible to HCMV infection from breast milk, so infants are at risk for primary HCMV infection [26, 27]. Because the infant cell-mediated and humoral immune system is immature, some infants (particularly <28 days of age) cannot produce an effective response to HCMV infections. (ii) The half-life of specific maternal IgG in infants is about 20 to 30 days [28, 29]. As infants are exposed to external HCMV, maternal HCMV-specific IgG may be depleted to clear the virus. The HCMV IgG concentration in the 28 days age group was much lower than the high concentration observed in the <28 days age group, suggesting that the 28 days group may have increased risk of active HCMV infection (Table 2).

HCMV has a diverse tropism in its host and infects most types of cells, including epithelial and endothelial cells, fibroblasts, smooth muscle cells, and various hematopoietic cells [30]. During congenital infection, fetal lungs are particularly targeted by HCMV [31, 32], leaving patients vulnerable to respiratory diseases, which account for 36.9% of all HCMV cases (Table 3). HCMV IgM⁺ individuals with respiratory infections showed that 11 of 58 cases were negative by Real-time PCR assay. The reason for this result may be that HCMV IgM was likely present, but the infection had been resolved. The liver is one of the most vulnerable organs infected by HCMV [33], and HCMV is the leading cause of infant hepatitis syndrome (IHS) [34]. In this study, IHS accounts for 8.6% in HCMV IgM⁺ patients. Although serological results suggest HCMV infection, further study is needed to distinguish whether HCMV infection and/or mixed infections with other pathogens results in these diseases.

In summary, this is the first study to our knowledge to screen for HCMV infection in hospitalized children in Wenzhou (Southeastern China). We observed a high HCMV prevalence rate of 83.7%. Although no evidence was shown that HCMV was the cause of these respiratory infections, respiratory infection is a leading disease among hospitalized children positive for HCMV antibodies. The high prevalence of HCMV infection emphasizes HCMV diagnosis, prevention, and therapy for young children.