CHAPTER 64: INFECTIONS DUE TO CAMPYLOBACTER AND RELATED ORGANISMS

Bacteria of the genus Campylobacter and of the related genera Arcobacter and Helicobacter (Chap. 60) cause a variety of inflammatory conditions. Although acute diarrheal illnesses are most common, these organisms may cause infections in virtually all parts of the body, especially in compromised hosts, and these infections may have late nonsuppurative sequelae. The designation Campylobacter comes from the Greek for “curved rod” and refers to the organism’s vibrio-like morphology.

Campylobacters are motile, non-spore-forming, curved, gram-negative rods. Originally known as Vibrio fetus, these bacilli were reclassified as a new genus in 1973 after their dissimilarity to other vibrios was recognized. More than 15 species have since been identified. These species are currently divided into three genera: Campylobacter, Arcobacter, and Helicobacter. Not all of the species are pathogens of humans. The human pathogens fall into two major groups: those that primarily cause diarrheal disease and those that cause extraintestinal infection. The principal diarrheal pathogen is Campylobacter jejuni, which accounts for 80–90% of all cases of recognized illness due to campylobacters and related genera. Other organisms that cause diarrheal disease include Campylobacter coli, Campylobacter upsaliensis, Campylobacter lari, Campylobacter hyointestinalis, Campylobacter fetus, Arcobacter butzleri, Arcobacter cryaerophilus, Helicobacter cinaedi, and Helicobacter fennelliae. The two Helicobacter species causing diarrheal disease, H. cinaedi and H. fennelliae, are intestinal rather than gastric organisms; in terms of the clinical features of the illnesses they cause, these species most closely resemble Campylobacter rather than Helicobacter pylori (Chap. 60) and thus are considered in this chapter. The pathogenic roles of Campylobacter concisus, Campylobacter ureolyticus, Campylobacter troglodytis, and Campylobacter pyloridis are uncertain. A new subspecies—C. fetus subspecies testudinum—has been described, chiefly in Asian patients; its close resemblance to strains isolated from reptiles suggests a food source.

The major species causing extraintestinal illnesses is C. fetus. However, any of the diarrheal agents listed above may cause systemic or localized infection as well, especially in compromised hosts. Neither aerobes nor strict anaerobes, these microaerophilic organisms are adapted for survival in the gastrointestinal mucous layer. This chapter focuses on C. jejuni and C. fetus as the major pathogens in and prototypes for their groups. The key features of infection are listed by species (excluding C. jejuni, described in detail in the text below) in Table 64-1.

Campylobacters are found in the gastrointestinal tract of many animals used for food (including poultry, cattle, sheep, and swine) and many household pets (including birds, dogs, and cats). These microorganisms usually do not cause illness in their animal hosts. In most cases, campylobacters are transmitted to humans in raw or undercooked food products or through direct contact with infected animals. In the United States and other developed countries, ingestion of contaminated poultry that has not been sufficiently cooked is the most common mode of acquisition (30–70% of cases). Other modes include ingestion of raw (unpasteurized) milk or untreated water, contact with infected household pets, travel to developing countries (campylobacters being among the leading causes of traveler’s diarrhea; Chaps. 6 and 30), oral-anal sexual contact, and (occasionally) contact with an index case who is incontinent of stool (e.g., a baby).

Campylobacter infections are common. Several studies indicate that, in the United States, diarrheal disease due to campylobacters is more common than that due to Salmonella and Shigella combined. Infections occur throughout the year, but their incidence peaks during summer and early autumn. Persons of all ages are affected; however, attack rates for C. jejuni are highest among young children and young adults, whereas those for C. fetus are highest at the extremes of age. Systemic infections due to C. fetus (and to other Campylobacter and related species) are most common among compromised hosts. Persons at increased risk include those with AIDS, hypogammaglobulinemia, neoplasia, liver disease, diabetes mellitus, and generalized atherosclerosis as well as neonates and pregnant women. However, apparently healthy nonpregnant persons occasionally develop transient Campylobacter bacteremia as part of a gastrointestinal illness.

In contrast, in many developing countries, C. jejuni infections are hyperendemic, with the highest rates among children <2 years old. Infection rates fall with age, as does the illness-to-infection ratio. These observations suggest that frequent exposure to C. jejuni leads to the acquisition of immunity.

C. jejuni infections may be subclinical, especially in hosts in developing countries who have had multiple prior infections and thus are partially immune. Symptomatic infections mostly occur within 2–4 days (range, 1–7 days) of exposure to the organism in food or water. The sites of tissue injury include the jejunum, ileum, and colon. Biopsies show an acute nonspecific inflammatory reaction, with neutrophils, monocytes, and eosinophils in the lamina propria, as well as damage to the epithelium, including loss of mucus, glandular degeneration, and crypt abscesses. Biopsy findings may be consistent with Crohn’s disease or ulcerative colitis, but these “idiopathic” chronic inflammatory diseases should not be diagnosed unless infectious colitis, specifically including that due to infection with Campylobacter species and related organisms, has been ruled out.

The high frequency of C. jejuni infections and their severity and recurrence among hypogammaglobulinemic patients suggest that antibodies are important in protective immunity. The pathogenesis of infection is uncertain. Both the motility of the strain and its capacity to adhere to host tissues appear to favor disease, but classic enterotoxins and cytotoxins (although they have been described and include cytolethal distending toxin, or CDT) appear not to play substantial roles in tissue injury or disease production. The organisms have been visualized within the epithelium, albeit in low numbers. The documentation of a significant tissue response and occasionally of C. jejuni bacteremia further suggests that tissue invasion is clinically significant, and in vitro studies are consistent with this pathogenetic feature.

The pathogenesis of C. fetus infections is better defined. Virtually all clinical isolates of C. fetus possess a proteinaceous capsule-like structure (an S-layer) that renders the organisms resistant to complement-mediated killing and opsonization. As a result, C. fetus can cause bacteremia and can seed sites beyond the intestinal tract. The ability of the organism to switch the S-layer proteins expressed—a phenomenon that results in antigenic variability—may contribute to the chronicity and high rate of recurrence of C. fetus infections in compromised hosts.

The clinical features of infections due to Campylobacter and the related Arcobacter and intestinal Helicobacter species causing enteric disease appear to be highly similar. C. jejuni can be considered the prototype, in part because it is by far the most common enteric pathogen in the group. A prodrome of fever, headache, myalgia, and/or malaise often occurs 12–48 h before the onset of diarrheal symptoms. The most common signs and symptoms of the intestinal phase are diarrhea, abdominal pain, and fever. The degree of diarrhea varies from several loose stools to grossly bloody stools; most patients presenting for medical attention have ≥10 bowel movements on the worst day of illness. Abdominal pain usually consists of cramping and may be the most prominent symptom. Pain is usually generalized but may become localized; C. jejuni infection may cause pseudoappendicitis. Fever may be the only initial manifestation of C. jejuni infection, a situation mimicking the early stages of typhoid fever. Febrile young children may develop convulsions. Campylobacter enteritis is generally self-limited; however, symptoms persist for >1 week in 10–20% of patients seeking medical attention, and clinical relapses occur in 5–10% of such untreated patients. Studies of common-source epidemics indicate that milder illnesses or asymptomatic infections may commonly occur.

C. fetus may cause a diarrheal illness similar to that due to C. jejuni, especially in normal hosts. This organism also may cause either intermittent diarrhea or nonspecific abdominal pain without localizing signs. Sequelae are uncommon, and the outcome is benign. C. fetus may also cause a prolonged relapsing systemic illness (with fever, chills, and myalgias) that has no obvious primary source; this manifestation is especially common among compromised hosts. Secondary seeding of an organ (e.g., meninges, brain, bone, urinary tract, or soft tissue) complicates the course, which may be fulminant. C. fetus infections have a tropism for vascular sites: endocarditis, mycotic aneurysm, and septic thrombophlebitis may all occur. Infection during pregnancy often leads to fetal death. A variety of Campylobacter species and H. cinaedi can cause recurrent cellulitis with fever and bacteremia in immunocompromised hosts.

Except in infection with C. fetus, bacteremia is uncommon, developing most often in immunocompromised hosts and at the extremes of age. Three patterns of extraintestinal infection have been noted: (1) transient bacteremia in a normal host with enteritis (benign course, no specific treatment needed); (2) sustained bacteremia or focal infection in a normal host (bacteremia originating from enteritis, with patients responding well to antimicrobial therapy); and (3) sustained bacteremia or focal infection in a compromised host. Enteritis may not be clinically apparent. Antimicrobial therapy, possibly prolonged, is necessary for suppression or cure of the infection.

Campylobacter, Arcobacter, and intestinal Helicobacter infections in patients with AIDS or hypogammaglobulinemia may be severe, persistent, and extraintestinal; relapse after cessation of therapy is common. Hypogammaglobulinemic patients also may develop osteomyelitis and an erysipelas-like rash or cellulitis.

Local suppurative complications of infection include cholecystitis, pancreatitis, and cystitis; distant complications include meningitis, endocarditis, arthritis, peritonitis, cellulitis, and septic abortion. All these complications are rare, except in immunocompromised hosts. Hepatitis, interstitial nephritis, and the hemolytic-uremic syndrome occasionally complicate acute infection. Reactive arthritis and other rheumatologic complaints may develop several weeks after infection, especially in persons with the HLA-B27 phenotype. Guillain-Barré syndrome or its Miller Fisher (cranial polyneuropathy) variant follows Campylobacter infections uncommonly—i.e., in 1 of every 1000–2000 cases or, for certain C. jejuni serotypes (such as O19), in 1 of every 100–200 cases. Despite the low frequency of this complication, it is now estimated that Campylobacter infections, because of their high incidence, may trigger 20–40% of all cases of Guillain-Barré syndrome. The presence of sialylated lipopolysaccharides on C. jejuni strains is a form of molecular mimicry that promotes autoimmune recognition of sialylated cell surface molecules on axons. Asymptomatic Campylobacter infection also may trigger Guillain-Barré syndrome. Immunoproliferative small-intestinal disease (alpha chain disease), a form of lymphoma that originates in small-intestinal mucosa-associated lymphoid tissue, has been associated with C. jejuni; antimicrobial therapy has led to marked clinical improvement.

In patients with Campylobacter enteritis, peripheral leukocyte counts reflect the severity of the inflammatory process. However, stools from nearly all Campylobacter-infected patients presenting for medical attention in the United States contain leukocytes or erythrocytes. Gram- or Wright-stained fecal smears should be examined in all suspected cases. When the diagnosis of Campylobacter enteritis is suspected on the basis of findings indicating inflammatory diarrhea (fever, fecal leukocytes), clinicians can ask the microbiology laboratory to attempt the visualization of organisms with characteristic vibrioid morphology by direct microscopic examination of stools with Gram’s staining or to use phase-contrast or dark-field microscopy to identify the organisms’ characteristic “darting” motility. Confirmation of the diagnosis of Campylobacter infection is based on identification of an isolate from cultures of stool, blood, or another site. Campylobacter-specific media should be used to culture stools from all patients with inflammatory or bloody diarrhea. Because all Campylobacter species are fastidious, they will not be isolated unless selective media or other selective techniques are used. Not all media are equally useful for isolation of the broad array of campylobacters; therefore, failure to isolate campylobacters from stool does not entirely rule out their presence. Species-specific polymerase chain reaction techniques have been developed to facilitate exact diagnoses. The detection of the organisms in stool almost always implies infection; there is a brief period of postconvalescent fecal carriage and no obvious commensalism in humans. In contrast, Campylobacter sputorum and related organisms found in the oral cavity are commensals that only rarely have pathogenic significance. Because of the low levels of metabolic activity of Campylobacter species in standard blood culture media, Campylobacter bacteremia may be difficult to detect unless laboratorians check for low-positive results in quantitative assays.

The symptoms of Campylobacter enteritis are not sufficiently unusual to distinguish this illness from that due to Salmonella, Shigella, Yersinia, and other pathogens. The combination of fever and fecal leukocytes or erythrocytes is indicative of inflammatory diarrhea, and definitive diagnosis is based on culture or demonstration of the characteristic organisms on stained fecal smears. Similarly, extrain-testinal Campylobacter illness is diagnosed by culture. Infection due to Campylobacter should be suspected in the setting of septic abortion, and that due to C. fetus should be suspected specifically in the setting of septic thrombophlebitis. It is important to reiterate that (1) the presentation of Campylobacter enteritis may mimic that of ulcerative colitis or Crohn’s disease, (2) Campylobacter enteritis is much more common than either of the latter (especially among young adults), and (3) biopsy may not distinguish among these entities. Thus a diagnosis of inflammatory bowel disease should not be made until Campylobacter infection has been ruled out, especially in persons with a history of foreign travel, significant animal contact, immunodeficiency, or exposure incurring a high risk of transmission.

Nearly all patients recover fully from Campylobacter enteritis, either spontaneously or after antimicrobial therapy. Volume depletion probably contributes to the few deaths that are reported. As stated above, occasional patients develop reactive arthritis or Guillain-Barré syndrome or its variants. Systemic infection with C. fetus is much more often fatal than that due to related species; this higher mortality rate reflects in part the population affected. Prognosis depends on the rapidity with which appropriate therapy is begun. Otherwise healthy hosts usually survive C. fetus infections without sequelae. Compromised hosts often have recurrent and/or life-threatening infections due to a variety of Campylobacter species.