Epidemiologic characteristics of Campylobacter infections in high-income countries: a systematic review

Introduction. The Campylobacter is the most common bacterial cause of foodborne illnesses in high-income countries. In contrast to other infectious diseases, the number of Campylobacter cases has increased in developed countries over the last ten years. A systematic review has been conducted to identify the factors contributing to incidence of Campylobacter infection in developed countries and to estimate it by age, sex, geography, and season. Materials and methods. The review was limited to studies published in English from 2010–2021; eight nationwide surveillance and register-based cohort studies, which met the selection criteria, were included in the review. Results. While the highest incidence of Campylobacter infection was reported among young children living in rural areas, the highest number of Campylobacter cases among adults was recorded in urban settings. Nevertheless, population-wise, children and older adults are most affected, while the incidence rates are higher in males than in females, with cases peaking every summer. Conclusion. Campylobacter infection is a public health concern in high-income countries, being difficult to eradicate and having become an urgent challenge to the existing well-developed surveillance systems. Additionally, the threat of antibiotic resistance in Campylobacter is growing at an alarming rate. The reasons behind Campylobacter affecting more men than women as well as the age and geographic distribution of the infection still need thorough research.


Introduction
Campylobacter bacteria are bacterial enteric pathogens responsible for diarrheal illnesses such as gastroenteritis. It has been estimated that Campylo bacter species cause around 96 million foodborne infections worldwide every year [1]. Campylobacter typically are comma or s-shaped gram-negative bacteria. The genus Campylobacter consists of 32 species and 9 subspecies; however, two species, C. jejuni and C. coli are most common pathogens in humans and the leading cause of Campylobacter outbreaks [2]. Campylobacter infection is classified both as zoonotic and foodborne. It has a zoonotic nature because is carried by animals, being especially common for chickens [3] and is foodborne because can be transmitted to humans through undercooked and cross-contaminated foods of animal origin. Furthermore, contaminated water, unpasteurized milk, and rare, though possible human-to-human transmission are also a common source of foodborne Campylobacter infection [4].
Campylobacter infection is usually self-limiting, causing mild to severe symptoms like diarrhea, abdominal cramps, fever, body aches, nausea, vomiting, and fatigue. However, Campylobacter infection can be invasive and fatal when pathogens enter the bloodstream, causing bacteraemia. Campylobacter infection can be severe among elderly, immunosuppressed, HIV-positive, alcohol-dependent individuals, or in patients who had gastrointestinal surgery [5]. Post-infection complications may include Guillain-Barré syndrome, Miller-Fisher syndrome [6], inflammatory bowel disease, colorectal cancer [7], and reactive arthritis [8].
Campylobacter infection poses a global threat to human health. It remains a persistent problem in developed countries. For example, in the United States, Campylobacter infections annually cause an estimated 1.3 million illnesses, around 13,240 hospitalizations, and 119 deaths with a cost of $1.7 billion in medical care [9]. Furthermore, in other high-income countries such as the United Kingdom and members of the European Union, in 2016, the EU member states collectively reported 246,307 infection cases [10], and 52,381 infection cases were reported in England and Wales [11]. In the same year, 243,49 confirmed cases of Campy lobacter infection were reported in Australia. Hence, it is evident that infections caused by Campylobacter species place a substantial burden on the public health system in high-income countries.
Therefore, this study aims to assess epidemiologic characteristics of Campylobacter infection in high-income countries by analysing the national surveillance data and published studies. The objectives of this study are as follow: • To explore the relationship between Campylobacter infection and age. • To explore the relationship between Campylobacter infection and gender. • To explore the relationship between Campylobacter infection and geographical factors. • To explore the relationship between Campylobacter infection and seasonal factors.

Protocol
This systematic review is conducted according to the PRISMA guidelines.

Search Strategy
The PubMed and Google Scholar search engines were used to find the articles with the following keywords and keyword combinations: Campylobacter, Campylobacter species, foodborne illness outbreaks, epidemiologic trends, epidemiologic characteristics, analytical studies, national surveillance. The search span covered the period from 2010 through 2021, because the epidemiology of the pathogens is rapidly changing. The latest and updated data are instrumental for providing valid information about the current situation. A total of 1,628 and 25,100 articles were retrieved from PubMed and Google Scholar, respectively.

Inclusion Criteria
• Studies must be in English.
• Studies must be either analytical or based on national surveillance data. • Studies must focus on outbreaks caused by Campylo bacter infection. • Studies must have multi-component settings and outcomes. • Studies must be performed in high-income countries.
• Clinical data used in the studies must be limited to humans.
Exclusion Criteria • Studies that are not in English.
• Studies that are not analytical or not based on national surveillance data. • Studies that do not focus on high-income countries.

Data Extraction
The data extraction process was performed in four steps using the PRISMA guidelines (Fig. 1).
The four steps were as follows: In the latter, data on author names, publication dates, location, subject numbers, age range, gender, surveillance and intervention period, demographic distribution, geographical distribution, seasonal distribution were extracted.
No meta-analysis was performed, as the stu dies lacked methodological consistency, including target population, measurement variables, and statistical methods.

Quality Assessment
The quality of the studies was assessed against four categories of biases: 1) selection bias; 2) detection bias; The studies were assessed using a 7 point-rating scale. The points were given to the studies according to the requirements of quality assessment. Table 1 shows the complete list of categories and scores.

Characteristics of studies
The fundamental characteristics of the studies are presented in Table 2. Out of 8 selected studies, 1 was conducted in England and Wales [12], 1 in Germany [13], 1 in Australia [14], 1 in Israel [15], 1 in the United States [16], 1 in Denmark [17], 1 in New Zealand [18], and 1 in Ireland [19]. In all the studies, the gender referred to males and females. However, age groups varied from study to study. In England and Wales, the age range was 0-100 years [12], in Germany, the age range was 0-70+ years [13], in Australia, the age range was 0-80 years 14], in Israel, the age range was 0-65+ years [15], in the United States, the age range was 0-60+ years [16], in Denmark, the age range was 0-90 years [17], in New Zealand, the age range was 0-15 years [18], and in Ireland, the age range was 0-65+ years [19].
All the cases analysed in the studies were laboratory confirmed. The researchers from England and Wales [12], USA [16], New Zealand [18], and Ireland [19] used national data sets to collect the data on Cam pylobacter cases for interventions, while researchers from Germany [13], Australia [14], Israel [15], and Denmark [17] collected the data from national centres for disease control. The data ranged widely by their epidemiologic focus. However, collectively, the studies covered the age, gender, geographic location, and season. Some studies also presented data on ethnicity, hospitalizations, travel-related infections, deprivation index, and clinical details.

Epidemiologic characteristics of Campylobacter
The gender, age and geographic distribution of Campylobacter incidence, the relationship between the case rates and seasons, and the epidemiologic demography of cases from different countries are presented in Table 3.
Reported cases by country. Campylobacter classification. Four studies [12,13,15,16] mentioned the type of Campylobacter that had caused outbreaks in the countries, while such data were not available in the other 4 studies [14,[17][18][19]. In England and Wales, Israel, and the United States, the Campylobacter species that caused the outbreaks were identified as C. jejuni and C. coli. In Germany, the outbreaks were caused by C. jejuni, C. coli, C. lari, C. fe tus, and C. upsaliensis. Gender distribution. All the studies show that males have higher incidence rates of Campylobacter infection than females. However, the incidence rates varied widely across countries, time periods, and studies. In England and Wales, during 1989-2009, there were 14% more reported cases of infection in males than in females with an incidence rate ratio of 1.14. In Germany, from 2001 through 2010, the mean incidence was higher in men (96/100,000 population) than in women (83/100,000 population) with an incidence rate ratio of 1.15. In contrast to other age groups, among the 20-29-year-olds, women demonstrated higher incidence (113/100,000 population) compared to men (101/100,000). In Australia, from 1998 through 2013, the incidence was 20% higher among men than among women, with an incidence rate ratio of 1.20. For the 1999-2012 period, no Israeli data on incidence rate ratios were found; however, there were data that men accounted for 56.1% of all infection cases, while women comprised 43.9%.
In the United States, during 2004-2012, men and women accounted for 54.78% and 45.22% of all re-ЖУРНАЛ МИКРОБИОЛОГИИ, ЭПИДЕМИОЛОГИИ И ИММУНОБИОЛОГИИ. 2021;98(5) DOI: https://doi.org/10.36233/0372-9311-167 ОБЗОРЫ ported cases of Campylobacter infection, respectively, with an incidence rate ratio of 1.25. In Denmark, during 2000-2015, the incidence among men was 73.2 cases per 100,000 population, while the incidence among women was 64.5 cases per 100,000 population, with an incidence rate ratio of 1.14. In Ireland, from 2004 through 2012, 53.4% and 46.7% of all Campylobacter cases were recorded in men and in women, respectively, with an incidence rate ratio of 1.15. Only in New Zealand, during 1997-2016, gender differences in the incidence were insignificant, with 51% and 49% of all Campylobacter cases reported in men and women, respectively.
Age distribution. In England and Wales, from 1989 through 2009, higher numbers of Campylo bacter cases were reported among young adults (under 40 years) living in London. However, starting from 2000, the downward trend was observed in the number of Campylobacter cases in the 0-4-year-old age group. Nevertheless, all factors considered, the age-specific incidence rates were highest among senior citizens. In Germany, from 2001 through 2010, the Campylobacter incidence was highest among children from 0 to 4 years old compared to all other age groups (123/100,000 and 69/100,000, respectively). Interestingly, a high incidence was also recorded in the 20-29-year-old age group (107/100,000) compared to all other age groups (69/100,000).
In Australia, from 1998 through 2013, the highest age-specific incidence rates of Campylobacter infection were observed in the 1-4-year-old age group, both in males and females (254.5/100,000 and 204.2/100,000, respectively). Overall, the lowest incidence was reported among females aged 10-19 years. In Israel, from 1999 through 2012, the increase in Campylobacter incidence was observed in all age ranges. Nevertheless, the 0-4-year-old age group was reported as most affected (394.6/100,000) compared to other age groups.
In the United States, from 2004 through 2012, the highest incidence rates of Campylobacter infection were recorded among children aged 0-4 years (26.3/100,000). In the meantime, three states (Alaska, Connecticut, and Maine) reported the highest incidence rates among people aged ≥60 years. Overall, in all the states, the lowest incidence rates of Campylobacter infection were observed among the 10-19-year-old age group. However, the incidence rates increased among all age groups from 2004-2006 through 2010-2012, senior citizens aged ≥60 years being most affected.
Geographical distribution. From 1898 through 2009, in England and Wales, the study used postcodes to identify the geographic distribution of campylobacter cases. Cases of Campylobacter per 100,000 population were higher in areas of low population density (rural) compared to areas of high population density (urban). Note that less postcode reporting in areas of high population density could introduce some bias; however, the subset analysis of areas with over 90% postcode reporting showed higher incidence in rural settings.
From 2001 through 2012, in Germany, the incidence in rural settings was 69/100,000 population and in urban areas -73/100,000 population. Children living in rural regions were more frequently affected by Campylobacter infection than children living in urban areas, which is especially obvious in the age group of <10 years (130/100,000 and 83/100,000). On the contrary, the incidence among 20-69-year-olds living in urban settings was higher than among their peers living in rural settings (77/100,000 and 64/100,000, respectively). In addition, the incidence of Campylobacter infection was higher in the eastern German federal states than in the western German federal states.
In Australia, from 1998 through 2013, the geographical distribution was analysed state-by-state rather than by urban/rural area of residence. Over the observed period, the Campylobacter incidence rates varied from state to state. The highest incidence (177.5/100,000 and 172.2/100,000) was reported in South Australia in 2001 and 2012; the lowest incidence (69.2/100,000 and 66.7/100,000) was reported in Victoria in 1998 and 2011.
In the United States, the Campylobacter incidence was higher in rural areas (14.2/100,000) compared to urban areas (11/100,000). In addition, the study also reported the following geographical areas: the West, the Northwest, the Midwest, and the South. In the West, the Campylobacter incidence rates were highest (16.2/100,000), while in the Northwest, the incidence rates were lower (13.3/100,000) as compared to the rates reported in the West. However, the lowest incidence rates were reported in the South (6.8/100,000) and in the Midwest (13/100,000).
The study from Israel did not provide any data on geographical distribution. In Denmark, during 2000-2015, the country was divided into four zones designated as urban, intermediate, distant, and rural. Overall, the highest Campylobacter incidence was recorded in intermediate areas (106.4/100,000) and urban settings (61.2/100,000). Furthermore, the Campy lobacter incidence in the 0-4-year-old age group was higher in distant areas (142/100,000) and in rural areas (225.6/100,000). On the contrary, the Campylobacter incidence in the age group 50+ years was higher in intermediate areas (106.4/100,000) and urban areas (149.5/100,000).
From 1997 through 2016, in New Zealand, the study mentioned the relationship between the Campy lobacter incidence and geographical locations, though it did not provide any explanatory information about the distribution. Yet, the study mentioned that the highest incidence was recorded in South Canterbury with an incidence rate ratio of 1.77. In Ireland, during 2004-2016, no data on incidence in rural or urban areas were available; however, the highest Campylobacter incidence (58.7/100,000 population) was reported in the Midlands (a rural area).
Seasonal Distribution. In England and Wales, from 1989 through 2009, the Campylobacter incidence tended to peak in summer. The increased rate of infection between week 18 (early May) and week 22 (early June) is consistently reported every year. In Germany, from 2001 through 2010, the Campylobacter incidence increased from May to July and peaked in August. However, a small peak in the monthly incidence was also recorded in January.
During 1998-2013, in Australia, the Campylo bacter incidence demonstrated similar rates in winter and autumn, while the highest incidence was recorded in spring and summer, with incidence rate ratios of 1.18, and 1.17, respectively. In Israel, from 1999 through 2012, the incidence was reported to peak from April through August.
In the United States, from 2004 through 2012, the highest Campylobacter incidence rates were reported during June-August and the lowest rates were observed during December-January. Interestingly, a small peak in the incidence was observed in January in the age group <30 years. In Denmark, the highest Campylo bacter incidence rates were recorded during May-October, with a peak in August during 2000-2015.
In New Zealand, from 1997 through 2016, the highest Campylobacter incidence rates were recorded during summer months from December through February. In Ireland, a sharp increase in the Campylobacter incidence was observed in summer, during April-May, reaching a peak in August. The univariate analysis showed the incidence rate ratio of 1.57 in spring and incidence rate ratios of 1.45 and 1.09 in summer and autumn, respectively.

Discussion
The systematic review presents the analysis of 8 studies. It has been found that epidemiologic characteristics of Campylobacter infections vary from country to country and depend on various factors such as age, gender, season/weather, and geographical areas.
It has been found that Campylobacter incidence was higher among men compared to women in all eight studies, except for the German 20-29-year-old age group where the incidence was higher among women than men. Although higher Campylobacter incidence rates among men still lack explanation, it can be assumed that there are factors that may contribute to increased susceptibility to Campylobacter infections among men compared to women. Among them, there are such factors as culture, sex hormones, behaviour, genetics, and gut microbiome [20][21][22]. Regarding possible cultural factors, in all the eight countries in this study, there is no evidence that the gender of a child has any influence on seeking for medical care for acute infections. Similarly, there is no evidence that adult men in these eight countries are more likely than women to seek medical care for acute infections, though there is some evidence that men tend to use health services less than women do [23]. One of the behaviour-related factors mentioned is that men are more likely to get Campylobacter infection as they tend to spend more time outdoors as compared to women [19]. However, sex hormones, genetics, and gut microbiome may also play a role in gender distribution of incidence, urging for further research.
In all 8 studies, the 0-4-year-old age group was most affected by the Campylobacter infection. High Campylobacter incidence rates reported among the 0-4-year-olds are not surprising and can be caused by multiple factors, including poor hygiene practices, higher chances of being clinically tested, having close contacts with pets or animals, and not having a strong immune system. However, these high incidence rates of Campylobacter infection among young children are in line with the epidemiology of other gastrointestinal infections showing a comparable age-specific pattern [13,17]. In addition, in Denmark, 20-24 and 25-29-yearold age groups were also among the age groups most affected by Campylobacter infections. It may be associated with the fact that young adults leave home to pursue education or to work, and they may not follow basic food hygiene practices when learning how to cook for themselves [24].
Furthermore, in case of urban vs rural areas, higher incidence rates of Campylobacter infection were observed in rural areas. What causes such urban/rural difference in Campylobacter incidence rates remains unclear. The contributing factors may include proximity to ruminants and other farm animals or differences in access to healthcare [12]. On the contrary, in Demark, higher numbers of Campylobacter cases were recorded in urban areas than in rural settings, and the reasons are still unclear.
Seasonal outbreaks of Campylobacter infection were mostly reported in spring and summer in all the countries. Campylobacter infection outbreaks in spring and summer can be explained by existence of favourable conditions for pathogens, which tend to thrive due to environmental and climate factors; Campylobacter ЖУРНАЛ МИКРОБИОЛОГИИ, ЭПИДЕМИОЛОГИИ И ИММУНОБИОЛОГИИ. 2021;98(5) DOI: https://doi.org/10.36233/0372-9311-167 ОБЗОРЫ pathogens become more prevalent in poultry during warm seasons, causing an increase in Campylobacter incidence that reaches its peak in summer [25]. Other reasons that may be responsible for seasonal outbreaks include people's eating habits and hygiene practices. In addition, a small peak of Campylobacter incidence was reported in winter both in the United States and Germany. However, further research is needed to explain the relationship between this peak and the winter season.
Additionally, only three studies [12,13,17] discussed the relationship between travel and Campylo bacter incidence, suggesting that surveillance systems need to concentrate on imported infection cases and their contribution to the local incidence. Imported cases should be given more focused attention, considering increasing antibiotic resistance of Campylobacter pathogens [26].

Conclusion
Undoubtedly, outbreaks of Campylobacter infection remain a serious public health concern in high-income countries. Different Campylobacter species affect age groups, genders, and locations (urban/rural) in different seasons of the year. Although there is treatment available for Campylobacter infection, the growing antibiotic and antimicrobial resistance of Campylobacter poses a serious threat. Based on the literature synthesis, it can be concluded that while Campylobacter infections are found in every age, gender, locality, their case rates are highest among very young or very old age groups, mostly men, living in rural areas, with incidence peaks in summer. While further research is required to understand the above patterns of Campylobacter incidence, there is also a need for promoting health education in prevention of such outbreaks in general population.

Strengths of the Study
The study thoroughly assessed the literature describing Campylobacter infection cases in different high-income countries during different periods. Epidemiologic characteristics of Campylobacter infection in humans are presented in relation to age, gender, area of residence, and season.

Limitations of the Study
The study was unable to synthesise the data on Campylobacter infection cases in terms of ethnicity, travel, mortality and morbidity, as only very few studies addressed such categories. Therefore, these aspects remained uncovered.