Cytomegalovirus infection and development of allergic diseases in early childhood: Interaction with EBV infection?

doi:10.1016/j.jaci.2004.08.009

Journal of Allergy and Clinical Immunology

Volume 114, Issue 6, December 2004, Pages 1434-1440

https://doi.org/10.1016/j.jaci.2004.08.009 Get rights and content

Background

Chronic replication of cytomegalovirus and EBV in early life may affect the immune system and play a role in the development of allergy in children.

Objective

To assess the relation between cytomegalovirus infection and allergic disorders in children, including a possible interaction with EBV infection.

Methods

From a prospective birth cohort study in Stockholm, on factors of importance for development of allergy, 2581 four-year-old children were enrolled. The classification of allergic diseases was based on questionnaire answers and determination of IgE antibodies to common airborne and food allergens. IgG to cytomegalovirus was determined by a commercial ELISA and to EBV by indirect immunofluorescence.

Results

A total of 1191 (46%) children were cytomegalovirus-seropositive. There were no significant associations between seropositivity to cytomegalovirus and allergic manifestations, such as bronchial asthma, suspected allergic rhinitis, or atopic dermatitis. Seropositivity to cytomegalovirus alone, ie, without seropositivity to EBV, was related to IgE antibodies to airborne and food allergens (adjusted odds ratio, 1.8; 95% CI, 1.2-2.9).An antagonism between cytomegalovirus and EBV in relation to sensitization to airborne and food allergens was suggested (P = .05).

Conclusion

The study does not support the hypothesis that previous cytomegalovirus infection plays an important role in the pathogenesis of bronchial asthma, suspected allergic rhinitis, or atopic dermatitis in children. However, in the absence of EBV infection, cytomegalovirus infection may be related to sensitization to airborne and food allergens.

Section snippets

Study subjects

The study was based on a birth cohort including 4089 infants (2065 boys and 2024 girls) born from February 11, 1994, until November 22, 1996, in Stockholm. The aim was to assess the role of various environmental and lifestyle factors during early childhood for development of allergic disorders. The BAMSE study design has been presented in detail previously.²⁷ Briefly, the parents of the included families answered 4 questionnaires over time concerning risk factors, symptoms, and health outcomes

Results

If the prevalence of allergic outcomes and risk factors for development of allergy were differently associated with viral seropositivity in participants and nonparticipants (ie, with and without blood samples, respectively), the study might be biased. To assess such potential bias, the distribution of socioeconomic characteristics, allergic outcomes, and respiratory symptoms among the 2581 participants and in 1161 nonparticipants was studied.²⁴ The only statistically significant differences

Discussion

The prevalence of cytomegalovirus seropositivity of approximately 46% in young children found in this study is in line with previous epidemiologic studies in developed countries.34., 35. The seroprevalence to cytomegalovirus was higher in children whose mothers were 25 years and younger. A possible explanation is that increase of cytomegalovirus shedding including virus in breast milk can be related to more recent primary infections. The increase in primary infection of cytomegalovirus in

References (47)

W.W. Busse
Mechanisms and advances in allergic diseases
J Allergy Clin Immunol
(2000)
R. Beasley et al.
Prevalence and etiology of asthma
J Allergy Clin Immunol
(2000)
F.D. Martinez
Maturation of immune responses at the beginning of asthma
J Allergy Clin Immunol
(1999)
D.T. Umetsu et al.
Regulatory T cells control the development of allergic disease and asthma
J Allergy Clin Immunol
(2003)
A. Sheikh et al.
There is no evidence of an inverse relationship between Th2-mediated atopy and Th1-mediated autoimmune disorders: lack of support for the hygiene hypothesis
J Allergy Clin Immunol
(2003)
J.E. Gern et al.
The role of viral infections in the natural history of asthma
J Allergy Clin Immunol
(2000)
E. von Mutius
The environmental predictors of allergic disease
J Allergy Clin Immunol
(2000)
N. Laske et al.
No difference in type 1 T-cell immune responses to human cytomegalovirus antigens between atopic children and nonatopic children
J Allergy Clin Immunol
(2003)
N. Laske et al.
Infantile natural immunization to herpes group viruses is unrelated to the development of asthma and atopic phenotypes in childhood
J Allergy Clin Immunol
(2002)
E. Lucht et al.
Epstein-Barr virus (EBV) DNA in saliva and EBV serology of HIV-1-infected persons with and without hairy leukoplakia
J Infect
(1995)

K. Numazaki et al.

Transmission of cytomegalovirus

Lancet

(2001)

S.C. Klein et al.

Promotion of IL8, IL10, TNFα and TNFβ production by EBV infection

Leuk Res

(1996)

C. Almqvist et al.

Heredity, pet ownership, and confounding control in a population-based birth cohort

J Allergy Clin Immunol

(2003)

M. Gdalevich et al.

Breast-feeding and the onset of atopic dermatitis in childhood: a systematic review and meta-analysis of prospective studies

J Am Acad Dermatol

(2001)

E. Isolauri et al.

Breast-feeding of allergic infants

J Pediatr

(1999)

C.B. Wilson

The ontogeny of T lymphocyte maturation and function

J Pediatr

(1991)

S.L. Prescott et al.

Development of allergen specific T-call memory in atopic and normal children

Lancet

(1999)

E.G. Kallas et al.

Cytomegalovirus-specific IFMgamma and IL-4 are produced by antigen expanded human blood lymphocytes from seropositive volunteers

Immunol Lett

(1998)

M.A. Baumann et al.

Interleukin-5 is an autocrine growth factor for Epstein-Barr virus-transformed B-lymphocytes

Blood

(1992)

S.D. Message et al.

Viruses in asthma

Br Med Bull

(2002)

J.M. Smart et al.

Increased Th1 and Th2 allergen-induced cytokine responses in children with atopic disease

Clin Exp Allergy

(2002)

M. Calvani et al.

Correlation between Epstein-Barr virus antibodies, serum IgE and atopic disease

Pediatr Allergy Immunol

(1997)

H. Okudaira et al.

Concepts of the pathogenesis of allergic disease: possible roles of Epstein-Barr virus infection and Interleukin-2 production

Int Arch Allergy Immunol

(1999)

Cited by (32)

Determinants of Ethnic Differences in Cytomegalovirus, Epstein-Barr Virus, and Herpes Simplex Virus Type 1 Seroprevalence in Childhood
2016, Journal of Pediatrics
To identify whether there are ethnic differences in cytomegalovirus (CMV), Epstein-Barr virus (EBV), and herpes simplex virus type 1 (HSV-1) seroprevalence rates in children at 6 years of age, and when present, to evaluate how these differences can be explained by sociodemographic and environmental factors.
This study was embedded within a multi-ethnic population-based prospective cohort study. Serum IgG levels against CMV, EBV, and HSV-1 were measured by enzyme-linked immunosorbent assay in 4464 children (median age 6.0 years). Information on demographics and characteristics were assessed by questionnaires. Herpesvirus seroprevalences between Surinamese-Creole, Surinamese-Hindustani, Turkish, Moroccan, Cape Verdean Antillean, and Native Dutch children were compared.
Non-Western ethnicity was an independent risk factor for CMV (aOR, 2.16; 95% CI 1.81-2.57), EBV (1.76; 1.48-2.09), and HSV-1 seropositivity (1.52; 1.39-1.66). Among the ethnic groups, CMV seroprevalences ranged between 29% and 65%, EBV between 43% and 69%, and HSV-1 between 13% and 39%. Low family net household income, low maternal educational level, crowding, and lifestyle factors explained up to 48% of the ethnic differences in HSV-1 seroprevalences, and up to 39% of the ethnic differences in EBV seroprevalences. These factors did not explain ethnic differences in CMV seroprevalences.
Socioeconomic position and factors related to lifestyle explain only a part of the large ethnic differences in EBV and HSV-1 seroprevalences, whereas they do not explain ethnic differences in CMV seroprevalences in childhood.
Increased association between febrile convulsion and allergic rhinitis in children: A nationwide population-based retrospective cohort study
2014, Pediatric Neurology
Citation Excerpt :
Certain studies have demonstrated increased production of IL-1, TNF-α, and IL-6 in allergic rhinitis, with these proinflammatory cytokines contributing to the acute-phase response of inflammatory and immune diseases.14-17 With specific regard to allergic rhinitis and atopy, increased association with specific viral infections including HSV-I, rhinovirus, hepatitis B, and cytomegalovirus have also been reported.18-21 FC and allergic rhinitis are both common disorders among children, and according to previous literature, seem to share similar association with certain viral infections and proinflammatory cytokines.
Febrile convulsions and allergic rhinitis are both common childhood disorders and both are considered as generally benign disorders. Yet, especially in the case of allergic rhinitis, adverse effects on school performance and limited socialization are found. The relationship between febrile convulsions and allergic rhinitis has not been previously reported; thus, this article seeks to explore the association between these two disorders by collecting data from the Taiwanese nationwide cohort database.
A total of 1304 children with febrile convulsions were identified as the case cohort, and controls were matched based on age, sex, urbanization levels, and parents' occupation on a 1 to 4 ratio. Cox's proportional hazards regression model was used to estimate the hazard ratio and confidence interval of allergic rhinitis disorder among children with febrile convulsions.
During an average 6.7 years follow-up period, the incidence of allergic rhinitis in the febrile convulsions case group was higher (65.16 vs 51.45 per 1000 person-years). After 11 years of follow-up, the allergic rhinitis incidence in the febrile convulsion patients was approximate 4% higher than controls (log-rank test P < 0.0001). Risk of allergic rhinitis in the febrile convulsions group was found to be 1.21 times higher than in the control group (95% confidence interval, 1.08-1.36). This risk of allergic rhinitis development is further increased (0.94 vs 18.9) with frequency of febrile convulsions–related medical visits (one to three visits vs more than three visits, P < 0.0001).
Febrile convulsions may be associated with allergic rhinitis occurrence in children. Children with more than three febrile convulsion–related medical visits had a significantly higher cumulative incidence of allergic rhinitis. Both disorders have previously been reported to have similar cytokine profiles and specific viral infection association. More studies are required to explore a possible link between the two disorders.
Epstein-Barr Virus Infections
2010, Pediatric Allergy: Principles and Practice Expert Consult: Second Edition
Early-life EBV infection protects against persistent IgE sensitization
2010, Journal of Allergy and Clinical Immunology
Infection with EBV has previously been implicated in influencing allergic disorders, but its precise role remains contradictory. The timing of primary infection may contribute to the discrepancies.
This study aimed at investigating whether the time-point of primary EBV infection during childhood could be of importance in modulating the risk of developing IgE sensitization.
A total of 219 Swedish infants were followed prospectively to 5 years of age with clinical examinations, skin prick testing, specific IgE analyses, and determination of serostatus against EBV.
After analysis of the children's EBV serostatus, we found that 5-year-olds who were infected with EBV before the age of 2 years were at a significantly lower risk of being persistently IgE-sensitized—that is, sensitized at both 2 and 5 years of age (adjusted odds ratio, 0.34; 95% CI, 0.12-0.94). In contrast, contraction of EBV after 2 years of age was highly associated with late-onset IgE sensitization (adjusted odds ratio, 4.64; 95% CI, 1.57-13.69). Persistently sensitized 5-year-olds had higher specific-IgE levels than children with late-onset IgE sensitization (P < .01).
Our data support the value of early-life microbial exposure for protection against the development of IgE sensitization and underscore the proximate postnatal years as an important period during which EBV could contribute to an allergo-protective immune profile.
Changes in seroprevalence to four herpesviruses over 30 years in Swedish children aged 9-12 years
2006, Journal of Clinical Virology
Changing social conditions and life-styles in Sweden may have affected the spread of varicella-zoster virus (VZV), herpes simplex virus (HSV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV).
To study possible changes over 30 years in prevalence of antibodies against VZV, HSV, CMV, and EBV in Swedish children, using modern serological methods.
Serum samples from 819 Swedish children who were 9–12 years old in 1967–1968, in 1977–1978 (two cohorts), and in 1997, respectively, were examined. IgG antibodies against VZV, HSV, and CMV were measured by well validated enzyme-linked immunosorbent assays and against EBV by indirect immunoflourescense.
The seropositivity for VZV for 9–12 years old children was 50% in 1967–1968, 74–82% in 1977–1978, and 98% in 1997. The corresponding figures were 31%, 53%, 50%, and 58% for CMV, 35%, 35%, 32%, and 38% for HSV, and 64% in 1967–1968 and in 1977–1978 (both cohorts), and 62% in 1997 for EBV.
The seroprevalence for VZV increased significantly from 1967–1968 to 1997, and there was also a significant but smaller increase in the CMV seroprevalence, while seroprevalence to HSV and EBV remained relatively stable.
Early-life infections in association with the development of atopic dermatitis in infancy and early childhood: a nationwide nested case–control study
2022, Journal of the European Academy of Dermatology and Venereology

View all citing articles on Scopus

: Supported by grants from the Swedish Institute (New Visby Program), the Swedish Foundation for Health Care Sciences and Allergy Research, the Heart-Lung Foundation, and the Asthma and Allergy Foundation.

View full text

Basic and clinical immunologyCytomegalovirus infection and development of allergic diseases in early childhood: Interaction with EBV infection?

Background

Objective

Methods

Results

Conclusion

Section snippets

Study subjects

Results

Discussion

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Infect

Lancet

Leuk Res

J Allergy Clin Immunol

J Am Acad Dermatol

J Pediatr

J Pediatr

Lancet

Immunol Lett

Blood

Viruses in asthma

Br Med Bull

Increased Th1 and Th2 allergen-induced cytokine responses in children with atopic disease

Clin Exp Allergy

Correlation between Epstein-Barr virus antibodies, serum IgE and atopic disease

Pediatr Allergy Immunol

Concepts of the pathogenesis of allergic disease: possible roles of Epstein-Barr virus infection and Interleukin-2 production

Int Arch Allergy Immunol

Basic and clinical immunology
Cytomegalovirus infection and development of allergic diseases in early childhood: Interaction with EBV infection?