Chapter 194 Campylobacter
Campylobacter jejuni and Campylobacter coli are global zoonoses and are among the most common causes of human intestinal infections. Infection with these organisms may be followed by severe immunoreactive diseases and possibly immunoproliferative disorders.
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
| SPECIES | DISEASES IN HUMANS | COMMON SOURCES |
|---|---|---|
| C. jejuni | Gastroenteritis, bacteremia, Guillain-Barré syndrome | Poultry, raw milk, cats, dogs, cattle, swine, monkeys, water |
| C. coli | Gastroenteritis, bacteremia | Poultry, raw milk, cats, dogs, cattle, swine, monkeys, oysters, water |
| C. fetus | Bacteremia, meningitis, endocarditis, mycotic aneurysm, diarrhea | Sheep, cattle, birds |
| C. hyointestinalis | Diarrhea, bacteremia, proctitis | Swine, cattle, deer, hamsters, raw milk, oysters |
| C. lari | Diarrhea, colitis, appendicitis, bacteremia, urinary tract infection | Seagulls, water, poultry, cattle, dogs, cats, monkeys, oysters, mussels |
| C. upsaliensis | Diarrhea, bacteremia, abscesses, enteritis, colitis, hemolyticuremic | Cats, other domestic pets |
| C. concisus | Diarrhea, gastritis, enteritis, periodontitis | Human oral cavity |
| C. sputorum | Diarrhea, bedsores, abscesses, periodontitis | Human oral cavity, cattle, swine |
| C. rectus | Periodontitis | |
| C. mucosalis | Enteritis | Swine |
| C. jejuni subspecies doylei | Diarrhea, colitis, appendicitis, bacteremia, urinary tract infection | Swine |
| C. curvus | Gingivitis, alveolar abscess | Poultry, raw milk, cats, dogs, cattle, swine, monkeys, water, human oral cavity |
| C. gracilis | Head and neck abscess, abdominal abscess, empyema | |
| C. cryaerophila | Diarrhea | Swine |
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.
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.
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.
Diarrhea is usually caused by C. jejuni (90-95%) or C. coli and rarely by C. lari, C. hyointestinalis, or C. upsaliensis. The incubation period is 1-7 days. Patients typically have a prodrome comprising fever, headache, and myalgia and within a day develop loose, watery stools or, less commonly, bloody, mucus-containing stools that are characteristic of dysentery. In severe cases, blood appears in the stools 2-4 days after the onset of symptoms. Fever may be the only manifestation initially, but 60-90% of older children also complain of abdominal pain. The abdominal pain is periumbilical and may be cramping, sometimes persisting after the stools return to normal. The abdominal pain can mimic appendicitis or intussusception.
Mild disease lasts 1-2 days and resembles viral gastroenteritis. Most patients recover in <1 wk, although 20-30% of patients remain ill for 2 wks and 5-10% are symptomatic for >2 wks. Fatalities are rare. Persistent or recurrent Campylobacter gastroenteritis and emergence of erythromycin resistance during therapy have been reported in immunocompetent persons, patients with hypogammaglobulinemia (congenital or acquired), and patients with AIDS. Persistent infection can mimic chronic inflammatory bowel disease, and thus Campylobacter infection should be ruled out when considering a diagnosis of inflammatory bowel disease. Fecal shedding of the organisms in untreated patients usually lasts for 2-3 wk, with a range from a few days to several months. Shedding tends to be relatively longer in young children. Acute appendicitis, mesenteric lymphadenitis, and ileocolitis have been reported in patients who have had appendectomies during C. jejuni infection.
With the exception of bacteremia due to C. fetus, bacteremia with Campylobacter occurs most often among malnourished children, patients with chronic illnesses or immunodeficiency (HIV, others), and at the extremes of age and is usually asymptomatic. C. fetus causes bacteremia in adults with or without identifiable focal infection, usually in the setting of underlying conditions such as malignancy or diabetes mellitus. When symptomatic, C. jejuni bacteremia is associated with fever, headache, malaise, and abdominal pain. Relapsing or intermittent fever is associated with night sweats, chills, and weight loss when the illness is prolonged. Lethargy and confusion can occur, but focal neurologic signs are unusual without cerebrovascular disease or meningitis. A cough is present occasionally, usually without pulmonary parenchymal involvement. Diarrhea, jaundice, and hepatomegaly are uncommon. Moderate leukocytosis may be found. Transient asymptomatic bacteremia, rapidly fatal septicemia, and prolonged bacteremia of 8-13 wk have been described. Occasional reports describe bacteremia with C. upsaliensis.
Focal infections caused by C. jejuni are rare and occur mainly among neonates and immunocompromised patients, with examples including meningitis, pneumonia, thrombophlebitis, pancreatitis, cholecystitis, ileocecitis with right lower quadrant pain mimicking appendicitis, urinary tract infection, arthritis, peritonitis, myocarditis, pericarditis, and endocarditis. C. fetus shows a predilection for vascular endothelium, causing endocarditis, pericarditis, thrombophlebitis, and mycotic aneurysms, and can also cause meningitis, septic arthritis, osteomyelitis, urinary tract infection, lung abscess, and cholangitis. C. hyointestinalis has been associated with proctitis, C. upsaliensis with breast abscesses, and C. rectus with periodontitis.
Severe perinatal infections are uncommon and are caused most often by C. fetus and rarely by C. jejuni. Maternal C. fetus and C. jejuni infections may be asymptomatic and can result in abortion, stillbirth, premature delivery, or neonatal infection with sepsis and meningitis. Neonatal infection with C. jejuni is associated with diarrhea that may be bloody.
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.
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.
Reactive arthritis can accompany Campylobacter enteritis in adolescents and adults, especially patients who are positive for HLA-B27. This manifestation appears 5-40 days after the onset of diarrhea, involves mainly large joints, and resolves without sequelae. The arthritis is typically migratory and occurs without fever. Synovial fluid lacks bacteria. Reactive arthritis with conjunctivitis, urethritis, and rash (including erythema nodosum) also occurs but is less common.
Guillain-Barré syndrome (GBS) is an acute demyelinating disease of the peripheral nervous system characterized clinically by acute flaccid paralysis and is the most common cause of neuromuscular paralysis worldwide (Chapter 608). GBS carries a mortality rate of ∼2%, and ∼20% of patients with this disease develop major neurologic sequelae. C. jejuni is an important causal factor for GBS, which has been reported 1-12 wk after culture-proven C. jejuni gastroenteritis in 1 of every 3,000 C. jejuni infections. Stool cultures obtained from patients with GBS at the onset of neurologic symptoms have yielded C. jejuni in >25% of the cases. Serologic studies suggest that 20-45% of patients with GBS have evidence of recent C. jejuni infection. The management of GBS includes supportive care, intravenous immunoglobulin, and plasma exchange.
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.
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%.
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.
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