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Campylobacter Infections
SECTION II: PATHOGENS
PART A: Bacterial and Mycobacterial Infections
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CHAPTER 19 Campylobacter Infections Ban Mishu Allos • Albert J. Lastovica
INTRODUCTION Campylobacters are bacteria that often produce an acute gastrointestinal illness. Infections with these organisms occur in every part of the world, including arctic, temperate, and tropical climates.1 In developing countries, especially those in tropical areas, they are hyperendemic and important causes of morbidity and possibly mortality in young children. Campylobacter infections also are an important cause of diarrhea in persons residing in developed countries who travel to developing countries in the tropics.2,3
THE AGENT Campylobacter species are microaerophilic, comma-shaped, Gram-negative rods that were first recognized as causes of infectious abortion in animals in the early twentieth century4 and later were determined also to cause infectious abortion in women.5 Over the next decades, the organisms were reported to cause bacteremia, meningitis, endocarditis, and abscesses in immunocompromised patients.6,7 A group of related organisms also were isolated from the blood of patients with diarrhea.8 During the last three decades of the twentieth century, campylobacters were recognized as one of the most common bacterial causes of diarrhea worldwide. Although the organisms were first called Vibrio, they were assigned to a new genus, Campylobacter, in 1973;9 this scheme was later modified so that the opportunistic organism was called Campylobacter fetus, and the related vibrios were called C. jejuni and C. coli.10 In 2000, the complete genome of C. jejuni was sequenced.11 Currently the whole genome sequences for eight Campylobacter species have been determined.12 The use of filtration with antibiotic-free culture systems13 and other newer techniques14,15 have led to the recognition that many other “atypical” species of Campylobacter and closely related genera also may produce human disease16 (Table 19.1). Such species include C. fetus, C. concisus, C. curvus, C. lari, C. insulaenigrae,17 C. jejuni subsp. doylei, C. rectus, C. sputorum, C. upsaliensis, Helicobacter cinaedi, Helicobacter fennelliae, Arcobacter butzleri, Arcobacter cryaerophila, and C. hyointestinalis. New pathogenic species of Campylobacter are being identified with some regularity. In tropical countries such as South Africa, such “atypical” campylobacters comprise more than 50% of the Campylobacter species isolated.18–20 In contrast, in the United States and other developed nations, C. jejuni accounts for greater than 95% of Campylobacter species isolated.21 Other studies of Campylobacter, in Thailand,22 Hong Kong,23 and the Central African Republic,24 show a higher incidence of C. coli relative to that seen in industrialized nations. However, since methods designed to optimize detection of C. jejuni might not support growth of other species, the contribution of these organisms to the burden of human disease may be
underestimated. An efficient isolation and identification protocol for all species of Campylobacter and the related genera Helicobacter and Arcobacter has been developed.20 Campylobacters grow best at the body temperatures of warm-blooded animals. Optimal growth for C. jejuni is at 42°C at which campylobacters will survive only a few days, but at 4°C they can persist for weeks in substances such as water, feces, urine, or milk.25 Similarly, the organism may flourish and grow in an alkaline environment but will not last 5 minutes at pH less than 2.3.25
EPIDEMIOLOGY The epidemiology of Campylobacter infections is markedly different in tropical developing countries than in the developed world (Table 19.2). Infections are hyperendemic among young children. In tropical countries such as Bangladesh, South Africa, The Gambia, Zaire, India, Australia, Indonesia, and China, the rate of isolation of Campylobacter is greatest in infants and declines with age.26 Although national surveillance programs for campylobacteriosis do not exist in developing countries, estimates from laboratory-based surveillance suggest that the incidence of this infection among children less than 5 years of age may be more than 100 times higher than the rate among children in developed nations.27 Campylobacters frequently can be isolated from asymptomatic children and adults in developing countries.28 In contrast, in developed countries, infection is almost always recognized in association with illness, recognized asymptomatic infections are uncommon, and young children are not at greatest risk. In the developing nations mentioned previously, breastfed children are usually protected, but a high rate of infection with concomitant watery diarrhea is observed after they are weaned.29 In addition to early weaning, close proximity to animals and lack of toilets are important risk factors for the development of early-childhood diarrheal illnesses in general, and those caused by Campylobacter in particular.27,30 The apparent absence of multiple infections within a household31 suggests that person-to-person transmission is not an important mode of spread, even in developing countries. Infections in adults and older children usually are asymptomatic and durations of excretion are short, suggesting that acquired immunity is protective. The importance of acquired protective immunity is further supported by studies in developing countries showing that rising serum antibodies to Campylobacter are associated with a lower rate of infection.32,33 Outbreaks of Campylobacter infection, which occur regularly in developed countries, do not occur in developing countries because of this high level of immunity. Campylobacters are ubiquitous in the environment in tropical climates and infections occur year-round. The late summer and early fall peak in the incidence of Campylobacter infections observed in temperate climates is not seen in tropical countries.26,28,34
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Table 19.1 Clinical and Epidemiologic Features Associated with “Atypical” Campylobacters and Related Organisms Species
Clinical Presentation
Epidemiological Data
C. coli C. fetus
Fever, diarrhea, abdominal pain Bacteremia, sepsis, meningitis, vascular infection, abortion Watery or bloody diarrhea, vomiting, abdominal pain Enteritis, bacteremia Diarrhea, bacteremia Abdominal pain, diarrhea
Clinically and epidemiologically similar to C. jejuni Found in healthy sheep and cattle; may cause spontaneous abortion and infertility Causes proliferative enteritis in swine
C. hyointestinalis C. insulaenigrae C. jejuni subsp. doylei C. lari C. sputorum C. upsaliensis H2-requiring campylobactersa Helicobacter cinaedi, H. fennelliae H. pullorum
H. rappini Arcobacter butzleri Arcobacter cryaerophilia
Pulmonary, axillary, groin and perianal abscesses Watery diarrhea, low-grade fever, abdominal pain, bacteremia, occasionally abortion, abscesses Periodontitis, diarrhea, rarely bacteremia Chronic mild diarrhea, proctitis, abdominal cramps, bacteremia Rare human pathogen, occasionally associated with diarrhea, rarely bacteremia Gastroenteritis; a few reports document bacteremia Fever, diarrhea, abdominal pain, nausea, rarely bacteremia Diarrhea, rarely bacteremia
Isolated from healthy seals and a porpoise Increasing evidence as a human pathogen Seagulls colonized; transmitted to humans via contaminated water Has been isolated from dairy cows Found in dogs, cats; may have autumn seasonality in tropical countries Role as a human pathogen not established Increased in homosexual men and in children in developing countries; may cause bacteremia in HIV+ hosts Isolated from asymptomatic hens and from hens with hepatitis Animal reservoir not known Enzootic in human primates Isolated from mussels in brackish water
a
Includes C. retus, C. curvus, and C. concisus.
Campylobacteriosis in humans
Table 19.2 Clinical and Epidemiologic Characteristics of Campylobacter Infections in Developed Versus Tropical Developing Countries Characteristic Peak age group affected Endemicity of infection Occurrence of outbreaks Seasonality Predominant mode of transmission Clinical expression Asymptomatic infection Nature of diarrhea Abdominal cramps Bacterial load in stools of infected persons Presence of immunity in typical adult
Developed Countries
Developing Countries
15–29 years Endemic Common Summer and fall peaks Food-borne
<2 years Hyperendemic Rare Year-round
Inflammatory Uncommon Inflammatorya Common High
Noninflammatory Usual Watery Rare Low
No
Yes
Uncertain
Food, water
Major
Febrile inflammatory diarrhea
Fecal carriage
Probably minor
Enzootic infection of Fecal wild and domesticated contamination animals Ongoing transmission
Probably minor
Major
Campylobacter infections
Figure 19.1 Campylobacter infections life cycle.
a
Stools frequently contain gross or occult blood, and leukocytes.
146
Although rotavirus, enterotoxigenic Escherichia coli, and Shigella infections are more common than Campylobacter as causes of diarrhea in tropical countries,30,35,36 campylobacters are among the most common bacterial cause of community-acquired diarrhea in developed countries.37–39 However, even in developing countries, Campylobacter infections are increasing and in some areas surpassing Shigella and E. coli as causes of diarrhea.40 Furthermore, the prevalence of Campylobacter infections is higher in tropical climates than in cooler ones. Even among healthy, asymptomatic children in countries such as Bangladesh, South Africa, The Gambia, and Central African Republic, Campylobacter may be isolated from 10% to 40% of children from a single culture.28,31,41–43
Campylobacter infection is one of the most common causes of diarrhea among travelers to developing countries44 and in Thailand is the most common cause.33,45 Most human infections with Campylobacter in developing countries occur because of consumption of or exposure to animals or their products (Fig. 19.1). Campylobacters live as commensals in the gastrointestinal tract of a variety of animals, especially avian species. Not surprisingly, campylobacters are frequently isolated from poultry and other animals in developing countries,46–51 but the extent of the contribution of this source to human illness has not been determined.52 Interestingly, even in developed nations, the incidence of infection in rural areas is higher, similar
THE DISEASE In developing countries, the clinical consequences of infection with Campylobacter differ from those seen in the developed world. When children in tropical settings develop diarrhea as a result of Campylobacter infection, it frequently is watery and there usually is little or no evidence of an inflammatory process.56 Although symptomatic infection is most likely to occur during the first few months and years of life, asymptomatic infections outnumber symptomatic ones by 2 to 1, even among children less than 5 years of age.57 Infection among children in tropical countries is quite common; more than two infections per year are likely during the first 5 years of life.31,57 Among young children in Bangladesh, the estimated rate is eight Campylobacter infections per year.28 In developed areas, Campylobacter infections usually produce an acute gastrointestinal illness that is indistinguishable from illness caused by other “inflammatory” enteric bacteria such as Salmonella and Shigella. Illness usually begins abruptly with abdominal cramps and diarrhea. Children in developing countries who develop symptomatic Campylobacter infection also typically experience loose stools with mucus, along with fever and vomiting.58 However, although half of Campylobacter-infected patients presenting for medical attention in developed countries have bloody diarrhea,37 in tropical climates the diarrhea usually does not contain blood. Less than one-third of Campylobacter-infected children in Thailand have bloody stools; most have mucoid stools that are neither watery nor bloody; about one-third have watery diarrhea.22,58 Campylobacter infections among persons living in tropical areas also are less likely to produce abdominal cramps.28 The illness usually resolves within 1 to 2 weeks; about 20% of patients will have relapsing symptoms lasting several weeks. Although Campylobacter infections occur frequently in HIVinfected persons residing in developed countries,59 a similar phenomenon is not always observed in developing nations.60–62 Complications of Campylobacter infections are rare and usually the result of local invasion. Massive gastrointestinal hemorrhage may occur. Other complications include cholecystitis, pancreatitis, obstructive hepatitis, and splenic rupture.63–66 Neonatal sepsis and death can occur if the mother is infected during the third trimester.67 Extraintestinal complications of Campylobacter infections are rare68 but are more common in malnourished children. Such complications include bacteremia, meningitis, and purulent arthritis. C. jejuni, C. upsaliensis, and other Campylobacter species have been associated with pediatric bacteremia.20 Infection may lead to fulminant sepsis and death. The postinfection complication, Guillain–Barré syndrome (GBS), occurs at an estimated rate of 1 per 2000 infections.69 A particularly severe form of GBS, acute motor axonal neuropathy, occurs in seasonal epidemics among children in rural China and also may be associated with preceding C. jejuni infection.70 Reactive arthritis also may occur after Campylobacter infection and is most common in persons who carry the HLA-B27 phenotype.71–73 C. jejuni was recently implicated as a cause of immunoproliferative small intestine disease (a form of lymphoma) in a 45-year-old woman in Cameroon.74 In patients in developed countries, the pathologic lesion of Campylobacter enteritis is infiltration of the lamina propria with acute and chronic inflammatory cells and destruction of epithelial glands with crypt abscess formation.75 The site of tissue injury is usually the jejunum, ileum, and colon.75,76 This nonspecific colitis may be indistinguishable from ulcerative colitis or Crohn’s disease; hence the importance of diagnosing this treatable infection before immunosuppressive therapy is given for inflammatory bowel disease. The pathology of Campylobacter enteritis among patients in tropical and developing countries has not been well described but, based on the clinical presentation, is presumably milder.
Three factors important in the ability of Campylobacter to produce illness include the dose of organisms reaching the small intestine, the host’s immunity to the organism, and the virulence of the particular strain. Infection leads to multiplication of the organism in the intestine. The number of bacterial cells required to cause illness is unknown, but a high dose is likely needed to infect 50% of subjects.77 In general, the higher the inoculum, the shorter the incubation period (usually 1 day to 1 week) and the higher the attack rate. In developed countries, Campylobacter-infected persons shed between 106 and 109 colony-forming units per gram of stool.25 However, the intestinal bacterial load is lower among similarly infected persons in developing nations.32 Furthermore, in developing areas, the duration and number of organisms excreted are highest in infants and decline with age, also consistent with increasing acquisition of immunity.58 Characteristics of campylobacters that enable them to adhere to and invade intestinal cells include the presence of flagella, high molecularweight plasmids, superficial adhesins, fimbriae, and chemotactic factors.77–85 Campylobacters must be flagellated to colonize, invade, and cause disease.86 In vivo studies have demonstrated that flagella synthesis genes are needed for maximal C. jejuni invasiveness.87,88 Although the bacteria do not possess fimbriae per se, fimbriae-like filaments enable the organisms to attach to epithelial cells.89 Additionally, several C. jejuni surface proteins (e.g., PEB1, CadF) appear to function in attachment and subsequent colonization and invasion.89 Invasion of epithelial cells by C. jejuni results in cellular injury and, ultimately, in diarrhea. The mechanism of invasion is complex and not completely understood.90 Despite early reports to the contrary,91 the low level of enterotoxin production that occasionally has been observed in vitro does not appear to be important in the pathogenesis of Campylobacter infections.85,92 Enterotoxin production cannot be demonstrated in vivo, and infected patients do not form antibodies against enterotoxin.93 All C. jejuni isolates possess a gene that codes for cytolethal distending toxin; however, not all isolates produce this toxin, and its role in causing disease is not established.94 Some have suggested the toxin may play a role in pathogenesis by inducing death of macrophages, thus suppressing innate immunity.95,96 Specific immunity to Campylobacter may be acquired and plays a crucial role in curtailing disease severity. In developing countries where these infections are hyperendemic, infection and illness rates decline with age, again suggesting the acquisition of immunity. Volunteer studies also have shown that short-term specific immunity to Campylobacter occurs.77,97 Humoral immunity appears to play an important role in containing Campylobacter infection. After infection, serum antibodies (IgA, IgG, and IgM) peak in 2–4 weeks, then rapidly decline.98 The importance of humoral immunity is further supported by studies showing that in hypogammaglobulinemic patients, Campylobacter infections are severe, prolonged, and difficult to eradicate.99 Children in tropical settings develop steadily rising serum IgA antibodies to Campylobacter. Once these high levels are achieved, IgG levels, which also rise through early childhood, begin to decline.58,100,101 These data suggest that frequent exposure to Campylobacter leads to the development of solid “gut immunity,” which precludes sensitization of IgG-producing cells. Such gut immunity correlates well with the declining incidence of infection with age, the lower proportion of infections that are symptomatic, and the reduced bacterial level and duration of excretion.58 Recent studies showed that campylobacters induced maturation and cytokine production in dendritic cells, indicating that these bacteria elicit innate immune responses.102 Persons with human immunodeficiency virus (HIV) infection have more frequent, persistent, severe, and extraintestinal Campylobacter infections than the general population in developed nations.103,104 Although these observations could suggest that cellular immunity also plays an important role in protection against Campylobacter, many such patients have defects in humoral responses as well.
Chapter 19
PATHOGENESIS AND IMMUNITY
Campylobacter Infections
to patterns observed in developing nations.53 In Africa, campylobacters also have been isolated from surface domestic water sources used for human consumption54 and from dairy products.55 The main vehicles of human infection in developed countries are water, milk, raw meat, and most importantly, poultry. Person-to-person transmission of Campylobacter is infrequent in both developed and developing countries.
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Serum killing of Campylobacter species occurs via complementmediated bactericidal activity.105 This could explain why bacteremia due to Campylobacter species is uncommon except in immunodeficient persons, or is due to the serum-resistant C. fetus.105 Serum-resistant campylobacters have been isolated from the cerebrospinal fluid of patients with meningitis.106
DIAGNOSIS In developing countries, the simplest and most inexpensive method for diagnosis of Campylobacter infection is direct examination of stools after Gram or Wright staining. Stools also can be directly examined for the presence of white blood cells or lactoferrin and erythrocytes, which are nonspecific findings associated with inflammatory agents but which also suggest the presence of a bacterial enteric pathogen, such as Campylobacter. The gold standard for detection of Campylobacter infection is culture of the organism from stool, blood, or other site of infection. Because Campylobacter infection cannot be differentiated from infections due to other bacterial enteric pathogens on clinical grounds, isolation of the organism using a selective technique is the only way to make the diagnosis with certainty. Cephalothin-containing selective media will suppress most fecal flora while permitting the growth of most C. jejuni strains. However, some Campylobacter species (and even a few C. jejuni strains) are cephalothin-susceptible, and must be isolated on less selective media or on antibiotic-free media after filtration of the stool sample.20 In tropical countries, many patients may have mixed infections with Campylobacter and other enteric pathogens.22,58 In addition, several species of Campylobacter and related species may be co-isolated from the same clinical sample.20 Therefore, the precise contribution of Campylobacter infection to these children’s illnesses may be difficult to assess. Campylobacter infection also may be mistaken for inflammatory bowel disease. Campylobacter enterocolitis may produce crypt abscesses (which are frequent in ulcerative colitis) and granulomas (which are common in Crohn’s disease).75,76,107 Persons suspected of having inflammatory bowel disease should have cultures for several different Campylobacter species performed as part of their diagnostic workup. Serologic testing occasionally may be useful for detecting recent Campylobacter infection.105,108 However, this technique is unlikely to be helpful in tropical developing countries where infection is hyperendemic and background infection rates are high. Polymerase chain reaction (PCR) to detect Campylobacter in stools is beginning to be used in some clinical laboratories in developed nations.109,110 However, the clinical significance of a positive PCR assay in a patient in a developing country might be difficult to interpret and the costs associated with such testing preclude wide usage.
TREATMENT AND PROGNOSIS
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Antimicrobial treatment of Campylobacter infections, if initiated early in the illness, reduces the duration of bacterial excretion in stools.111,112 However, most patients with Campylobacter enteritis, and certainly those with asymptomatic or mild infection, do not need antimicrobial therapy. Even patients whose symptoms lead them to seek medical care may not require measures other than encouragement to keep well hydrated. Occasionally, intravenous fluids are needed, especially in the very young and very old. In developing countries, oral hydration solutions are the best method of maintaining fluid and electrolyte balance, unless volume depletion is severe. The prognosis for most patients with Campylobacter infection is favorable; symptoms usually resolve within 1 week without antimicrobial therapy. Antibiotics should be given to Campylobacter-infected patients in certain high-risk groups or clinical circumstances. Because Campylobacter infection may have deleterious effects on the fetus, pregnant women should receive prompt therapy.67 Similarly, HIV-infected or other immunocompromised patients should receive antibiotics. With the
expanding HIV epidemic in developing countries, extraintestinal infection will be increasingly common. Immunocompetent persons with fever greater than 38.3°C (101°F), bloody stools, symptoms lasting more than 1 week, or worsening symptoms also may benefit from antimicrobial therapy. Campylobacters are susceptible to a wide variety of antimicrobial agents, including macrolides, quinolones, nitrofurans, and aminoglycosides. Care should be taken before prescribing tetracycline because more than 20% of campylobacters are resistant.113,114 Susceptibility to ampicillin, metronidazole, and trimethoprim-sulfamethoxazole is variable. There is almost universal resistance of Campylobacter to cephalo sporins, penicillin, vancomycin, and rifampin. Erythromycin remains the treatment of choice for most patients with infections due to Campylobacter. Erythromycin has low toxicity, has a relatively narrow spectrum of activity, and is inexpensive. Because erythromycin stearate is incompletely absorbed, it can exert a local effect throughout the bowel, in addition to its systemic effects. In most developed countries, the rate of erythromycin resistance among Campylobacter species has remained under 10%.115–117 Higher rates of resistance have been reported from developing countries, such as Thailand,35 but resistance remains low in other countries, such as India and Kenya.118,119 The rate of erythromycin resistance is substantially higher among C. coli strains.114,120–122 The newer macrolides, azithromycin and clarithromycin, have excellent activity against Campylobacter.123–126 Although they achieve higher concentrations in tissue, they provide little clinical advantage over erythromycin and are considerably more expensive. Strains resistant to erythromycin also will be resistant to these newer macrolides. The activity of clindamycin against C. jejuni is equivalent to that of erythromycin. At one time, it appeared that quinolones, such as ciprofloxacin, had emerged as the treatment of choice for bacterial diarrhea in general and for Campylobacter enteritis in particular.127 Unfortunately, rapidly emerging resistance of campylobacters to quinolones in tropical regions and in other parts of the world has limited their effectiveness.112,128,129Widespread use of fluoroquinolones in poultry has led to the transfer of antibioticresistant strains to humans.130,131 Nalidixic acid resistance commonly but not invariably crosses with resistance to ciprofloxacin.114 Resistance to this agent has paralleled the increasing resistance to fluoroquinolones. In special circumstances when therapy is required, and when a patient is intolerant of many agents or when a strain has an unusual antibiotic resistance pattern, alternative agents such as chloramphenicol may be used; nearly all campylobacters are susceptible to chloramphenicol.114,132 This agent is especially useful in tropical developing countries because of its low cost. For persons with bacteremia and other extraintestinal suppurative infections, gentamicin and imipenem are active against campylobacters and the rate of resistance to these agents is less than 1%. Gentamicin is ineffective against Campylobacter in the gut; therefore, oral therapy with an effective, absorbable drug also must be given.
PREVENTION AND CONTROL Campylobacters are so ubiquitous in the environment of most tropical developing nations that there is no possibility of reducing the reservoirs of infection. Rather, prevention must focus on interrupting the path of transmission to humans from animals, animal products, or environmental sources contaminated by animals or humans. Poultry, livestock, pets, and wild animals are the major reservoirs. Therefore, as for many bacterial enteric pathogens, a basic tenet of prevention is adequate hand washing; this is especially important in tropical areas for people who handle animals and food within a household. Especially important is the awareness of the necessity for proper cooking and storage of foods of animal origin. The safe disposal of sewage and the protection and purification of water supplies also are fundamental to control of most diseases due to enteric pathogens, including Campylobacter. Programs to improve water safety in developing countries may impact the number of infections.133 Excreta from sheep, cattle, and wild and domestic birds should not be
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Chapter 19
infection of humans is “accidental” given that humans are not required for completion of their life cycle, the natural acquisition of immunity in developing countries and the identification of group antigens suggest that vaccination will be feasible. There is no proven benefit of antibiotic prophylaxis to prevent Campylobacter infection in travelers to tropical and subtropical environments.
Campylobacter Infections
allowed to contaminate a community’s water supplies. Chlorination reliably inactivates Campylobacter.134 Control of Campylobacter infections in developing countries will likely be difficult unless an effective vaccine is developed. Because of the diversity of serotypes of C. jejuni, the possibility of vaccination for prevention of infection must be based on group antigens. Since Campylobacter
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CHAPTER 19 Campylobacter Infections Ban Mishu Allos • Albert J. Lastovica
INTRODUCTION Campylobacters are bacteria that often produce an acute gastrointestinal illness. Infections with these organisms occur in every part of the world, including arctic, temperate, and tropical climates.1 In developing countries, especially those in tropical areas, they are hyperendemic and important causes of morbidity and possibly mortality in young children. Campylobacter infections also are an important cause of diarrhea in persons residing in developed countries who travel to developing countries in the tropics.2,3
THE AGENT Campylobacter species are microaerophilic, comma-shaped, Gram-negative rods that were first recognized as causes of infectious abortion in animals in the early twentieth century4 and later were determined also to cause infectious abortion in women.5 Over the next decades, the organisms were reported to cause bacteremia, meningitis, endocarditis, and abscesses in immunocompromised patients.6,7 A group of related organisms also were isolated from the blood of patients with diarrhea.8 During the last three decades of the twentieth century, campylobacters were recognized as one of the most common bacterial causes of diarrhea worldwide. Although the organisms were first called Vibrio, they were assigned to a new genus, Campylobacter, in 1973;9 this scheme was later modified so that the opportunistic organism was called Campylobacter fetus, and the related vibrios were called C. jejuni and C. coli.10 In 2000, the complete genome of C. jejuni was sequenced.11 Currently the whole genome sequences for eight Campylobacter species have been determined.12 The use of filtration with antibiotic-free culture systems13 and other newer techniques14,15 have led to the recognition that many other “atypical” species of Campylobacter and closely related genera also may produce human disease16 (Table 19.1). Such species include C. fetus, C. concisus, C. curvus, C. lari, C. insulaenigrae,17 C. jejuni subsp. doylei, C. rectus, C. sputorum, C. upsaliensis, Helicobacter cinaedi, Helicobacter fennelliae, Arcobacter butzleri, Arcobacter cryaerophila, and C. hyointestinalis. New pathogenic species of Campylobacter are being identified with some regularity. In tropical countries such as South Africa, such “atypical” campylobacters comprise more than 50% of the Campylobacter species isolated.18–20 In contrast, in the United States and other developed nations, C. jejuni accounts for greater than 95% of Campylobacter species isolated.21 Other studies of Campylobacter, in Thailand,22 Hong Kong,23 and the Central African Republic,24 show a higher incidence of C. coli relative to that seen in industrialized nations. However, since methods designed to optimize detection of C. jejuni might not support growth of other species, the contribution of these organisms to the burden of human disease may be
underestimated. An efficient isolation and identification protocol for all species of Campylobacter and the related genera Helicobacter and Arcobacter has been developed.20 Campylobacters grow best at the body temperatures of warm-blooded animals. Optimal growth for C. jejuni is at 42°C at which campylobacters will survive only a few days, but at 4°C they can persist for weeks in substances such as water, feces, urine, or milk.25 Similarly, the organism may flourish and grow in an alkaline environment but will not last 5 minutes at pH less than 2.3.25
EPIDEMIOLOGY The epidemiology of Campylobacter infections is markedly different in tropical developing countries than in the developed world (Table 19.2). Infections are hyperendemic among young children. In tropical countries such as Bangladesh, South Africa, The Gambia, Zaire, India, Australia, Indonesia, and China, the rate of isolation of Campylobacter is greatest in infants and declines with age.26 Although national surveillance programs for campylobacteriosis do not exist in developing countries, estimates from laboratory-based surveillance suggest that the incidence of this infection among children less than 5 years of age may be more than 100 times higher than the rate among children in developed nations.27 Campylobacters frequently can be isolated from asymptomatic children and adults in developing countries.28 In contrast, in developed countries, infection is almost always recognized in association with illness, recognized asymptomatic infections are uncommon, and young children are not at greatest risk. In the developing nations mentioned previously, breastfed children are usually protected, but a high rate of infection with concomitant watery diarrhea is observed after they are weaned.29 In addition to early weaning, close proximity to animals and lack of toilets are important risk factors for the development of early-childhood diarrheal illnesses in general, and those caused by Campylobacter in particular.27,30 The apparent absence of multiple infections within a household31 suggests that person-to-person transmission is not an important mode of spread, even in developing countries. Infections in adults and older children usually are asymptomatic and durations of excretion are short, suggesting that acquired immunity is protective. The importance of acquired protective immunity is further supported by studies in developing countries showing that rising serum antibodies to Campylobacter are associated with a lower rate of infection.32,33 Outbreaks of Campylobacter infection, which occur regularly in developed countries, do not occur in developing countries because of this high level of immunity. Campylobacters are ubiquitous in the environment in tropical climates and infections occur year-round. The late summer and early fall peak in the incidence of Campylobacter infections observed in temperate climates is not seen in tropical countries.26,28,34
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Table 19.1 Clinical and Epidemiologic Features Associated with “Atypical” Campylobacters and Related Organisms Species
Clinical Presentation
Epidemiological Data
C. coli C. fetus
Fever, diarrhea, abdominal pain Bacteremia, sepsis, meningitis, vascular infection, abortion Watery or bloody diarrhea, vomiting, abdominal pain Enteritis, bacteremia Diarrhea, bacteremia Abdominal pain, diarrhea
Clinically and epidemiologically similar to C. jejuni Found in healthy sheep and cattle; may cause spontaneous abortion and infertility Causes proliferative enteritis in swine
C. hyointestinalis C. insulaenigrae C. jejuni subsp. doylei C. lari C. sputorum C. upsaliensis H2-requiring campylobactersa Helicobacter cinaedi, H. fennelliae H. pullorum
H. rappini Arcobacter butzleri Arcobacter cryaerophilia
Pulmonary, axillary, groin and perianal abscesses Watery diarrhea, low-grade fever, abdominal pain, bacteremia, occasionally abortion, abscesses Periodontitis, diarrhea, rarely bacteremia Chronic mild diarrhea, proctitis, abdominal cramps, bacteremia Rare human pathogen, occasionally associated with diarrhea, rarely bacteremia Gastroenteritis; a few reports document bacteremia Fever, diarrhea, abdominal pain, nausea, rarely bacteremia Diarrhea, rarely bacteremia
Isolated from healthy seals and a porpoise Increasing evidence as a human pathogen Seagulls colonized; transmitted to humans via contaminated water Has been isolated from dairy cows Found in dogs, cats; may have autumn seasonality in tropical countries Role as a human pathogen not established Increased in homosexual men and in children in developing countries; may cause bacteremia in HIV+ hosts Isolated from asymptomatic hens and from hens with hepatitis Animal reservoir not known Enzootic in human primates Isolated from mussels in brackish water
a
Includes C. retus, C. curvus, and C. concisus.
Campylobacteriosis in humans
Table 19.2 Clinical and Epidemiologic Characteristics of Campylobacter Infections in Developed Versus Tropical Developing Countries Characteristic Peak age group affected Endemicity of infection Occurrence of outbreaks Seasonality Predominant mode of transmission Clinical expression Asymptomatic infection Nature of diarrhea Abdominal cramps Bacterial load in stools of infected persons Presence of immunity in typical adult
Developed Countries
Developing Countries
15–29 years Endemic Common Summer and fall peaks Food-borne
<2 years Hyperendemic Rare Year-round
Inflammatory Uncommon Inflammatorya Common High
Noninflammatory Usual Watery Rare Low
No
Yes
Uncertain
Food, water
Major
Febrile inflammatory diarrhea
Fecal carriage
Probably minor
Enzootic infection of Fecal wild and domesticated contamination animals Ongoing transmission
Probably minor
Major
Campylobacter infections
Figure 19.1 Campylobacter infections life cycle.
a
Stools frequently contain gross or occult blood, and leukocytes.
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Although rotavirus, enterotoxigenic Escherichia coli, and Shigella infections are more common than Campylobacter as causes of diarrhea in tropical countries,30,35,36 campylobacters are among the most common bacterial cause of community-acquired diarrhea in developed countries.37–39 However, even in developing countries, Campylobacter infections are increasing and in some areas surpassing Shigella and E. coli as causes of diarrhea.40 Furthermore, the prevalence of Campylobacter infections is higher in tropical climates than in cooler ones. Even among healthy, asymptomatic children in countries such as Bangladesh, South Africa, The Gambia, and Central African Republic, Campylobacter may be isolated from 10% to 40% of children from a single culture.28,31,41–43
Campylobacter infection is one of the most common causes of diarrhea among travelers to developing countries44 and in Thailand is the most common cause.33,45 Most human infections with Campylobacter in developing countries occur because of consumption of or exposure to animals or their products (Fig. 19.1). Campylobacters live as commensals in the gastrointestinal tract of a variety of animals, especially avian species. Not surprisingly, campylobacters are frequently isolated from poultry and other animals in developing countries,46–51 but the extent of the contribution of this source to human illness has not been determined.52 Interestingly, even in developed nations, the incidence of infection in rural areas is higher, similar
THE DISEASE In developing countries, the clinical consequences of infection with Campylobacter differ from those seen in the developed world. When children in tropical settings develop diarrhea as a result of Campylobacter infection, it frequently is watery and there usually is little or no evidence of an inflammatory process.56 Although symptomatic infection is most likely to occur during the first few months and years of life, asymptomatic infections outnumber symptomatic ones by 2 to 1, even among children less than 5 years of age.57 Infection among children in tropical countries is quite common; more than two infections per year are likely during the first 5 years of life.31,57 Among young children in Bangladesh, the estimated rate is eight Campylobacter infections per year.28 In developed areas, Campylobacter infections usually produce an acute gastrointestinal illness that is indistinguishable from illness caused by other “inflammatory” enteric bacteria such as Salmonella and Shigella. Illness usually begins abruptly with abdominal cramps and diarrhea. Children in developing countries who develop symptomatic Campylobacter infection also typically experience loose stools with mucus, along with fever and vomiting.58 However, although half of Campylobacter-infected patients presenting for medical attention in developed countries have bloody diarrhea,37 in tropical climates the diarrhea usually does not contain blood. Less than one-third of Campylobacter-infected children in Thailand have bloody stools; most have mucoid stools that are neither watery nor bloody; about one-third have watery diarrhea.22,58 Campylobacter infections among persons living in tropical areas also are less likely to produce abdominal cramps.28 The illness usually resolves within 1 to 2 weeks; about 20% of patients will have relapsing symptoms lasting several weeks. Although Campylobacter infections occur frequently in HIVinfected persons residing in developed countries,59 a similar phenomenon is not always observed in developing nations.60–62 Complications of Campylobacter infections are rare and usually the result of local invasion. Massive gastrointestinal hemorrhage may occur. Other complications include cholecystitis, pancreatitis, obstructive hepatitis, and splenic rupture.63–66 Neonatal sepsis and death can occur if the mother is infected during the third trimester.67 Extraintestinal complications of Campylobacter infections are rare68 but are more common in malnourished children. Such complications include bacteremia, meningitis, and purulent arthritis. C. jejuni, C. upsaliensis, and other Campylobacter species have been associated with pediatric bacteremia.20 Infection may lead to fulminant sepsis and death. The postinfection complication, Guillain–Barré syndrome (GBS), occurs at an estimated rate of 1 per 2000 infections.69 A particularly severe form of GBS, acute motor axonal neuropathy, occurs in seasonal epidemics among children in rural China and also may be associated with preceding C. jejuni infection.70 Reactive arthritis also may occur after Campylobacter infection and is most common in persons who carry the HLA-B27 phenotype.71–73 C. jejuni was recently implicated as a cause of immunoproliferative small intestine disease (a form of lymphoma) in a 45-year-old woman in Cameroon.74 In patients in developed countries, the pathologic lesion of Campylobacter enteritis is infiltration of the lamina propria with acute and chronic inflammatory cells and destruction of epithelial glands with crypt abscess formation.75 The site of tissue injury is usually the jejunum, ileum, and colon.75,76 This nonspecific colitis may be indistinguishable from ulcerative colitis or Crohn’s disease; hence the importance of diagnosing this treatable infection before immunosuppressive therapy is given for inflammatory bowel disease. The pathology of Campylobacter enteritis among patients in tropical and developing countries has not been well described but, based on the clinical presentation, is presumably milder.
Three factors important in the ability of Campylobacter to produce illness include the dose of organisms reaching the small intestine, the host’s immunity to the organism, and the virulence of the particular strain. Infection leads to multiplication of the organism in the intestine. The number of bacterial cells required to cause illness is unknown, but a high dose is likely needed to infect 50% of subjects.77 In general, the higher the inoculum, the shorter the incubation period (usually 1 day to 1 week) and the higher the attack rate. In developed countries, Campylobacter-infected persons shed between 106 and 109 colony-forming units per gram of stool.25 However, the intestinal bacterial load is lower among similarly infected persons in developing nations.32 Furthermore, in developing areas, the duration and number of organisms excreted are highest in infants and decline with age, also consistent with increasing acquisition of immunity.58 Characteristics of campylobacters that enable them to adhere to and invade intestinal cells include the presence of flagella, high molecularweight plasmids, superficial adhesins, fimbriae, and chemotactic factors.77–85 Campylobacters must be flagellated to colonize, invade, and cause disease.86 In vivo studies have demonstrated that flagella synthesis genes are needed for maximal C. jejuni invasiveness.87,88 Although the bacteria do not possess fimbriae per se, fimbriae-like filaments enable the organisms to attach to epithelial cells.89 Additionally, several C. jejuni surface proteins (e.g., PEB1, CadF) appear to function in attachment and subsequent colonization and invasion.89 Invasion of epithelial cells by C. jejuni results in cellular injury and, ultimately, in diarrhea. The mechanism of invasion is complex and not completely understood.90 Despite early reports to the contrary,91 the low level of enterotoxin production that occasionally has been observed in vitro does not appear to be important in the pathogenesis of Campylobacter infections.85,92 Enterotoxin production cannot be demonstrated in vivo, and infected patients do not form antibodies against enterotoxin.93 All C. jejuni isolates possess a gene that codes for cytolethal distending toxin; however, not all isolates produce this toxin, and its role in causing disease is not established.94 Some have suggested the toxin may play a role in pathogenesis by inducing death of macrophages, thus suppressing innate immunity.95,96 Specific immunity to Campylobacter may be acquired and plays a crucial role in curtailing disease severity. In developing countries where these infections are hyperendemic, infection and illness rates decline with age, again suggesting the acquisition of immunity. Volunteer studies also have shown that short-term specific immunity to Campylobacter occurs.77,97 Humoral immunity appears to play an important role in containing Campylobacter infection. After infection, serum antibodies (IgA, IgG, and IgM) peak in 2–4 weeks, then rapidly decline.98 The importance of humoral immunity is further supported by studies showing that in hypogammaglobulinemic patients, Campylobacter infections are severe, prolonged, and difficult to eradicate.99 Children in tropical settings develop steadily rising serum IgA antibodies to Campylobacter. Once these high levels are achieved, IgG levels, which also rise through early childhood, begin to decline.58,100,101 These data suggest that frequent exposure to Campylobacter leads to the development of solid “gut immunity,” which precludes sensitization of IgG-producing cells. Such gut immunity correlates well with the declining incidence of infection with age, the lower proportion of infections that are symptomatic, and the reduced bacterial level and duration of excretion.58 Recent studies showed that campylobacters induced maturation and cytokine production in dendritic cells, indicating that these bacteria elicit innate immune responses.102 Persons with human immunodeficiency virus (HIV) infection have more frequent, persistent, severe, and extraintestinal Campylobacter infections than the general population in developed nations.103,104 Although these observations could suggest that cellular immunity also plays an important role in protection against Campylobacter, many such patients have defects in humoral responses as well.
Chapter 19
PATHOGENESIS AND IMMUNITY
Campylobacter Infections
to patterns observed in developing nations.53 In Africa, campylobacters also have been isolated from surface domestic water sources used for human consumption54 and from dairy products.55 The main vehicles of human infection in developed countries are water, milk, raw meat, and most importantly, poultry. Person-to-person transmission of Campylobacter is infrequent in both developed and developing countries.
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Section II PATHOGENS
PART A: Bacterial and Mycobacterial Infections
Serum killing of Campylobacter species occurs via complementmediated bactericidal activity.105 This could explain why bacteremia due to Campylobacter species is uncommon except in immunodeficient persons, or is due to the serum-resistant C. fetus.105 Serum-resistant campylobacters have been isolated from the cerebrospinal fluid of patients with meningitis.106
DIAGNOSIS In developing countries, the simplest and most inexpensive method for diagnosis of Campylobacter infection is direct examination of stools after Gram or Wright staining. Stools also can be directly examined for the presence of white blood cells or lactoferrin and erythrocytes, which are nonspecific findings associated with inflammatory agents but which also suggest the presence of a bacterial enteric pathogen, such as Campylobacter. The gold standard for detection of Campylobacter infection is culture of the organism from stool, blood, or other site of infection. Because Campylobacter infection cannot be differentiated from infections due to other bacterial enteric pathogens on clinical grounds, isolation of the organism using a selective technique is the only way to make the diagnosis with certainty. Cephalothin-containing selective media will suppress most fecal flora while permitting the growth of most C. jejuni strains. However, some Campylobacter species (and even a few C. jejuni strains) are cephalothin-susceptible, and must be isolated on less selective media or on antibiotic-free media after filtration of the stool sample.20 In tropical countries, many patients may have mixed infections with Campylobacter and other enteric pathogens.22,58 In addition, several species of Campylobacter and related species may be co-isolated from the same clinical sample.20 Therefore, the precise contribution of Campylobacter infection to these children’s illnesses may be difficult to assess. Campylobacter infection also may be mistaken for inflammatory bowel disease. Campylobacter enterocolitis may produce crypt abscesses (which are frequent in ulcerative colitis) and granulomas (which are common in Crohn’s disease).75,76,107 Persons suspected of having inflammatory bowel disease should have cultures for several different Campylobacter species performed as part of their diagnostic workup. Serologic testing occasionally may be useful for detecting recent Campylobacter infection.105,108 However, this technique is unlikely to be helpful in tropical developing countries where infection is hyperendemic and background infection rates are high. Polymerase chain reaction (PCR) to detect Campylobacter in stools is beginning to be used in some clinical laboratories in developed nations.109,110 However, the clinical significance of a positive PCR assay in a patient in a developing country might be difficult to interpret and the costs associated with such testing preclude wide usage.
TREATMENT AND PROGNOSIS
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Antimicrobial treatment of Campylobacter infections, if initiated early in the illness, reduces the duration of bacterial excretion in stools.111,112 However, most patients with Campylobacter enteritis, and certainly those with asymptomatic or mild infection, do not need antimicrobial therapy. Even patients whose symptoms lead them to seek medical care may not require measures other than encouragement to keep well hydrated. Occasionally, intravenous fluids are needed, especially in the very young and very old. In developing countries, oral hydration solutions are the best method of maintaining fluid and electrolyte balance, unless volume depletion is severe. The prognosis for most patients with Campylobacter infection is favorable; symptoms usually resolve within 1 week without antimicrobial therapy. Antibiotics should be given to Campylobacter-infected patients in certain high-risk groups or clinical circumstances. Because Campylobacter infection may have deleterious effects on the fetus, pregnant women should receive prompt therapy.67 Similarly, HIV-infected or other immunocompromised patients should receive antibiotics. With the
expanding HIV epidemic in developing countries, extraintestinal infection will be increasingly common. Immunocompetent persons with fever greater than 38.3°C (101°F), bloody stools, symptoms lasting more than 1 week, or worsening symptoms also may benefit from antimicrobial therapy. Campylobacters are susceptible to a wide variety of antimicrobial agents, including macrolides, quinolones, nitrofurans, and aminoglycosides. Care should be taken before prescribing tetracycline because more than 20% of campylobacters are resistant.113,114 Susceptibility to ampicillin, metronidazole, and trimethoprim-sulfamethoxazole is variable. There is almost universal resistance of Campylobacter to cephalo sporins, penicillin, vancomycin, and rifampin. Erythromycin remains the treatment of choice for most patients with infections due to Campylobacter. Erythromycin has low toxicity, has a relatively narrow spectrum of activity, and is inexpensive. Because erythromycin stearate is incompletely absorbed, it can exert a local effect throughout the bowel, in addition to its systemic effects. In most developed countries, the rate of erythromycin resistance among Campylobacter species has remained under 10%.115–117 Higher rates of resistance have been reported from developing countries, such as Thailand,35 but resistance remains low in other countries, such as India and Kenya.118,119 The rate of erythromycin resistance is substantially higher among C. coli strains.114,120–122 The newer macrolides, azithromycin and clarithromycin, have excellent activity against Campylobacter.123–126 Although they achieve higher concentrations in tissue, they provide little clinical advantage over erythromycin and are considerably more expensive. Strains resistant to erythromycin also will be resistant to these newer macrolides. The activity of clindamycin against C. jejuni is equivalent to that of erythromycin. At one time, it appeared that quinolones, such as ciprofloxacin, had emerged as the treatment of choice for bacterial diarrhea in general and for Campylobacter enteritis in particular.127 Unfortunately, rapidly emerging resistance of campylobacters to quinolones in tropical regions and in other parts of the world has limited their effectiveness.112,128,129Widespread use of fluoroquinolones in poultry has led to the transfer of antibioticresistant strains to humans.130,131 Nalidixic acid resistance commonly but not invariably crosses with resistance to ciprofloxacin.114 Resistance to this agent has paralleled the increasing resistance to fluoroquinolones. In special circumstances when therapy is required, and when a patient is intolerant of many agents or when a strain has an unusual antibiotic resistance pattern, alternative agents such as chloramphenicol may be used; nearly all campylobacters are susceptible to chloramphenicol.114,132 This agent is especially useful in tropical developing countries because of its low cost. For persons with bacteremia and other extraintestinal suppurative infections, gentamicin and imipenem are active against campylobacters and the rate of resistance to these agents is less than 1%. Gentamicin is ineffective against Campylobacter in the gut; therefore, oral therapy with an effective, absorbable drug also must be given.
PREVENTION AND CONTROL Campylobacters are so ubiquitous in the environment of most tropical developing nations that there is no possibility of reducing the reservoirs of infection. Rather, prevention must focus on interrupting the path of transmission to humans from animals, animal products, or environmental sources contaminated by animals or humans. Poultry, livestock, pets, and wild animals are the major reservoirs. Therefore, as for many bacterial enteric pathogens, a basic tenet of prevention is adequate hand washing; this is especially important in tropical areas for people who handle animals and food within a household. Especially important is the awareness of the necessity for proper cooking and storage of foods of animal origin. The safe disposal of sewage and the protection and purification of water supplies also are fundamental to control of most diseases due to enteric pathogens, including Campylobacter. Programs to improve water safety in developing countries may impact the number of infections.133 Excreta from sheep, cattle, and wild and domestic birds should not be
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Chapter 19
infection of humans is “accidental” given that humans are not required for completion of their life cycle, the natural acquisition of immunity in developing countries and the identification of group antigens suggest that vaccination will be feasible. There is no proven benefit of antibiotic prophylaxis to prevent Campylobacter infection in travelers to tropical and subtropical environments.
Campylobacter Infections
allowed to contaminate a community’s water supplies. Chlorination reliably inactivates Campylobacter.134 Control of Campylobacter infections in developing countries will likely be difficult unless an effective vaccine is developed. Because of the diversity of serotypes of C. jejuni, the possibility of vaccination for prevention of infection must be based on group antigens. Since Campylobacter
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