Pediatric Campylobacter Infections

Factors responsible for the diseases caused by C jejuni are not well known. Based on clinical illness, researchers have postulated the following mechanisms:[1]

• Adherence and production of heat-labile enterotoxins, inducing secretory diarrhea

• Invasion and proliferation within the intestinal epithelium, leading to cell damage and inflammatory response

• Translocation of the organism into the intestinal mucosa and proliferation in the lamina propria and mesenteric lymph nodes, leading to extraintestinal infections such as meningitis, cholecystitis, urinary tract infection, and mesenteric adenitis

Information on the pathogenesis of Campylobacter infections other than C jejuni is scarce. Bacteremia is more common with C fetus infection. A surface protein in C fetus inhibits the C3b binding responsible for both the serum and phagocytic resistance of the organism, making the organism resistant to the bactericidal effects of human serum. After oral ingestion, C fetus may colonize the intestinal tract, resulting in portal bacteremia. In immunocompetent hosts, the organism is phagocytosed by the reticuloendothelial cells in the liver, preventing further spread. However, in patients that have predisposing factors that might serve as a local site of infection such as a gravid uterus, bacteremia can lead to severe complications. Infants may be affected hematogenously or by ascending infection during amnionitis and premature rupture of membranes.

Frequency

United States

In the United States, 2 million symptomatic enteric Campylobacter infections are estimated per year (1% of the US population per year).[2] Incidence in the rural population is 5-6 times higher because of increased consumption of raw milk. Among all age groups, the highest incidence occurred among children younger than 5 years; hospitalization occurred in 927 of cases (4.6%), and 8 individuals died.[3] According to the Foodborne Diseases Active Surveillance Network (FoodNet) of the Centers for Diseases Control and Prevention (CDC) which collects data on the incidence of infection with foodborne pathogens, in 2017, 9,421 cases of laboratory-confirmed (by isolation of bacteria from a clinical specimen by culture or by culture- independent diagnostics tests) Campylobacter infections were reported in the United States with an overall incidence rate of 19.1 cases per 100,000 population. This was a 10% increase compared to 2014-2016.[4]  

International

In developing and developed countries, continuous increases in the number of C jejuni infections has been seen, with incidence rates as high as 73 cases per 100,000 population reported.[5]

In England and Wales, an increase of laboratory confirmed Campylobacter cases was noted, from 44,544 per year in 2004 to 64,582 per year in 2011. Between 2004 and 2011, a 36% increase of cases occurred among children younter than 10 years, a 25% increase occurred among persons aged 10-45 years, and an 81% increase occurred among those aged 50 years and older.[6]

Overall, Campylobacter gastroenteritis is still common during the first 5 years of life.[7, 8, 9] Isolation rates in children with acute diarrhea range from 10-46%.[7, 9, 10]

Mortality/Morbidity

The vast majority of patients fully recover from C jejuni infection within 5 days (range, 2-10 d), either spontaneously or after appropriate antimicrobial therapy. Infection with C fetus is a concern in immunocompromised patients, pregnant women, and neonates. Previously healthy patients usually recover without complications.

Race

Campylobacter infection has no race predilection.

Sex

In England and Wales, incidence was higher in males from birth until age 17 years and in females aged 20-36 years.[11]

Age

Individuals of any age can be infected with C jejuni enteritis. The rate of infection differs between developed and developing countries. In developed countries, the peak attack rates are in infants younger than 1 year; a second, broader peak attack rate occurs in persons aged 20-29 years.[12] In developing countries, symptomatic infection chiefly affects children younger than 5 years and declines with age.[13, 14] This is likely due to the development of protective immunity secondary to a high level of exposure to the organism early in life.

In contrast to the age-specific distribution of Campylobacter enteritis, the highest rate of bacteremia occurs in patients aged 69 years and older.[15] Roughly 30% of isolates are C jejuni, 9% are C coli, and 53% are C fetus.

Clinical manifestations of all Campylobacter species infections that cause enteric illness overlap and appear identical. These manifestations include the following:

Mild episodes of diarrhea subside within 7 days in 60-70% of cases, last for 2 weeks in 20-30%, and persist longer than 2 weeks in 5-10% of cases. In one third to one half of patients, initial symptoms include periumbilical cramping, intense abdominal pain that mimics appendicitis, malaise, myalgias, headache, and vomiting.

Watery secretory diarrhea consists of more than 10 stools per day and is frequently seen in younger children. Dehydration occurs in approximately 10% of these children.

Inflammatory diarrhea symptoms are indistinguishable from those caused by Shigella organisms, Escherichia coli, and Salmonella species. They are characterized by malaise, fever, abdominal cramps, tenesmus, bloody stools, and fecal leukocytes on light microscopy.

Rarely, in young adults and adolescents, inflammatory diarrhea can be severe and can be confused with Crohn disease and ulcerative colitis. Toxic megacolon with massive bleeding may occasionally occur. In asymptomatic neonates, C jejuni has been isolated from blood-streaked formed stools or hematochezia.

Bacteremia with C jejuni is uncommon and is most frequently found in patients with immunodeficiency,[16] patients with chronic illness,[15] and patients at extremes of ages. Bloodstream infections and systemic infections by C fetus are rare. The 3 patterns of bacteremia are as follows:

• Transient bacteremia in a normal host with acute Campylobacter enteritis: These patients usually completely recover without treatment.

• Secondary bacteremia or deep focus of infection such as meningitis, pneumonia, endocarditis, and thrombophlebitis in a normal host: Bacteremia usually originates from the intestinal tract and responds to antimicrobial therapy.

• Chronic bacteremia with relapses that can persist for several months occurring in an immunocompromised host: In these patients, bacteremia can also arise from an infected indwelling catheter. Many such patients do not have acute enteritis.

Localized extraintestinal infections are uncommon manifestations and include cholecystitis, arthritis, urinary tract infection, pancreatitis, osteomyelitis, and meningitis.[17, 18] These manifestations may be the initial presentation of C jejuni infection or may occur simultaneously with bacteremia. They frequently are seen in patients who are immunocompromised or who are at extremes of age. Appropriate treatment is necessary.

Because of the affinity of C fetus for the genital tract (and by the tropism for fetal tissue), C fetus,[19, 20] and rarely C jejuni,[20, 21] are associated with perinatal infection. Abortion or stillbirth and premature labor have been described. Infants are often premature and develop signs and symptoms suggestive of sepsis, including fever, cough, respiratory distress, vomiting, diarrhea, cyanosis, convulsions, and jaundice. Infection typically progresses to meningitis, which may be rapidly fatal or may result in serious neurologic sequelae. The source of the organism in these cases has been the mother.

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• The abdomen is frequently tender upon palpation, especially the right lower quadrant.

• Rarely, splenomegaly may be present.

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• Individuals at increased risk for Campylobacter enteritis include the following:

  • Those with occupational exposure to cattle, sheep, and other farm animals[22]

  • Laboratory workers

  • Those in contact with the excreta of infected persons

  • Homosexual men

• The following underlying conditions increase risk for Campylobacter bacteremia, suggesting the importance of both humoral and cell-mediated immunity:[15, 16, 23]

  • Hypogammaglobulinemia

  • Human immunodeficiency virus (HIV) infection

  • Kwashiorkor

  • Pregnancy

  • Malignancy

  • Extremes of age

  • Alcoholism

  • Diabetes mellitus

  • Postsplenectomy status

  • Human leukocyte antigen B27 (HLA-B27) - Increases risk for immunoreactive complications, such as reactive arthritis or Reiter syndrome

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• Microbiologic studies in Campylobacter infection

  • Presumptive diagnosis can be made by examination of fecal specimens by darkfield or phase-contrast microscopy, which demonstrates the characteristic darting motility, and a Gram stain of the stool, which shows Vibrio forms (slim, short, curved rods). RBCs and neutrophils are present in stool in approximately 75% of patients with Campylobacter enteritis.

  • Definitive diagnosis of infection is based on isolation of organisms from stool culture or from another site.

  • Culture of C jejuni from stool requires special isolation techniques and special media such as Campy-BAP or Skirrow. These media contain antibiotics that reduce the emergence of other enteric microorganisms. Inoculated media should be incubated in 5% oxygen and 10% carbon dioxide at 42°C. If C fetus or other atypical enteric species are suspected, isolation from stool requires inoculation on media lacking antibiotics and at 37°C. Filtration technique may be needed. Routine media are adequate for isolation of Campylobacter from normally sterile sites such as blood, body fluids, and tissues.

• Hematology and blood chemistries

  • Peripheral WBC count is usually within the reference range; however, a left shift may occur.

  • The alanine aminotransferase level and the erythrocyte sedimentation rate (ESR) may be slightly elevated.

  • Other laboratory evaluations are within the reference ranges.

• Serology

  • Diagnostic rise usually occurs after symptoms have resolved. Because the median duration of fecal excretion in the convalescent phase is less than 3 weeks, serology testing may be more sensitive than culture for the diagnosis of recent C jejuni infection.

  • Although serologic testing is also useful for epidemiologic investigations it is not recommended for routine diagnosis.

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• DNA probes and polymerase chain reaction are mainly research tools at this time and are not routinely performed.[24]

• A reanalysis of a case-control study by Liu et al reported that Campylobacter jejuni incidence was two times greater with quantitative real-time PCR than with methods including culture, EIA, and reverse-transcriptase PCR.[25]

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• In patients with Campylobacter colitis with history of acute onset of diarrhea, abdominal pain and rectal bleeding, sigmoidoscopy done early (within 5 d) during the illness revealed hyperemic rectal mucosa with occasional shallow aphthous ulcers, whereas findings of granularity and hyperemia were seen in patients whose sigmoidoscopy were done later (≥ 7 d) during the illness.[26]

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• The spectrum of histologic findings in the intestinal tract ranges from minimal edema with acute and chronic inflammatory cells without vascular congestion, to moderate inflammation and cryptitis, to crypt abscess formation.

• For perinatal infections secondary to C jejuni and C fetus, the placenta may have areas of necrosis, infarction, microabscesses, and inflammation.[19]

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• Evaluation of patients with Campylobacter infections can usually be performed on an outpatient basis.

• Intravenous hydration and inpatient care may be necessary for patients who are severely dehydrated and cannot tolerate oral hydration.

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• Occasionally, acute abdominal pain may be the only presenting symptom, often mimicking acute appendicitis and resulting in immediate laparotomy.

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• Consultation with an infectious disease specialist and a gastroenterologist may be necessary for complicated cases.

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• Because rehydration and electrolyte replacement are the mainstays for treating diarrheal disease, oral rehydration with an electrolyte and glucose solution is necessary.

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• Permit activity as tolerated.

Most C jejuni infections are generally mild and self-limited. The need to administer antimicrobials in uncomplicated cases is still controversial. Correction of electrolyte abnormalities and rehydration are the mainstay of treatment for enteritis due to Campylobacter species. Antimicrobial therapy should be considered in immunocompromised hosts or in individuals with fever, increasing bloody diarrhea, or symptoms that last longer than 1 week.[27]

C jejuni is usually sensitive to erythromycin, azithromycin, gentamicin, tetracycline, and chloramphenicol. Reports of antimicrobial resistant strains, including those resistant to ciprofloxacin and doxycycline, are increasing in most countries.[28, 29, 30]

A meta-analysis was done to assess the effects of antibiotic treatment versus placebo on duration of symptoms in patients with Campylobacter infections.[27] This study included 11 randomized controlled trials with a total of 479 patients. Ninety one of 479 were pediatric patients and accounted for 19% of the participants. Antibiotics tested included erythromycin (6 trials), ciprofloxacin,[3] and norfloxacin.[3] This meta-analysis showed a decrease in duration of symptoms by 1.3 days with antibiotic treatment compared with placebo. Antibiotic treatment also decreases the duration of fecal shedding. In addition, antibiotics were beneficial if initiated within the first 3 days of illness, with a mean decrease of symptoms of 0.35 days of earlier treatment.

The recommended duration for antibiotic treatment for gastroenteritis is 3-5 days. Antimicrobial therapy for all immunocompromised patients with C jejuni bacteremia should be selected based on a laboratory susceptibility test. Begin therapy with gentamicin, imipenem, third-generation cephalosporins, or chloramphenicol until susceptibility test results are available.

Because infections with C fetus are usually systemic, intravenous antibiotics are usually required. Aminoglycosides, such as gentamicin and carbapenem, are usually used for empiric treatment. Based on in vitro susceptibility test results,[31, 32] alternatives for C fetus bacteremia include ampicillin, chloramphenicol, and third-generation cephalosporins. Duration of therapy is empiric. Patients with CNS infection require treatment for 2-3 weeks with a third-generation cephalosporin, ampicillin, or chloramphenicol Those with endovascular infection should be treated for at least 4 weeks with gentamicin as the drug of choice (DOC). Treatment with ampicillin or third-generation cephalosporins are other alternatives. Erythromycin is the DOC in patients with diarrheal illness secondary to C fetus infection.

Class Summary

When given early in gastroenteritis, erythromycin and azithromycin shorten the duration of illness and aid excretion of organisms, as well as preventing relapse.

Erythromycin (E.E.S., E-Mycin, Eryc, Ery-Tab)

Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes causing RNA-dependent protein synthesis to arrest.

In children, age, weight, and severity of infection determine proper dosage. When bid dosing is desired, half-total daily dose may be taken q12h. For more severe infections, double the dose.

Azithromycin (Zithromax)

Acts by binding to 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Nucleic acid synthesis is not affected. Concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues. Treats mild-to-moderate microbial infections.

Plasma concentrations are very low, but tissue concentrations are much higher, giving it value in treating intracellular organisms. Has a long tissue half-life. Single dose is recommended.

May become DOC because of safety profile, ease of use, and improved GI tract tolerability relative to erythromycin. Administer caps and PO susp on an empty stomach, at least 1 h before or 2 h after meals. Tab and PO powder (sachet) may be administered with food.

Class Summary

These agents may be used in children but are not approved for children younger than 9 years because of the risk of dental staining.

Tetracycline (Sumycin)

Inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunit(s).

Class Summary

These drugs represent an alternative to tetracycline.

Clindamycin (Cleocin)

Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Class Summary

Reserve these drugs for treatment of infections caused by organisms not sensitive to less toxic agents.

Gentamicin (Garamycin, Pediatric Gentamicin Sulfate)

Aminoglycoside antibiotic for gram-negative coverage. Used in combination with both an agent against gram-positive organisms and one that covers anaerobes.

Class Summary

Ciprofloxacin and other fluoroquinolones are alternative agents to erythromycin but are not approved for those younger than 18 years.

Ciprofloxacin (Cipro)

Inhibits bacterial DNA synthesis and, consequently, growth. Continue treatment for at least 2 d after signs and symptoms have disappeared.

Class Summary

Alternatives for C fetus bacteremia include ampicillin, imipenem, chloramphenicol, and third-generation cephalosporins. Reported synergistic combinations include ampicillin with gentamicin and imipenem with gentamicin. Duration of therapy is empiric.

Imipenem and cilastatin sodium (Primaxin)

Carbapenem antibiotic. For treatment of multiple organism infections in which other agents do not have wide-spectrum coverage or are contraindicated due to potential for toxicity.

Chloramphenicol (Chloromycetin)

Binds to 50 S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. Effective against gram-negative and gram-positive bacteria.

Ceftriaxone (Rocephin)

Third-generation cephalosporin. Arrests bacterial growth by binding to one or more penicillin-binding proteins.

Ampicillin (Marcillin, Omnipen)

Broad-spectrum penicillin. Bactericidal activity against susceptible organisms.

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• Assess the resolution of illness and patient compliance with medication.

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• Evaluate protracted cases of Campylobacter infection further to rule out other causes of fever, diarrhea, and sepsis.

• Provide close monitoring and support in the intensive care unit for immunoreactive complications such as Guillain-Barré syndrome (GBS).

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• Rehydrate intravenously or orally.

• Administer antibiotics as indicated.

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• Patients with immunoreactive complications such as GBS may require transfer to a chronic care facility for rehabilitation after their condition stabilizes.

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• Guillain-Barré syndrome

  • GBS is a disorder of peripheral nerves and is characterized by ascending paralysis.

  • Strong evidence suggests an association between preceding C jejuni infection and GBS.[33] The antigenic similarity between specific regions (terminal tetrasaccharide) of lipopolysaccharide of C jejuni and human gangliosides (GM1) led to the concept of molecular mimicry.[34] This concept implies the sharing of homologous epitopes between the bacterial lipopolysaccharide and ganglioside surface components of the peripheral nerve. Immune response from simple C jejuni infection could induce antibodies that cross-react to the gangliosides and trigger GBS.

  • Other variants of GBS associated with c jejuni infection include the following:

    • Acute motor axonal neuropathy (AMAN), or Chinese paralytic syndrome, is characterized by a rapid onset of paralysis with progression to tetraplegia and respiratory failure and occurs in children in northern China during summer and fall.[35]

    • Fisher syndrome is characterized by ophthalmoplegia, areflexia, and cerebellar ataxia.

• Reactive arthritis

  • Incidence and prevalence of Campylobacter- associated reactive arthritis varies among different reports, ranging from 0.6-24%.[36, 37]

  • Development of reactive arthritis has been associated with human leukocyte antigen (HLA)-B27 allele; in these individuals, the disease is more severe than in individuals without HLA-B27.[38] However, a more recent population-based study did not show the association.[39]

  • Arthritis starts a few days to several weeks after the episode of diarrhea. The course is usually self-limited, ranging from 1 week to several months (< 6 mo).[36]

• Other infrequently reported complications are as follows:

  • Reiter syndrome

  • Erythema nodosum

  • Hepatitis

  • Intestinal nephritis

  • Hemolytic-uremic syndrome

  • Immunoglobulin A (IgA) nephropathy

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• Most patients fully recover after C jejuni infection, with or without antibiotics.

• Campylobacter septicemia in patients with immune deficiencies (including congenital hypogammaglobulinemia, acquired hypogammaglobulinemia, malnutrition, HIV) and in neonates is associated with a high mortality rate.

• Even with plasmapheresis and intravenous immunoglobulin, as many as 20% of patients with GBS may require mechanical ventilation. Between 15% and 20% of all patients may develop severe neurologic deficit. GBS disease may result in mortality in 5-10% of all patients. Because GBS secondary to C jejuni may be more severe, the number of patients who require mechanical ventilation, experience severe neurologic sequelae, and die may also be higher.

• Previously healthy persons infected with C fetus usually recover without sequelae. This infection may be lethal to patients with altered immune status and neonates. Prognosis for these patients depends on the early administration of fluids and appropriate antimicrobial therapy.

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• Tips for preventing campylobacteriosis

  • Thoroughly cook all poultry products. If served undercooked poultry in a restaurant, return it for further cooking.

  • Wash hands with soap before and after handling raw foods of animal origin.

  • Prevent cross-contamination in the kitchen

    • Use separate cutting boards for foods of animal origin and other foods.

    • Carefully clean all cutting boards, countertops, and utensils with soap and hot water after preparing raw food of animal origin.

  • Avoid consuming unpasteurized milk[40] and untreated surface water.

  • Make sure that persons with diarrhea, especially children, carefully and frequently wash their hands with soap to reduce the risk of spreading infection.

  • Wash hands with soap after contact with pet feces.