Version May 2024
INTRODUCTION — Campylobacters are small gram-negative bacteria first recognized as causes of abortion in cattle and sheep in the early twentieth century [1]. A few decades later, the organism (originally called Vibrio) was reported as an occasional cause of illness in humans [2]. In 1973, a new genus, Campylobacter, was designated [3]. It was not until the 1980s that the full impact of Campylobacter infections on human health began to be appreciated; they are now known to be a leading cause of acute diarrhea and systemic illness worldwide. (See "Causes of acute infectious diarrhea and other foodborne illnesses in resource-abundant settings".)
Campylobacter spp are common commensals in the gastrointestinal tract of animals, especially poultry; thus, animal-to-human transmission of infections occurs frequently. The microbiology, pathogenesis, and epidemiology of Campylobacter infection will be reviewed here. The clinical features and treatment of Campylobacter infection are discussed separately. (See "Campylobacter infection: Clinical manifestations, diagnosis, and treatment".)
MICROBIOLOGY — Campylobacters belong to a distinct group of specialized gram-negative bacteria designated rRNA superfamily VI [4]. Apart from the genus Campylobacter, the group also contains Arcobacter and Helicobacter. Arcobacters are closely related to campylobacters, and some cause intestinal infection in humans. Helicobacter pylori is well known as a cause of gastritis and peptic ulcer disease, but there are other Helicobacter species that cause infection of the human gut. (See "Campylobacter: Infection with less common species and related bacteria" and "Pathophysiology of and immune response to Helicobacter pylori infection".)
A feature common to all these bacteria is that they are adapted to colonize the surface of the mucous membranes of the alimentary and reproductive tracts. This adaptation is reflected in their morphology. The combination of spiral shape and long polar flagella leads to rapid motility that enables the organisms to "corkscrew" their way through mucus with a facility denied to conventional bacteria (picture 1).
Most members of this group are microaerophilic, or partially anaerobic, and most undergo transformation into coccoid forms when exposed to adverse conditions, especially oxidation [5]. These appear to be degenerative forms, but some believe they are potentially dormant forms capable of long survival [6]. Although some campylobacters can survive in cold water for several weeks, even months, they are not necessarily in coccal form. In general, these bacteria are fragile and easily destroyed by heat, desiccation, acidity, irradiation, and disinfectants.
Campylobacter species — Many Campylobacter spp ("atypical" campylobacters) have now been recognized to cause human disease, as these organisms have been isolated from stool samples using filtration and antibiotic-free culture medium [7]. Eighteen species of Campylobacter are currently recognized, and new species are being discovered with regularity. Most have been isolated at some time from humans. However, the most important species to cause human disease are Campylobacter jejuni and Campylobacter coli, the principal causes of Campylobacter enteritis. The remainder of this topic review will be devoted to infection with these two species.
C. jejuni has two subspecies: C. jejuni subsp. jejuni and C. jejuni subsp. doylei. The latter is a less common and a more fastidious organism than the former. For the sake of brevity, we will refer to C. jejuni subsp. jejuni simply as C. jejuni.
Detection in the laboratory — The standard method for detecting campylobacters in clinical specimens is by culture. However, it is possible to make a presumptive identification by the microscopic examination of fresh stools of patients who are in the acute phase of diarrheal illness (eg, using dark-field, phase-contrast, or stained smears). This is less sensitive than culture (50 compared to 94 percent) and is not practiced routinely [8]. Gram's stain is even less sensitive. C. jejuni appears as faint, gram-negative curved rods (picture 2). Direct microscopy of stool specimens may also reveal the presence of red blood cells or neutrophils, which are present in 75 percent of patients with Campylobacter enteritis [9].
The culture of Campylobacter spp is optimally performed using selective media and incubation in a gas mixture of 5 to 10 percent oxygen, 1 to 10 percent carbon dioxide, and ideally some hydrogen (picture 3). The optimum incubation temperature for C. jejuni and C. coli is 42 to 43ºC; as a result, the term "thermophilic" campylobacters is sometimes applied to these species. In laboratories with limited facilities, successful results can be obtained by incubation in a candle extinction jar, provided that the plates are incubated at this higher temperature.
Growth is usually visible after overnight incubation, but two days are needed before a negative report can be issued. The policy in many laboratories is to incubate for the full two days before opening the sealed containers.
Direct plating on solid media is adequate for the culture of diarrheal stools, because campylobacters are present in large numbers. However, enrichment culture in a selective broth is recommended when the stool is not fresh or for formed stools from suspected carriers. Enrichment culture is essential for food and environmental samples, which may also require special pretreatment to correct for "cold shock" or other bacterial injury; this requires a laboratory with special expertise.
The identification of Campylobacter colonies is simple. The bacteria have a characteristic appearance under the microscope, which, together with analysis for oxidase and catalase production, is all that is needed for diagnosis. From a clinical standpoint, it is not necessary to speciate the bacteria into C. jejuni or C. coli, since the diseases they cause are indistinguishable; in most regions, 90 to 95 percent of infections are due to C. jejuni [10]. However, there are occasions when speciation and strain typing are required for epidemiologic purposes.
Strain typing is a task best performed at specialized reference laboratories. Serologic typing is the most widely used method. Two systems are in general use: the Penner scheme based upon heat-stable lipopolysaccharide 'O' antigens (over 90 serogroups); and the Lior scheme based upon heat-labile surface protein antigens (112 serogroups) [11]. The use of a limited set of antisera from each scheme gives good discrimination, which can be enhanced by the addition of biotyping and/or phage typing.
Other methods for the direct detection of Campylobacter in clinical specimens, such as DNA probes and amplification by polymerase chain reaction (PCR), have been successful in research studies, and may be more sensitive than traditional cultures for the detection of and typing of these organisms [12-14]. The whole genome sequences for numerous Campylobacter species have been determined and this technology can be used to detect outbreaks and improve routine surveillance [15,16]. Use of culture-independent techniques such as nucleic acid amplification tests (NAAT) are rapidly expanding but have significant drawbacks. (see "Campylobacter infection: Clinical manifestations, diagnosis, and treatment", section on 'Microbiologic diagnosis of acute disease')
Other culture-independent diagnostic tools, such as stool antigen tests, are convenient and have become increasingly popular; however, their sensitivity, specificity, and positive predictive value for Campylobacter is quite variable [17]. Stool cultures remain the gold standard.
PATHOGENESIS — The bacterial and host factors responsible for the pathogenesis of and susceptibility to Campylobacter infection are just beginning to be identified.
Bacterial factors — Several factors contribute to the ability of Campylobacter to produce illness including:
●Number of organisms ingested
●Virulence of the infecting strain
●Host immunity
Volunteer studies established that the infective dose could be as low as 500 bacteria, although, a higher dose (9000 bacteria) was needed to produce illness in 50 percent of the subjects [18,19]. Campylobacters are sensitive to stomach acidity; as a result, underlying conditions or medications that reduce or buffer gastric acidity predispose to infection. Patients who use proton pump inhibitors are more susceptible to infection [20,21]. The dilution and washing action of water and the buffering action of milk might well explain the inordinate size of some water-borne and milk-borne outbreaks of Campylobacter enteritis (see below).
The mechanisms by which campylobacters are able to attach and invade the intestinal epithelium are complex and are facilitated by the presence of flagella, high molecular weight plasmids, superficial adhesins, and chemotactic factors [19,22-29]. Campylobacter possess fimbriae-like filaments that enable the organism to attach to intestinal epithelial cells [30]. The bacteria's flagellae promote the motility and chemotaxis needed for C. jejuni to colonize the intestinal tract [23,24]. The flagellar export apparatus is involved in the secretion of a number of proteins that affect invasion [31]. Interestingly, unlike Salmonella and other enteric bacterial pathogens, the flagellins of Campylobacter do not elicit production of pro-inflammatory cytokines such as IL-8, suggesting that flagellins may be important in the organism’s ability to evade innate immune responses [32]. Intact flagellar synthesis genes are required for maximal C. jejuni invasiveness [33,34]. A high-molecular-weight plasmid also enhances the invasive capabilities of C. jejuni virulence [25,35]. The plasmid, pVir, has been identified in some clinical Campylobacter isolates and was significantly associated with bloody stools [36]. C. jejuni may adhere to epithelial cells [37], which favors gut colonization. Following attachment, several other bacterial surface proteins (eg, PEB1, CadF) help the organisms to colonize and then invade the intestinal epithelial cells [30]. Other important adhesins include JIpA, a surface exposed lipoprotein [38], and CadF, which mediates adhesion by binding to fibronectin [39].
Low-level production of enterotoxin has been observed in vitro, but production cannot be demonstrated in vivo and the enterotoxin does not appear to play a role in the pathogenesis of Campylobacter [29,40]. All C. jejuni isolates possess a gene coding for cytolethal distending toxin that may affect cell cycle kinetics [41,42]; however, not all isolates produce this toxin and its role in disease is not known. Some have postulated that this toxin may play a role in suppressing innate immunity by inducing death of macrophages [43,44].
Course of disease — After an incubation period of about three days (range one to seven days), infection is established in the jejunum, ileum, and often the colon and rectum. A higher inoculum of bacteria is typically associated with a shorter incubation period and more severe illness. The histologic picture is that of acute mucosal inflammation with edema, cellular infiltration of the lamina propria, and crypt abscess formation. These findings are indistinguishable from those seen in salmonellosis and shigellosis. (See "Campylobacter infection: Clinical manifestations, diagnosis, and treatment".)
Host immune response — Humoral immune mechanisms likely play an important role in protection against infection with Campylobacter. Serum antibodies (eg, IgA, IgG, and IgM) peak two to four weeks postinfection and then decline [45]. Further support for the importance of a humoral immune mechanism in containing campylobacter infection is the observation that patients with hypogammaglobulinemia experience particularly severe and prolonged Campylobacter infections [46]. The role of cellular immune mechanisms in containing Campylobacter infections is unclear. However, the observation that HIV-infected persons have more severe and persistent disease, and develop extraintestinal Campylobacter infections, suggest that cell-mediated immunity may confer some protection against these infections [47,48]. The variety and distribution of the organism's capsular polysaccharides suggest the presence of homologous protective immunity between strains [49].
EPIDEMIOLOGY — Campylobacter enteritis is a leading cause of acute diarrhea worldwide.
Incidence — Campylobacters are found worldwide, including arctic, temperate, and tropical climates.
In the United States, the incidence of Campylobacter is assessed through the Foodborne Diseases Active Surveillance Network (FoodNet), which has collected data on nine major foodborne pathogens from selected sites since 1996. Throughout the course of the surveillance program, the incidence of Campylobacter has waxed and waned, but it has remained one of the two most frequently reported pathogens. In 2022, the incidence of Campylobacter infections was 19.2 infections per 100,000 persons, the highest incidence of all pathogens studied and an increase from 18.9 infections per 100,000 between 2016 to 2018 [50]. The reasons for these increases are uncertain; increasing reliance on culture-independent diagnostic tests could be playing a role.
Within the United States, there is considerable variation in the incidence of Campylobacter infections between states, with infections being more common in western states; for example, the infection rate in California is triple that in Tennessee [51,52].
In Europe and Israel, the incidence of Campylobacter infections has increased over the last decade [53,54].
Burden of disease — Mortality due to Campylobacter infection is low, even in patients who develop bacteremia [55]. In the United States, estimates are that 50 to 150 deaths annually are at least in part attributable to Campylobacter infection [10]. The total cost of health care and lost productivity for Campylobacter enteritis in the United States is estimated at $1.5 to $8.0 billion annually [56].
Demography — The age distribution of Campylobacter enteritis in industrialized countries is different from that of other enteric infections. Like most other infections, there is a high incidence in early childhood but, unlike others, there is a pronounced secondary peak in young adults (figure 1) with a mild male predominance [10,52,57]. The reasons for this peak are unknown. Adults tend to be more severely affected than children, while infants usually tolerate the infection well. Older adults are more likely to have severe illness and be hospitalized. However, older adults are also less likely to report typical symptoms (eg, bloody diarrhea, abdominal pain) associated with Campylobacter infection [58].
A different pattern is seen in resource-limited settings where infection is hyperendemic. High transmission rates mean that children become repeatedly infected early in life. Initial infections are often associated with diarrhea, but as immunity is gained, subsequent infections are increasingly likely to be asymptomatic [59,60]. Thus, the disease is virtually unknown in older children and adults. In one series of children from Bangladesh and Thailand, IgG antibodies to surface protein antigens of C. jejuni rose early in childhood and then gradually fell; in comparison, IgA antibodies increased progressively through childhood [59].
In temperate zones, Campylobacter enteritis has a remarkably constant seasonal pattern characterized by a sharp rise of incidence in early summer, a peak in midsummer, and then a steady decline to base levels in winter (figure 2). A slight secondary peak is sometimes evident in late fall. The reasons for this seasonal pattern are unknown. The seasonal variations in the incidence of Campylobacter infection are not observed in tropical climates.
Sources and transmission — C. jejuni and C. coli are carried by a wide variety of wild and domestic animals, notably birds [61,62]; C. coli is particularly associated with pigs. The bacteria are shed widely and can be found in almost any natural water, fresh or saline, in which they can survive for many weeks at temperatures below 15ºC. Water can be a direct source of human infection, though food contamination from food-producing animals is a more significant problem [63].
Any raw meat can be contaminated with campylobacters. It is almost impossible to prevent contamination of carcasses from gut contents at slaughter. With large animals (eg, cattle, sheep, pigs), the use of air-blast chilling causes surface drying and substantially reduces the number of organisms. Thus, red meats, except offal, are seldom heavily contaminated [64,65].
Contamination of poultry occurs more frequently. Broiler chicken flocks can become heavily colonized, and the bacteria are spread liberally when the carcasses undergo mass processing [66]. As a result, approximately 60 percent of retail broiler carcasses and their juices are contaminated with campylobacters, often with counts as high as 106 to 107 per chicken [67]. According to one study approximately 48 percent of Campylobacter infections are attributable to transmission via poultry [68-72]. Chickens are also a major source of quinolone-resistant Campylobacter infections, an effect that is related to quinolone use in poultry feeds in both the United States and Europe [73]. (See "Campylobacter infection: Clinical manifestations, diagnosis, and treatment", section on 'Antimicrobial therapy'.)
In general, infection is acquired from meat in one of two ways: consumption of raw or undercooked meat, or eating food that has become cross contaminated from raw meat [74]. A typical example of cross contamination would be the cutting up of bread or salad on an unwashed board that had just been used to handle raw chicken.
In a substantial proportion of Campylobacter cases the source of infection is unknown [68,75]. One survey of 218 human cases identified the following sources [75]:
●Chicken consumption – 48 percent
●Travel to underdeveloped countries – 9 percent
●Drinking non-home well or surface water – 8 percent
●Exposure to an animal with diarrhea – 6 percent
●Drinking raw milk – 5 percent
●Unknown – 24 percent
In resource-rich countries, most cases of Campylobacter enteritis are sporadic or part of small family outbreaks. Community outbreaks are uncommon, probably because campylobacters are unable to multiply in food like Salmonellae. Important exceptions are outbreaks caused by the distribution of contaminated water or milk, which have infected as many as 3000 people at a time [76-80].
Updated information on outbreaks may be found on websites maintained by the United States Centers for Disease Control and Prevention and the US Food and Drug Administration.
The following observations have been noted in outbreaks:
●In waterborne outbreaks, the water has been unchlorinated or there has been a fault in the chlorination or distribution system [76-78,81].
●In milk-borne outbreaks, the consumed milk has been raw or there has been a failure in the pasteurization process [79,80,82-85]. As an example, in England, increased sales of unpasteurized milk in vending machines have been associated new outbreaks of Campylobacter infection [86]. It is almost impossible to prevent milk becoming fecally contaminated even in the best run milking parlors. As a result, compulsory pasteurization of all milk sold to the public is the only remedy.
●Occasionally, the source of an outbreak is unknown. As an example, the first reported Campylobacter outbreak in China in more than 20 years occurred in 2018 among a group of Beijing high school students on a school trip [87]. The source was never identified, although a common poultry source was suspected.
Infection can also be acquired directly from animals or their carcasses. Direct transmission of this sort is usually occupational (eg, farmers, slaughterhouse workers, poultry processors), but domestic infection can also arise from contact with a pet, usually a puppy or kitten with Campylobacter diarrhea [75,88,89]. In 2017, a large multistate United States outbreak of multidrug-resistant C. jejuni infections occurred in puppies and was transmitted to more than 100 people [90].
Person-to-person infectivity is generally low, although caretakers for children in diapers or incontinent individuals are at risk for transmission. Sexual transmission, presumably through fecal-oral contact, has also been reported. As an example, in one study of a prolonged outbreak of a particular drug-resistant C. jejuni isolate, the vast majority of the 31 affected individuals were men who have sex with men, among whom there were high rates of sexually transmitted infections, including HIV infection [91].
Prevention — Because most Campylobacter infections are transmitted by preparing and consuming chicken, control of Campylobacter infections in broiler flocks is an important first step in reducing the incidence of this infection in humans. Methods used in mass processing and distribution of chicken may amplify the bacterial load. Strategies that have been suggested to reduce such amplification include improvement in chicken house hygiene and water supplies, flock vaccination, and competitive exclusion regimens feeding normal flora to chicks. Efforts to reduce cross-contamination during mass mechanized processing of broiler carcasses may also prove to be helpful in reducing poultry contamination with Campylobacter.
Food handling — Even with the employment of the best agricultural practices, it is unlikely that elimination of Campylobacter contamination of poultry will be achieved. The near universal contamination of poultry and the heavy bacterial burden makes such elimination impractical, if not impossible. Therefore, careful food handling practices in the kitchen should be directed towards reducing the risk of transmission to humans. Because C. jejuni is killed by heat, all meat, especially chicken, should be cooked to proper temperature (breasts to 170ºF, thighs to 180ºF). In addition to thorough cooking, care should be taken to avoid cross-contamination: cutting boards, knives, and other utensils used to prepare chicken should be thoroughly washed with hot, soapy water before being used to prepare salads or other foods eaten raw. Irradiation of food will kill Campylobacter as well as other pathogens, but is not yet acceptable to the public.
Animal transmission — The direct transmission from animals may also be prevented by simple hygienic measures of which hand washing is by far the most important; this is particularly relevant to school children and students on farm visits and to families with pets (see above).
Person-to-person transmission — Although person-to-person transmission of Campylobacter infection is unusual, all persons (and especially those who have diarrhea), should wash their hands after using the bathroom. Persons with diarrhea should avoid preparing and handling food until their illness resolves. To date, there have been no reports of transmission of Campylobacter infection by asymptomatic excretors. Asymptomatically infected food handlers or hospital workers need not be excluded from work. However, the importance of hand washing should be emphasized.
Water- and milk-borne transmission — The provision of purified water and the pasteurization (or other heat treatment) of all milk sold to the public are highly effective basic measures that prevent transmission of intestinal pathogens. Pregnant women, older adults, and persons who are immunocompromised should take particular care to avoid unpasteurized dairy products. Travelers to resource-limited settings and campers should be cautioned against drinking untreated water. Antibiotics are not routinely recommended for prophylaxis against diarrhea in travelers.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Campylobacter infection (The Basics)")
SUMMARY
●Campylobacter enteritis is a leading cause of acute diarrhea worldwide. Many Campylobacter spp ("atypical" campylobacters) are recognized to cause human disease; however, the most important species are Campylobacter jejuni and Campylobacter coli. (See 'Introduction' above and 'Campylobacter species' above.)
●Volunteer studies have established that the infective dose of Campylobacter can be as low as 500 bacteria. (See 'Bacterial factors' above.)
●In temperate zones, Campylobacter enteritis has a constant seasonal pattern characterized by a sharp rise of incidence in early summer, a peak in midsummer, and then a steady decline to base levels in winter. The seasonal variations are not observed in tropical climates. (See 'Demography' above.)
●C. jejuni and C. coli are carried by a wide variety of wild and domestic animals, notably birds. The bacteria are shed widely and can be found in almost any natural water, in which they can survive for many weeks at temperatures below 15ºC. Although water can be a direct source of human infection, it is the contamination by campylobacters of the food chain from food-producing animals that is the greater problem. (See 'Sources and transmission' above.)
●Any raw meat is likely to be contaminated with campylobacters as it is almost impossible to prevent contamination of carcasses from gut contents at slaughter. Approximately 60 percent of retail broiler carcasses and their juices are contaminated with campylobacters. (See 'Sources and transmission' above.)
●There are two ways infection is acquired from meats: eating raw or undercooked meat and eating uncooked or previously cooked food that has become cross contaminated from raw meat. (See 'Sources and transmission' above.)
●In industrialized countries, most cases of Campylobacter enteritis are sporadic or part of small family outbreaks. An important exception is community outbreaks caused by the distribution of contaminated water or milk. (See 'Sources and transmission' above.)
●Because most Campylobacter infections are transmitted by preparing and consuming chicken, control of Campylobacter infections in broiler flocks and care to prevent cross contamination during food handling are the most effective means to prevent transmission. (See 'Prevention' above and 'Food handling' above.)
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