Etiology

The family Campylobacteriaceae includes >20 species. Those known or considered pathogenic for humans include C. jejuni, C. fetus, C. coli, C. hyointestinalis, C. lari, C. upsaliensis, C. concisus, C. sputorum, C. rectus, C. mucosalis, C. jejuni subspecies doylei, C. curvus, C. gracilis, and C. cryaerophila. Additional Campylobacter species have been isolated from clinical specimens, but their roles as pathogens have not been established. C. jejuni and C. coli are the most important pathogens of the genus. More than 100 serotypes of C. jejuni have been identified.

Campylobacter organisms are thin (0.2-0.4 µm wide), curved, gram-negative, non–spore-forming rods (1.5-3.5 µm long) that usually have tapered ends. They are smaller than most other enteric bacterial pathogens and have variable morphology, including short comma- or S-shaped organisms and long, multispiraled, filamentous, seagull-shaped organisms. Individual organisms are usually motile with a flagellum at 1 or both poles. Growth on solid media results in small (0.5-1 mm), slightly raised, smooth colonies. Visible growth in blood cultures is often not apparent until 5-14 days after inoculation. Most Campylobacter organisms are microaerophilic and do not oxidize or ferment carbohydrates. Selective culture media developed to enhance isolation of C. jejuni may inhibit the growth of other Campylobacter species. C. jejuni has a circular chromosome of 1.64 million base pairs (30.6% G+C) that is predicted to encode 1,654 proteins and 54 stable RNA species. The genome is unusual in that there are virtually no insertion sequences or phage-associated sequences and very few repeat sequences.

Clinical presentations differ, in part, by species (Table 194-1). Intestinal disease is usually associated with C. jejuni and C. coli, and extraintestinal and systemic infections are most often associated with C. fetus. C. jejuni septicemia is increasingly recognized and can occur without gastrointestinal signs or symptoms. Less commonly, enteritis is recognized in association with isolation of C. lari, C. fetus, and other Campylobacter species.

Table 194-1 CAMPYLOBACTER SPECIES ASSOCIATED WITH HUMAN DISEASE

Epidemiology

Human campylobacterioses most commonly result from ingestion of contaminated poultry (chicken, turkey) or raw milk and less commonly from drinking water, pets (cats, dogs, hamsters), and farm animals. Infections are more common in resource-limited settings, are prevalent year-round in tropical areas, and can exhibit seasonal peaks in temperate regions (late summer and early fall in most of the USA). In industrialized countries, Campylobacter infections peak in early childhood and in persons 15-44 yr of age. Each year in the USA there are an estimated 2.4 million cases of Campylobacter infections, resulting in >100 deaths. Medical record keeping in the Netherlands has allowed analyses showing that each resident acquires asymptomatic Campylobacter infection every 2 years and that asymptomatic infection progresses to symptomatic infection in approximately 1% of colonized persons.

Although chickens are a classic source of Campylobacter, many animal sources of human food can harbor Campylobacter, including seafood. Additionally, many animals kept as pets carry Campylobacter, and insects inhabiting contaminated environments can acquire the organism. Direct or indirect exposure to this plethora of environmental sources is the origin of most human infections. Airborne transmission of Campylobacter can occur in farm workers. There is increasing evidence that the use of antimicrobials in animal foods increases the prevalence of antibiotic-resistant Campylobacter isolated from humans.

Human infection can result from exposure to as few as a few hundred colony-forming units. At times, C. jejuni and C. coli spread person to person, perinatally, and at child care centers where diapered toddlers are present. Persons infected with C. jejuni usually shed the organism for weeks but can shed for months.

Pathogenesis

The conceptual model for the pathogenesis of C. jejuni enteritis includes mechanisms to transit the stomach, adhere to intestinal mucosal cells, and initiate intestinal lumen fluid accumulation. Most Campylobacter isolates are acid sensitive. Host conditions associated with reduced gastric acidity and foods capable of shielding organisms in transit through the stomach are postulated to be factors that allow Campylobacter to reach the intestine. Subsequently, bacterial motility, surface proteins, and surface glycans facilitate adhesion to intestinal mucosal cells. Lumen fluid accumulation is associated with direct damage to mucosal cells resulting from bacterial invasion and potentially from a cholera-like toxin and other cytotoxins. Additionally, C. jejuni can have mechanisms that enable transit away from the mucosal surface. This armamentarium appears to be differentially deployed by various C. jejuni organisms.

Campylobacter differ from other enteric bacterial pathogens in that they have both N- and O-linked glycosylation capacities. N-linked glycosylation is associated with molecules expressed on the bacterial surface, and O-linked glycosylation appears limited to flagella. Slipped-strand mispairing in glycosylation loci results in modified, antigenically distinct surface structures. It is hypothesized that antigenic variation provides a mechanism for immune evasion.

C. fetus possesses a high molecular weight S layer protein that mediates high-level resistance to serum-mediated killing and phagocytosis and is thus thought to be responsible for the propensity to produce bacteremia. C. jejuni and C. coli are generally sensitive to serum-mediated killing, but serum-resistant variants exist. It has been suggested that these serum-resistant variants may be more capable of systemic dissemination.

There is a strong association between Guillain-Barré syndrome and preceding infection with some serotypes of C. jejuni (Chapter 608). Molecular mimicry between nerve tissue and Campylobacter surface antigens may be the triggering factor in Campylobacter-associated Guillain-Barré syndrome, including the Miller-Fisher variant, which is characterized by ataxia, areflexia, and ophthalmoplegia. Reactive arthritis and erythema nodosum can also occur. Most Campylobacter infections are not followed by immunoreactive complications, indicating that factors in addition to molecular mimicry are required for these complications.

There is increasing evidence of an association between Campylobacter infection and irritable bowel syndrome. It is proposed that low-grade inflammation caused by Campylobacter, below the threshold that can be detected by endoscopy, results in crosstalk with gut nerves, leading to symptoms.

Clinical Manifestations

The varied clinical presentations of Campylobacter infections link to the species involved and to host factors such as age, immunocompetence, and underlying conditions. The most common presentation is acute enteritis.

Diagnosis

The clinical presentation of Campylobacter enteritis can be similar to that of enteritis caused by other bacterial enteropathogens. The differential diagnosis includes Shigella, Salmonella, invasive Escherichia coli, E. coli O157:H7, Yersinia enterocolitica, Aeromonas, Vibrio parahaemolyticus, and amebiasis. Fecal leukocytes are found in as many as 75% of cases, and fecal blood is present in 50% of cases. The presence of bloody stools, fever, and abdominal pain should result in an evaluation for Campylobacter.

The diagnosis of Campylobacter enteritis is usually confirmed by identification of the organism in cultures of stool or rectal swabs. Selective media such as Skirrow or Butzler media and microaerophilic conditions (5-10% oxygen) are commonly used. Some C. jejuni grow best at 42°C. Filtration methods are available and can preferentially enrich for Campylobacter by selecting for their small size. These methods allow subsequent culture of the enriched sample on antibiotic free media, enhancing rates of isolation of Campylobacter organisms inhibited by the antibiotics included in standard selective media. Isolation of Campylobacter from normally sterile sites does not require enhancement procedures.

For rapid diagnosis of Campylobacter enteritis, direct carbol fuchsin stain of fecal smear, indirect fluorescence antibody test, dark-field microscopy, or latex agglutination can be used. Antigen detection by enzyme immunoassay is nearly as sensitive and specific as culture. Species-specific DNA probes and specific gene amplification by polymerase chain reaction (PCR) have been described. Serologic diagnosis is also possible.

Complications

Severe, prolonged C. jejuni infection can occur in patients with immunodeficiencies, including hypogammaglobulinemia and malnutrition. In patients with AIDS, an increased frequency and severity of C. jejuni infection have been reported; severity correlates inversely with CD4 count.

Treatment

Fluid replacement, correction of electrolyte imbalance, and supportive care are the mainstays of treatment of children with Campylobacter gastroenteritis (Chapter 332). Antimotility agents can cause prolonged or fatal disease and should not be used.

The need for antibiotic therapy in patients with uncomplicated gastroenteritis is controversial. Data suggest a shortened duration of symptoms and intestinal shedding of organisms if erythromycin ethylsuccinate or azithromycin is initiated early in the disease in patients with the dysenteric form of Campylobacter enteritis.

Most Campylobacter isolates are susceptible to macrolides, aminoglycosides, chloramphenicol, imipenem, and clindamycin and are resistant to cephalosporins, tetracyclines, rifampin, penicillins, trimethoprim, and vancomycin. Antibiotic resistance among C. jejuni has become a serious worldwide problem. Quinolone resistance has developed and is related to the use of quinolones in veterinary medicine. Erythromycin-resistant Campylobacter isolates remain uncommon, and erythromycin or azithromycin is the drug of choice if therapy is required. Antibiotics are recommended for patients with the dysenteric form of the disease, high fever, or a severe course and for children who are immunosuppressed or have underlying diseases. Sepsis is treated with parenteral antibiotics such as an aminoglycoside, meropenem, or imipenem.

For extraintestinal infection caused by C. fetus, prolonged therapy is advised. C. fetus isolates resistant to erythromycin have been reported.

Prognosis

Although Campylobacter gastroenteritis is usually self-limited, immunosuppressed children (including children with AIDS) can experience a protracted or severe course. Septicemia in newborns and immunocompromised hosts has a poor prognosis, with an estimated mortality rate of 30-40%.

Prevention

Most human campylobacterioses are sporadic and are acquired from infected animals or contaminated foods. Interventions to minimize transmission include preparing food under conditions that kill Campylobacter and that prevent recontamination after cooking (not using the same surfaces, utensils, or containers for both uncooked and cooked food), ensuring that water sources are not contaminated and that water is kept in clean containers, and taking steps to prevent direct transmission from infected persons or infected domestic pets. Breast-feeding appears to decrease symptomatic Campylobacter disease but does not reduce colonization.

Several approaches at immunization are being studied, including the use of live-attenuated organisms, subunit vaccines, and killed whole-cell vaccines.