Campylobacter Infections in Children

Campylobacter is one of the 2 most common causes of foodborne illness in the United States. It most commonly occurs in children younger than 5 years of age. Campylobacter species can cause a wide range of syndromes, from asymptomatic infections to severe systemic infections.After completing this article, readers should be able to:Campylobacter species are an important cause of infection throughout the world, especially in young children. Campylobacter jejuni is the most common Campylobacter species in the United States, where it is 1 of the top 2 causes of foodborne illness. (1) Other important species include Campylobacter upsaliensis, Campylobacter lari, and Campylobacter fetus, which can cause serious systemic infections in all age groups, particularly in immunocompromised patients.Campylobacter species infections cause gastroenteritis and typically present with diarrhea that may or may not be bloody, emesis, and abdominal pain. Campylobacter infection in children can mimic intussusception, appendicitis, or inflammatory bowel disease (IBD). Immune-mediated complications of Campylobacter infection include reactive arthritis and Guillain-Barré syndrome (GBS). Campylobacter infection is a nationally notifiable disease, and confirmed cases should be reported through the Centers for Disease Control and Prevention (CDC) Foodborne Diseases Active Surveillance Network.Most Campylobacter infections are mild and self-limited and require only supportive care, although some may lead to severe dehydration. Serious infection or infections in immunocompromised hosts may benefit from treatment with macrolide antibiotics. Increasing rates of fluoroquinolone resistance have been observed in Campylobacter isolates. (2)The largest source of Campylobacter infections is animals, especially wild and domestic birds. Strategies to prevent Campylobacter infection include thoroughly cooking poultry, preventing cross-contamination with other foods, properly chlorinating water and pasteurizing milk, and practicing hand hygiene after interacting with animals.The Campylobacter genus is composed of gram-negative, motile, curved or spiral-shaped bacilli. The name Campylobacter is derived from Greek and Latin and means “curved rod.” As of 2014, the genus included 26 species, approximately half of which cause disease in humans. (3) The organisms that are most commonly associated with infection in humans are C jejuni and Campylobacter coli. In 2015, 88% of all isolates that were speciated were C jejuni. (1) C jejuni contains 2 subspecies: C jejuni subspecies jejuni (typically referred to as C jejuni), which is the most commonly isolated cause of Campylobacter infection in the United States, and C jejuni subspecies doylei, which is much rarer. Other Campylobacter species that cause infection in humans are C fetus, C upsaliensis, C lari, and Campylobacter hyointestinalis. This review focuses on C jejuni and C coli, with a brief discussion of other, less common species at the end.There are multiple organisms and host factors that enable Campylobacter infection in humans. Studies in healthy volunteers as well as observational data from outbreaks have demonstrated that the inoculum required to cause Campylobacter enteritis in humans can be as low as 500 organisms. (4)(5)(6) Disruption of the gastric acid barrier allows for pathogenic flora, such as Campylobacter, to survive and flourish. Therefore, patients with reduced gastric acidity, including those receiving proton pump inhibitors, may be at higher risk for infection with Campylobacter. (7)(8)(9)(10) The incubation period is relatively short, ranging from 1 to 7 days, with an average of 3 days. Higher inocula may result in shorter incubation periods. Infection is typically established in the distal ileum and colon and initially causes a noninflammatory diarrhea. This is followed by a locally invasive stage that leads to cell damage and inflammation that can present with dysentery, which is occasionally followed by translocation across the intestinal epithelium, causing lymphadenitis and extraintestinal infection. Histologically, infection is identical to salmonellosis or shigellosis and is marked by acute mucosal inflammation and edema, which can include infiltration of the lamina propria and crypt abscess formation. (11)(12)The exact mechanisms of infection are not completely understood, but several virulence factors have been identified, including flagella, plasmids, adhesins, and chemotactic factors. (13) Initial infection is established when bacteria attach to intestinal epithelial cells via fimbriaelike filaments. Colonization of the gastrointestinal tract is then facilitated by flagella and chemotactic factors. Campylobacter flagellins do not seem to provoke proinflammatory cytokines, which may allow Campylobacter to evade innate immune response, differentiating it from other intestinal pathogens, including Salmonella. (14) There are a variety of other surface proteins and adhesins that facilitate colonization and invasion of intestinal epithelial cells. Some isolates of Campylobacter contain a high-molecular-weight plasmid, pVir, that has been associated with bloody stools and is thought to contribute to invasiveness. (15)The immune response to Campylobacter infection seems to be primarily humoral. Campylobacter-specific serum immunoglobulin (Ig) A level rises rapidly during the first 2 weeks after infection and then declines slowly over the next month. The IgM and IgG antibody levels rise more slowly and peak 2 to 3 weeks after development of symptoms. (16) Prolonged and severe infection has been reported in patients with hypogammaglobulinemia. (17) The role of cellular immunity in Campylobacter infection is less well defined, but it does seem to be important because patients with human immunodeficiency virus (HIV) are also at risk for more severe and prolonged disease as well as higher rates of extraintestinal infection. (18) In immunocompetent patients, infection with Campylobacter provides some immunity against future infection, especially infection with the same strain.Campylobacter is a leading cause of acute diarrhea domestically and internationally. In the United States, Campylobacter and Salmonella are the 2 most common causes of foodborne illness. In 2016 the incidence of Campylobacter enteritis confirmed by culture or culture-independent diagnostic tests (CIDTs) was 17.4 infections per 100,000 persons, making it the most commonly identified cause of foodborne illness in the United States. Campylobacter has been tracked through the Foodborne Diseases Active Surveillance Network since 1996 and has been a notifiable disease since 2015. Most Campylobacter infections are mild and self-limited, but in 2016, 20% of reported infections resulted in hospitalization and 26 attributable deaths were identified (mortality, 0.3%). (19)In the United States, the incidence of infection is highest in children younger than 5 years of age, but there is also a secondary peak in young adults. Infection rates are highest in the summer, and most infections are domestically acquired, although Campylobacter enteritis is also seen in returning international travelers. (1) In developing countries, the infection is hyperendemic, and symptomatic infection occurs almost exclusively in infants and young children, who can be infected repeatedly. Subsequent infections tend to be asymptomatic, making symptomatic disease rare in older children or adults. (20)(21)Campylobacter enteritis is usually sporadic; only 0.4% of identified infections in 2015 were associated with an outbreak. (1) Transmission to humans occurs through ingestion of contaminated food or water or by direct contact with fecal material from infected people or animals. Animal reservoirs, including wild and domestic birds and other animals, are the most common source of Campylobacter infections. Multiple studies have shown that most broiler chicken flocks, 60% to 80%, may be contaminated with Campylobacter at slaughter. (22) The main vehicle of transmission to humans is improperly cooked poultry; 1 study suggested that 48% of Campylobacter infections are attributable to poultry exposure. (23) Direct acquisition of infection from animals is less common and is usually associated with occupational exposure to poultry. Infection has been reported in association with domestic pets, especially puppies and kittens, that have Campylobacter diarrhea. (23) In the fall of 2017 an outbreak of multidrug-resistant Campylobacter was linked to puppies sold through a national pet store chain. (24) Person-to-person transmission is rarer, but caretakers of children or other individuals in diapers are at increased risk. Sexual transmission has also been reported, especially in men who have sex with men. (25)Outbreaks have been reported in association with the distribution of contaminated water or milk. Campylobacter can survive in water or milk for many weeks at low temperatures. Because Campylobacter is nearly ubiquitous in the environment, decontamination is the most important strategy to prevent transmission. Waterborne outbreaks have occurred in association with unchlorinated water or failed chlorination systems, and milk-associated outbreaks have been connected to raw milk or failures in the pasteurization process. (26)(27)(28)(29) Importantly, milk-borne outbreaks have been associated with raw milk that had passed routine testing because C jejuni can sometimes be difficult to culture. (29)The most common illness caused by C jejuni and C coli is gastroenteritis. Children present with diarrhea and abdominal pain, often accompanied by vomiting and fever. Infection can result in significant dehydration. Bloody stools are also seen in at least half of infected children. (30)(31) Fevers can be prominent, and seizures, meningismus, and encephalopathy have all been reported in association with Campylobacter infection. (26)(32) Bacteremia is rare and is seen primarily in patients who are immunocompromised. (33)(18)Perinatal C jejuni infection is rare but has been described. It can result in abortion, premature labor, and/or neonatal septicemia and meningitis. Symptomatic gastroenteritis in neonates is also possible, which may present with only grossly bloody stools or fever. Infection is generally acquired perinatally from mothers that shed Campylobacter either symptomatically or asymptomatically. Outbreaks in neonatal nurseries due to nosocomial spread have been reported. (34)Campylobacter infection can also mimic other gastrointestinal illnesses. Infants with Campylobacter enteritis may present with only bloody stools and vomiting without fever, which can be mistaken for intussusception. In older children, acute Campylobacter ileocecitis can cause severe right lower quadrant pain without diarrhea mimicking appendicitis. (35)(36) Campylobacter enteritis most commonly progresses from the small bowel distally, but rarely patients with severe infection may present with only colitis and bloody diarrhea that can be confused with IBD. (37) Imaging can be helpful in excluding other intra-abdominal processes, such as intussusception. The acute inflammatory changes of Campylobacter infection observed on histologic analysis should help differentiate it from the chronic changes of IBD. It has also been suggested that Campylobacter infection may play a role in the development of IBD. (38)Although the manifestations can be variable, Campylobacter gastroenteritis is usually relatively mild and self-limited, with symptoms lasting 24 to 48 hours in most patients. Excretion of the organism can last much longer than clinical symptoms. On average, shedding lasts 2 to 3 weeks, but it can range from 3 days to several months. (31) Shedding tends to be prolonged in younger children and patients with immunodeficiencies. Rarely, symptoms may persist for several weeks or relapse may occur after initial resolution. Chronic or recurrent infection is more common in immunocompromised patients, who can develop a prolonged relapsing syndrome that mimics IBD. This has been described in particular in patients with HIV, in whom long-term carriage and recurrent enteritis can be associated with bacteremia, fever, and debilitating illness. (18)(33)(39)(40)(41) The incidence of Campylobacter infection remains higher in patients with HIV than in the general population, but it has decreased significantly since the introduction of highly active antiretroviral therapy. (41)Extraintestinal manifestations without enteritis are rare, but septic arthritis, bursitis, osteitis, and soft tissue infections have been reported. Acute extraintestinal complications of enteritis include cholecystitis, peritonitis in patients with peritoneal dialysis, septic pseudoaneurysm, pericarditis, and myocarditis. Erythema nodosum, glomerulonephritis, hemolytic anemia, IgA nephropathy, postinfectious irritable bowel syndrome, and intestinal perforation have all been described as well.Late-onset immune-mediated complications of Campylobacter infection, including arthritis and GBS, have been well described.Reactive arthritis after Campylobacter enteritis can occur 3 to 40 days (mean, 11 days) after the onset of diarrhea. It is usually oligoarticular and asymmetrical, and it predominantly affects the knees. It is more common and possibly more severe in patients with HLA-B27 phenotype. The development of arthritis does not seem to be related to the severity of the initial illness. Symptoms generally last for up to 21 days, and most patients have spontaneous recovery within 6 months without long-term sequelae. The arthritis is reactive, not infectious; synovial fluid is sterile. Arthritis occurs in up to 7% of patients, but as many as 20% of patients report arthralgia. (42)Both serologic studies and culture surveys suggest that Campylobacter infection is the most commonly identified cause of GBS. Thirty percent to 40% of cases of GBS develop in patients who were infected with Campylobacter 10 to 14 days earlier. In the United States, 1 in 1,000 patients with Campylobacter enteritis goes on to develop GBS. Some studies have suggested that GBS associated with Campylobacter infection may have a poorer prognosis than GBS associated with other etiologies. (43)The primary mechanism for Campylobacter-associated GBS is molecular mimicry. The C jejuni lipopolysaccharide resembles GM1 ganglioside on peripheral nerve myelin. Infection can lead to the development of cross-reacting antibodies that cause nerve damage. The Miller Fisher variant of GBS, with more prominent cranial nerve involvement resulting in ophthalmoplegia, areflexia, and ataxia, is also more common in patients with Campylobacter infection. It is thought to be caused by antibodies that cross-react with Campylobacter lipopolysaccharide and ganglioside GQ1b in cranial nerve myelin. (44) Certain Campylobacter serotypes, especially Penner O19 and O41, seem to be more commonly associated with GBS. (43) There may be factors other than molecular mimicry that also play a role in the development of Campylobacter-associated GBS. Additional host factors seem to be important; some patients develop antibodies to GM1 ganglioside but do not develop neurologic symptoms. There may be an association between HLA types and the development of Campylobacter-associated GBS. (45)Campylobacter enteritis is often clinically indistinguishable from other viral or bacterial gastroenteridites. Diagnostic testing is not always indicated for children who present with acute diarrheal illnesses, with or without fever or vomiting, because determining the cause often does not change clinical management. However, Infectious Diseases Society of America guidelines suggest testing patients with fever or bloody diarrhea or others in whom treatment may be indicated, including anyone with immunodeficiencies. In addition, organism-specific diagnosis can be valuable for the management of outbreaks. Blood cultures are recommended in infants younger than 3 months of age, those with signs of sepsis or systemic manifestations, and immunocompromised patients. (46)Stool culture is the gold standard for the identification of Campylobacter species. Most laboratories specifically look for Campylobacter in standard stool cultures, but it can be difficult to isolate. Campylobacter grows best on media containing selective antibiotics and in microaerobic conditions with 5% to 10% oxygen, 1% to 10% carbon dioxide, and some hydrogen. C jejuni and C coli grow best at 107.6°F (42°C). Campylobacter is identified by its characteristic appearance as a comma- or spiral-shaped Gram-negative bacillus as well as oxidase and catalase production. Species-level identification is not typically performed, and of C jejuni from C coli is not usually for management. and can be helpful for or when species other than C jejuni or C coli are This is typically at of including acid is tests are generally more and have than Campylobacter from stool 20% to 40% more than However, because tests the of acid than the clinical is not always The identification of multiple is not and can be difficult to In addition, be to organisms such as and cultures of Campylobacter often are not when the organism is by resistance to and is common in Campylobacter treatment is and there is for cultures can be after identification by testing can be to Campylobacter infection in patients with reactive arthritis or GBS who have stool studies are not helpful in the diagnosis of acute Campylobacter Campylobacter infection is or it is important to to the source of infection, to prevent others from should be including of raw milk or contaminated or poultry, contaminated or and contact with animals and or exposure may also be although most infections are acquired infection typically in a self-limited enteritis that only supportive either or is the of acute management. should be due to of symptoms. have suggested that may diarrhea and stool in immunocompetent children with gastroenteritis of although the seems to be in viral than bacterial and the remains This benefit also has to be against of or with isolates in or immunocompromised patients who In with a of or the of diarrhea in children 6 months to 5 years of age with acute diarrhea. of 11 of treatment for the treatment of Campylobacter infections in children and that treatment reduced the of symptoms by days and the of Campylobacter in However, the self-limited of most Campylobacter the relatively benefit to treatment with and the risk of development of treatment of infection is usually not is recommended in patients with severe disease, which those with bloody fever, extraintestinal infection, or relapsing or prolonged symptoms that 1 It is also recommended for patients with infection who are or immunocompromised due to risk of severe GBS and other complications of Campylobacter infections are immune-mediated and usually develop symptoms of acute infection have Therefore, antibiotics are not included in the management of Campylobacter-associated patients the for treatment with including prolonged or severe symptomatic infection or patients with infection who the recommended treatment is 10 per for 3 days or 40 per in for 5 days. usually Campylobacter from the stool within 2 to 3 days. A longer days) may be in infections or in patients who are immunocompromised. are treatment in patients who are and to although it is important to testing to for should be to C jejuni and C coli are usually in to and data are to Campylobacter species are to and including and should be may also be treatment for Campylobacter infection, but resistance is the of for this In the this resistance was thought to in attributable to in poultry but this has been in the United since United data from indicated that resistance was present in of C jejuni isolates and of C coli. is significantly higher the United and is important to in travelers. macrolide resistance remains rare in the United of Campylobacter infection should on transmission from animals, milk or disease, and transmission. poultry is the most common source of Campylobacter infection, thoroughly cooking poultry and cross-contamination with other should be Campylobacter is by all but especially should be cooked to hygiene and of and after contact with raw poultry as well as contact between raw poultry and other are also hygiene is also important after contact with the of and especially puppies and kittens, where rates of Campylobacter carriage are milk should be and water should be with diarrhea should be from food and the of patients in and can infected but asymptomatic, as as hand hygiene is and children in diapers who are to have Campylobacter enteritis should be from symptoms have of children with or can be to should be for children who are with symptomatic Campylobacter contact for with of the infection with Campylobacter the risk of future symptomatic infection but is not completely patients with infections should the to C jejuni and C coli, C usually causes which may present as bloody diarrhea in of patients, and occasionally It can also occasionally cause vomiting but is usually than C jejuni infection. Bacteremia is primarily seen in or immunocompromised patients. It is more common in children than adults. C was initially isolated from and are to be its primary Infection may be associated with contact with is catalase or catalase and has a than C jejuni. It is to usually in media and not in cultures the of C is not but it is the most common Campylobacter species C jejuni and C in foodborne infections in the United States. are treatment of C to C jejuni and C coli, it is usually with although resistance has been reported in some Some isolates are to and is the most commonly isolated Campylobacter species in foodborne illnesses. It is common in but relatively rare in humans. It for less than 1% of Campylobacter isolates from humans and is predominantly seen in immunocompromised patients and It can be on conditions as C jejuni. are generally for C is rare but tends to cause more serious illness than C jejuni or C coli. It causes infections more commonly than gastroenteritis and is more common in patients at the of age. In 2015 only of cases of Campylobacter in the United were due to C fetus, but studies have shown that it is for to of Campylobacter It may not be identified in stool cultures because it grows best at and than at 107.6°F C jejuni. associated with C infection have been isolated infection that is self-limited or rapidly to and most infection associated with a infection such as or chronic bacteremia, seen most commonly in immunocompromised patients. infection has also been described and can be associated with spontaneous abortion, labor, and neonatal septicemia or meningitis. infection with C is rare but tends to be more severe than with C C is often to and are C is typically to and