Based on meta-analyses of national data from seven countries, over a period of 11-26 years, we found that the incidence rates for clinically manifested campylobacteriosis were 31%, 34%, 35% and 73% higher in males in infancy, young and late childhood and puberty, respectively. In young, older and senior age adults, they were 10%, 19% and 27% higher in males. The findings are remarkably consistent over countries and over a number of years. Our findings considerably extend those from population-based studies in multiple or single countries (9, 10, 25, 26), by producing age-specific pooled estimates of the incidence rate ratio accounting for country and time-period. A male predominance has been reported in the incidence of certain other infectious diseases, mainly in children (27, 28).
A major strength of the study is that it is based on national data with very large populations and consequently large numbers of cases and incidence rates based on reliable denominators. Selection bias has been minimized by using national data over different time periods, which should be representative of each country. The inclusion of seven countries, each evaluated over a number of years, allowed us to evaluate the consistency of the findings over different populations and many years. We do not believe that excluding countries that have poor diagnostic facilities or reporting of infectious diseases has created an important source of selection bias which would affect the sex differences in incidence rates. Since the clinical manifestations of campylobacteriosis vary widely, there could be significant under-reporting. However there is no reason to suspect that the under-reporting is related to the sex of the patient. Finally, differences that may exist in the laboratory methods used to confirm infection, both within and between countries, should also be unrelated to the sex of the patient.
While this study cannot address the mechanisms underlying the gender differences in the incidence of clinical campylobacteriosis, it is possible to speculate about possible cultural, behavioural, genetic, hormonal factors and microbiota. Regarding possible cultural factors, in the countries in this study, there is no evidence that the sex of the child influences seeking for medical care for acute infections. Similarly, there is no evidence to suggest that in these countries, adult men are more likely than women to seek medical care for acute conditions of comparable severity. If anything, studies have shown that women are more likely to seek medical care (29). Sex differences in exposure due to behavioural factors are unlikely to play a part in infants and very young children. In adults, exposure resulting from the care of young children could vary by sex, but since in the countries evaluated, women are likely to spend more time in the care of children, this would more likely bias the possibility of infection towards females. In addition, transmission of Campylobacter is mainly through food and water, and person-to person spread is considered to be uncommon (1,3,5). In the older age groups, it is conceivable that males may be more likely to be exposed as a result of consumption of inadequately cooked food eaten outside of the home (30).
Regarding genetic factors, females generally exhibit elevated humoral and cell-mediated immune responses compared to males, and this may be related to X-linked chromosome expression. X chromosomes contain genes associated with immune system and presence of two X chromosomes plays a major role in enhancing both innate and adaptive immune responses (31). Genetic factors could play a part through an interaction with sex hormones. Estradiol promotes innate immune signalling pathways, including macrophages, dendritic cells (DCs), granulocytes, and lymphocytes cell development. The hormone also enhances production of pro-inflammatory cytokines and chemokines in response to TLR (Toll-like receptor) ligand stimulation of dendritic cells and macrophages, a phenomenon that may explain the superior immune response to infection in females (32-34). Testosterone has the effect of depressing the innate and adaptive immune response (35). Thus it is conceivable that sex hormones are implicated in the mechanism of infection by Campylobacter jejuni. C. jejuni interferes with host innate immune signalling and the flagellins, FlaA and FlaB have been found to activate the innate immune receptor Toll-like receptor 5 (TLR5) (36). Al-Banna et al (6) have proposed that the immune response induced by C. jejuni induces a cascade of pro-inflammatory cytokines initiated by intestinal epithelial cells and innate cells, promoted by antigen-presenting cells and enhanced by T cells, but resolved by anti-inflammatory cytokines. Estrogen is known to impact on the cytokines in the immune response of innate immunity and anti-inflammatory cytokines (37). They could thus modify the response to infection and contribute to the sex differences in the incidence rates from campylobacteriosis.
In animal studies, Zeng et al (8) recently demonstrated that innate antibodies against enteropathogenic Escherichia coli (EPEC) were present only in female mice after puberty and developed as a response to estrogen. They showed that these antibodies enabled Kupffer cells to capture circulating EPEC and were not dependent on previous exposure to the antigen. Thus, differences in sex hormone levels could play a significant biological role in the immune response to infection with C. jejuni and result in higher incidence rates of campylobacteriosis in males.
Prior to puberty, it is not clear to what extent sex hormones play a role in the sex differences in disease. In the first year of life, sex hormone levels differ between males and females during the so-called “mini-puberty”. It is characterized by higher testosterone levels in boys at 1-3 months of age which decline at 6-9 months of age, whereas in girls, oestradiol levels remain elevated longer (38). Thus, sex hormones could conceivably play a role in affecting immune cells even in the first year of life and may be ''carried over'' from infancy into early childhood. It is of interest to note that the largest excess in incidence rates for males was in the age 10-14, where both hormonal and behavioural factors could be operating.
Microbiota can affect immunity by direct interaction with immune cells, by epigenetic modification and via the production of signaling biomolecules. Recent studies indicate sex-specific differences in immune responses based on the gut microbiota associated microorganisms, that significantly influence the function of innate and adaptive immunity (39,40).
As mentioned earlier, a serious complication of campylobacteriosis is the Guillain–Barré syndrome. It is interesting to note that there are reports that the Guillain Barré syndrome is also more common in males (41). It is not clear whether the excess incidence of Guillain–Barré syndrome in males is confined solely to those cases occurring as result of campylobacteriosis.
In conclusion, the remarkably consistent excess incidence of campylobacteriosis in males, particularly in infants and very young children, suggests and that sex-specific factors influence the manifestation of clinical disease. These findings should stimulate research on sex as a biological variable in the pathogenesis of campylobacteriosis.