In the present meta-analytic study 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. These results 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 (10-12), and provide age-specific pooled estimates of the male to female IRR, while controlling for country and different time-periods. We have used the same meta-analytic methods to combine data from various countries and time periods for other diseases and demonstrated a male predominance in viral meningitis and shigellosis in young children (13, 14). On the other hand, the incidence rates for pertussis were higher in females at all ages (29).
A major strength of the study is that it is based on national data with a relatively large numbers of cases. In addition, incidence rates based on populations which are 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, with data analysed over a number of years has permitted us to evaluate the consistency of the findings. We do not believe that excluding countries that have poor diagnostic facilities or reporting of infectious diseases should affect the sex differences in incidence rates, although other unknown factors might impact on the manifestations of the diseases in other countries. Since the clinical manifestations of campylobacteriosis vary widely, there could be significant under-reporting, but this should not differ between the sexes. Finally, differences in laboratory methods, either within or between countries, are unlikely to be related to the sex of the patients. Seasonal variation in the incidence of campylobacteriosis is well-documented with higher rates in the summer months (30). However, there is no reason to suspect that differences in warmer and cooler countries would impact on the sex differences.
As in other studies where we have used this methodology to identify consistencies in sex differences in infectious diseases (13,14, 29), however, in this study we cannot address the exact mechanisms underlying the sex differences in the incidence of clinical campylobacteriosis. There are a number of possibilities that have been postulated about the potential roles of cultural, behavioural, genetic, hormonal factors and microbiota (31-33). 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 although there is some evidence that women use health services more than men do (34). Sex differences in exposure due to behavioural factors are unlikely to play a part in infants and very young children. It is likely that women spend more time caring for young children, this could increase their risk of infection. However, transmission of Campylobacter is mainly through food and water, and person-to person spread has not been found to be common (1, 3, 5).
In the older age groups, males may be more likely to be exposed as a result of consumption of inadequately cooked food eaten outside of the home (35). The use of proton pump inhibitors is a factor that could influence the incidence of the disease in older people (36). However, this should not impact on the sex differences in the disease incidence unless there are differences between men and women in the use of proton pump inhibitors.
As regards genetic factors, the humoral and cell-mediated immune responses appear to be stronger in females and since the X chromosomes contain genes associated with immune system, this could be an important factor in the immune response to Campylobacter infection (37). Sex hormones could play an important role. Estradiol promotes innate immune signalling pathways and can enhance production of pro-inflammatory cytokines and chemokines in response to TLR (Toll-like receptor) ligand stimulation of dendritic cells and macrophages (38, 39). This could partly explain the more effective immune response among females. In addition, testosterone can depress the innate and adaptive immune response (40), increasing the male susceptibility to clinical disease.
All or some of these factors could influence the mechanism of infection by Campylobacter. It has been shown that Campylobacter 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) (41). Al-Banna et al (6) have proposed that the immune response induced by Campylobacter 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. Some or all of these factors could modify the immune 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 Campylobacter and result in higher incidence rates of campylobacteriosis in males.
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, estradiol levels remain elevated longer (42). Thus, sex hormones can affect immune cells in the first year of life and perhaps even later. 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 (33, 43).
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 (44). 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.