CORRESPONDENCE

Re: Birth Order, Atopy, and Risk of Non-Hodgkin Lymphoma

Andrew Kemp, Anne-Louise Ponsonby, Terry Dwyer

Affiliations of authors: The Children's Hospital at Westmead, Sydney, Australia (AK); Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Melbourne, Australia (A-LP, TD)

Correspondence to: Andrew Kemp, MBBS, FRACP, PhD, Department of Allergy, Immunology and Infectious Diseases, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145 Australia (e-mail: andrewk5{at}chw.edu.au).

In a recent article in the Journal, Grulich et al. reported that the risk of non-Hodgkin lymphoma was reduced in only and first-born children and that the risk increased linearly with the number of older siblings (1). The authors suggest that these findings may be due to decreased exposure to infections in the infant period in particular. We suggest that additional consideration of younger sibling number and sibship birth intervals would provide further insights into the timing and mechanism of this intriguing association.

In families with more than one child (and 95% of the case patients in this study were from such a family), early birth order also has the potential for an increased exposure time to younger siblings. We found that, in a normal adult population, exposure to younger infant siblings during the first 6 years of life was associated with altered measures of Epstein-Barr virus (EBV) infection, such as self- or parental report of infectious mononucleosis and high EBV immunoglobulin G titers, independent of the number of older siblings (2). These observations indicate that, in adult life, the response to a common viral infection (i.e., EBV) is influenced by exposure to younger siblings. One interpretation of our results is that exposure to younger siblings in early life protects against the acquisition of an EBV infection that is manifested as clinical mononucleosis and higher antibody titers in later life. EBV has been strongly implicated in some forms of lymphoma; because the virus persists in almost all infected individuals as a lifelong infection in the B-lymphocyte pool (3), it may be involved in the pathogenesis of non-Hodgkin B-cell lymphoma (4). In this context, it is of interest that younger but not older sibling exposure is strongly associated with a reduced risk of developing multiple sclerosis (2). Although the similar magnitude of risk reduction in only children and first-born children of larger sibships reported by Grulich et al. (1) might argue against a parallel mechanism for NHL, the potential importance of the younger sibling effect is, nonetheless, worthy of further examination.

Positive associations between multiple sclerosis and NHL (5,6) and the observation that EBV infection is a risk factor for both diseases (2,4) indicate the possibility of similar protective mechanisms. NHL and multiple sclerosis also have some common epidemiologic features, such as an increase in Western countries in recent decades (7). We suggest that the links between early-life sibling exposure, EBV infection, and lymphoma merit further consideration.

REFERENCES

(1) Grulich AE, Vajdic CM, Kaldor JM, Hughes AM, Kricker A, Fritschi L, et al. Birth order, atopy, and risk of non-Hodgkin lymphoma. J Natl Cancer Inst 2005;97:587–94.[Abstract/Free Full Text]

(2) Ponsonby AL, van der Mei I, Dwyer T, Blizzard L, Taylor B, Kemp A, et al. Exposure to infant siblings during early life and risk of multiple sclerosis. JAMA 2005;293:463–9.[Abstract/Free Full Text]

(3) Young LS, Rickinson AB. Epstein-Barr virus: 40 years on. Nat Rev Cancer 2004;4:757–68.[CrossRef][ISI][Medline]

(4) Mueller N, Mohar A, Evans A, Harris NL, Comstock GW, Jellum E, et al. Epstein-Barr virus antibody patterns preceding the diagnosis of non-Hodgkin's lymphoma. Int J Cancer 1991;49:387–93.[ISI][Medline]

(5) Vineis P, Crosignani P, Vigano C, Fontana A, Masala G, Stagnaro E, et al. Lymphomas and multiple sclerosis in a multicenter case-control study. Epidemiology 2001;12:134–5.[CrossRef][ISI][Medline]

(6) Zhang Y, Holford TR, Leaderer B, Zahm SH, Boyle P, Morton LM, et al. Prior medical conditions and medication use and risk of non-Hodgkin lymphoma in Connecticut United States women. Cancer Causes Control 2004;15:419–28.[CrossRef][ISI][Medline]

(7) Muller AM, Ihorst G, Mertelsmann R, Engelhardt M. Epidemiology of non-Hodgkin's lymphoma (NHL): trends, geographic distribution, and etiology. Ann Hematol 2005;84:1–12.[CrossRef][ISI][Medline]



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